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Posts Tagged ‘breast cancer genes’


Topics in Pathology

Larry H Bernstein, MD, FCAP, Curator

LPBI

Special Issues from Medscape Pathology

Journal of Clinical Pathology

Hospital Autopsy: Endangered or Extinct?

Angus Turnbull; Michael Osborn; Nick Nicholas

Disclosures

J Clin Pathol. 2015;68(8):601-604.

Abstract

Aim To determine the hospital autopsy rate for the UK in 2013.

Methods A study of data from a ‘Freedom of Information’ request to all (n=186) acute NHS Trusts within England (n=160), NHS Boards in Scotland (n=14) and Wales (n=7) and Social Care Trusts in Northern Ireland (n=5). Hospital autopsy rates were calculated from the number of hospital autopsies performed in 2013 as a percentage of total inpatient deaths in the Trust that year.

Results The UK response rate was 99% (n=184), yielding a mean autopsy rate of 0.69%. The mean rates were 0.51% (England), 2.13% (Scotland), 0.65% (Wales) and 0.46% (Northern Ireland). 23% (n=38) of all included respondents had a rate of 0% and 86% (n=143) a rate less than 1%.

Conclusions The decline in hospital autopsy has continued relentlessly and, for better or for worse, the practice is on the verge of extinction in the UK. The study highlights to health professionals and policy makers the magnitude of this decline. Further research should investigate the impact of this on patient safety, clinical audit, public health and medical education.

Introduction

Autopsy from the Greek ‘autos’ and ‘opsomeri’ means ‘to see for oneself’.[1,2] Its history stems from mummification and human dissection in 3000 BC, through ancient Greece where Hirophilus discovered the duodenum by live human dissection to Rokitansky (1804–1878), regarded as the father of the modern autopsy and who performed or supervised over 100 000 examinations.[1]

Autopsies in the UK comprise medicolegal (those required by HM coroner or in Scotland the procurator fiscal) and hospital consent (clinical) autopsies. Many doctors believe that autopsy is outdated while some argue that autopsies should remain an integral part of medicine, education, clinical audit and research.[1]

In 2013, 45% of registered deaths in England and Wales were reported to the coroner. Of these, 41% underwent coronial autopsy, accounting for approximately 20% of all deaths and over 94 000 autopsies.[3]

Hospital autopsy rates have been falling in the UK and worldwide for over half a century[4–15] (figure 1A, B) and account for a small minority of all autopsies in the UK.[1,3] Recent studies suggest autopsy rates of less than 10% for teaching hospitals and less than 5% elsewhere.[1,16]

Decline in hospital autopsy rates

Decline in hospital autopsy rates

Figure 1.

Decline in hospital autopsy rates over recent decades. (A) Autopsy rates from three first world countries, data collated from multiple studies. (B) Autopsy rates from four different hospitals/NHS Trusts, data collated from multiple studies.

http://img.medscape.com/article/849/356/849356-thumb1.png

The decline in hospital autopsy rates is well known, yet poorly researched and quantified. The majority of medical professionals and politicians in the UK are likely to be unaware of this conspicuous decline. Consequently, little has been done to address the falling rates and the implications of this are not yet fully understood, nor are the consequences.

A PubMed literature search yielded no research detailing a UK-wide autopsy rate within the past 20 years (search terms “hospital autopsy [title]”, “clinical autopsy [title]”, “autopsy rate [title]”). Given this and documented inter-hospital variation (figure 1B), we aimed to determine the current UK autopsy rate.

The structure of healthcare delivery varies throughout the UK. In England, the provision of acute services (emergency, inpatient and outpatient care) is provided by 186 organisations known as Acute National Health Service (NHS) Trusts—each of which may provide care from multiple hospital sites. In Scotland and Wales, the countries are divided into a number of defined geographical areas (Boards), each of which may contain several sites of healthcare delivery. In Northern Ireland, these geographical areas are known as Health and Social Care Trusts.

Method

Acute NHS Trusts within England (n=160), Boards within Wales (n=7) and Scotland (n=14) and Social Care Trusts within Northern Ireland (n=5) were contacted via ‘Freedom of Information’ requests. The level of response therefore is for the Trust/Board, not individual hospitals. If no reply was received within 4 months, reminders were sent.

The hospital autopsy rate was calculated as the number of autopsies performed on patients who died in the year 2013 as a percentage of total deaths which occurred in the hospital in that calendar year.

Studies indicate significantly higher autopsy rates in stillbirths, neonates and young children.[17,18]Therefore, data were excluded if they fell within the following categories:

  1. Children’s Hospital NHS Trusts
  2. Stillbirth, neonatal, perinatal and paediatric death
  3. Trusts with no recorded deaths
  4. Incomplete responses

Statistical analysis was performed using two-tailed χ2 tests (Prism 6 Software) between each country. The categories used were number of deaths that underwent autopsy and number of deaths not followed by autopsy. Bonferroni correction was used to compensate for the six pairwise comparisons, resulting in 99.25 CIs (p<0.008). Statistical outliers were determined with a ROUT test using a false-positive rate (Q) of 1%.

Results

A 99% (n=184) response rate was achieved for the UK; constituent country response rates were 99% (England), 100% (Scotland), 100% (Wales) and 100% (Northern Ireland). A total of 17 Trusts were removed, according to the exclusion criteria. Eight Trusts were concerned about patient identification because the number of autopsies was small and so provided a ‘fewer than’ figure. In these cases, a maximum possible rate was calculated.

Mean hospital autopsy rates were calculated as the total number of autopsies expressed as a percentage of the total number of deaths. The UK mean autopsy rate was 0.69% and varied considerably between countries. The highest mean autopsy rates were in Scotland (2.1%), followed by Wales (0.65%), England (0.51%) and Northern Ireland (0.46%). The study confirms that hospital autopsy rates are significantly lower than the most recent literature suggests and that there is evident inter-country variation (figure 2A, Table 1) and intra-country variation (figure 2A).

Figure 2.

The results from Freedom of Information request for UK and constituent countries. (A) Individual points representing each sample Trust/Board, non-parametric data, no statistical difference between countries. (B) Cumulative frequency histogram of autopsy rates for NHS Trusts/Boards in the UK.

autopsy rates

http://img.medscape.com/article/849/356/849356-thumb2.png

Inter-country pairwise comparisons using χ2 tests of significance (p<0.008) found Scotland to have a significantly higher hospital autopsy rate than each of the other countries (p<0.0001). Other pairwise comparisons failed to achieve significance (Table 2).

Twenty eight samples were statistical high outliers, 20 from England, 6 from Scotland, 1 from Wales and 1 from Northern Ireland. The mean hospital autopsy rate is skewed by these outliers, which typically were large teaching hospitals or small specialist centres. The top 5% (n=7) of Trusts within England performed 47% of the country’s autopsies and 75% of autopsies in Wales were performed in one health board.

Ninety-eight per cent of samples (n=164) had an autopsy rate of <5%, 86% (n=143) an autopsy rate <1% and 23% (n=38) of all samples did not perform a single autopsy in 2013 (figure 2B). This demonstrates that for a quarter of NHS Trusts/Boards in the UK, hospital autopsy is extinct and in only a fraction (1.8%) of specialist trusts do autopsy rates exceed 5%, the rate previously published for non-teaching hospitals.[1,18]

Hospital autopsy rates in children’s hospital NHS Trusts ranged from 0% to 21%. This higher figure is in agreement with other literature.[17,18]

Discussion

This study has demonstrated that the evident decline in hospital autopsy has continued, if not accelerated, over recent years and already the hospital autopsy is extinct in many NHS Trusts. With 23% of NHS Trusts/Boards having an autopsy rate of 0%, a large part of UK hospital autopsy is now performed in a small number of centres. These few demonstrate that if the provisions and attitudes allow, then hospital autopsy rates of the recent past are still achievable, despite recent legislative changes such as the Human Tissue Act 2004/2006. Trusts with higher autopsy rates tended to be small specialised centres or large teaching hospital Trusts; this influence was not measured in this study due to difficulties in defining a ‘teaching’ or ‘specialised’ Trust/Board. Given that 86% of Trusts/Boards in the UK now have a hospital autopsy rate of <1%, we must pose the question whether a revival in hospital autopsy is possible? In the near future, many of these organisations may join the 23% in which hospital autopsy is extinct, unless they implement those changes in policy and attitude present in the 1.8% of Trusts/Boards where hospital autopsy exceeds 5% of inpatient deaths?

The hospital autopsy rate in Scotland was significantly higher than the other countries (Table 2). The causes of this are uncertain but may include variations in the Human Tissue Act and Authority in Scotland or a lower procurator fiscal (coronial) autopsy rate.

A number of Trusts/Boards gave some explanations as to why their autopsy rate was low, these commonly surrounded provision of facilities. For example, one Trust does not employ an onsite histopathologist or have its own autopsy facilities. However, some Trusts/Boards which themselves do not have onsite hospital autopsy facilities have an agreement with neighbouring Trusts/Boards to carry out their autopsies. From the results, there is evidence of remote island providers that continue to implement autopsy despite no local facilities but which transport cadavers via boat or aeroplane to a separate hospital for autopsy. Thus, a lack of facilities does not preclude hospital autopsy although may add significantly to the cost.

Future research should investigate the differences in Trust/Board policies, clinician attitudes, facilities, funding and local demographics to determine how significantly higher autopsy rates can be achieved.

The strength of this study lies in the nationwide approach to calculating contemporary hospital autopsy rates. Previous studies have focused on single hospitals or Trusts; given the demonstrated wide inter-Trust variation this approach may lead to significant errors. A weakness of this study was that some hospital trusts were unable to separate the data for deaths and autopsies for children and adults. Therefore, mean adult autopsy rates may be slightly over-reported, rates being generally higher among paediatric deaths.

In England and Wales, 94 455 coronial autopsies were performed in 2013[3] yet only 1132 hospital autopsies were performed within the English and Welsh Trusts included in this study. Hospital autopsy now accounts for approximately 1.2% of total autopsies. With such low numbers, questions must be raised regarding the effect such decline has on quality assurance, public health, misdiagnosis (a key contributor to avoidable harm[19,20]), audit and the teaching of both medical students and trainee pathologists. Hospital autopsy presents classic cases used to train junior pathologists, given that many coronial postmortems are not used for training. Training in hospital autopsy will become ever more important given the impending lack of pathologists to cover coronial autopsy. The aim of this paper is to raise awareness of the extent of the decline and to prompt discussion on its consequences. While debate continues over the value of hospital autopsy in medical practice, if action is not taken imminently, the practice may disappear.

COMMENTARY

Prostate Cancer: Is It Time to Retire the Gleason Score?

George D. Lundberg, MD

Hello. I am Dr George Lundberg and this is At Large at Medscape.

If you are an American adult male, you either now have prostate cancer—whether or not you know it—or will likely develop it if you live long enough.

In an average recent year, some 220,000 American men are diagnosed with prostate cancer and some 27,000 die from it. That means, obviously, that it kills 12% of those it is found to afflict and does not kill 88%. Of those patients freshly diagnosed, 98.9% are alive at 5 years.

Does interventional therapy account for the good results of some of that nearly 90% of men who are diagnosed and don’t die? Well, yes, but probably not very many. Really bad prostate cancer tends to do its lethal thing, regardless of interventions.

Back when we collectively had a lot of autopsies, it was possible—even easy—- to follow and learn the natural history of many diseases.

Modern autopsy-less American physicians, including pathologists, are whizz-bang at computers, imaging, lab test panels, genes, microbiomes, electronic medical records, and coding. They are maybe not so great at physical exams, taking a useful personal and family history, or gross and microscopic pathology. This latter list is where physicians once got really good at understanding the natural history of diseases.

Now, epidemiologic facts, outcomes, and common sense have begun to prevail over the national hysteria of prostate-specific antigen (PSA) tests for all men. The hysteria tends to take this form: “Find that prostate cancer and root it out…no matter how small or indolent. That way, ‘Megalopolis U’ can keep those operating rooms, hospital beds, and—get this—unproven (but very elegant) proton beameconomic monstrosities really humming in order to satisfy the overpaid MBAs that determined that such were a good investment idea.”

But some prostate cancers really can kill. How about those? A pathologist named Donald Gleason came up with a numbering system intended to guide therapy based upon anaplasia and prognostic threat of prostate cancer. It was 1, 2, 3, 4, and 5. It makes sense. But then, another number dealing with the relative amount of each level of differentiation and pattern (also 1, 2, 3, 4, 5) got added, and combining the two scores became the Gleason score range of 2-10.

A reasonable human could interpret a 6 on a scale of 10 as middling, pretty bad, or a “better-whack-it-out”-type score. So, a team from Johns Hopkins Medical Institutions[1] has worked out the actual prognosis as falling back into 5 Prognostic Grade Groups (PGGs):

  • Gleason 1, 2, 3, 4, 5, and 6 become Prognostic Grade Group (PGG I);
  • Gleason 3 + 4 = 7 (PGG II);
  • Gleason 4 + 3 = 7 (PGG III);
  • Gleason 4 + 4 = 8 (PGG IV); and
  • Gleason 9-10 (PGG V).

This is so much simpler and less likely to confuse the treating clinician and the patient who is increasingly sharing in this treatment decision.

A European group has just published outcomes based on this PGG system,[2] and it fits nicely. Those many patients with low grades who may not need radical therapy will stand a better chance of notreceiving radical therapy with new low-sounding numbers.

And, by the way, how did “watchful waiting” as a good way to handle those prostate “cancers”—which, from histology, seem like they would behave as indolentomas—morph so quickly into “active surveillance”? My guess is that it is very hard to bill a patient, Medicare, or an insurance company for just letting the patient watch and wait.

Chicago Mayor Rahm—not his physician brother Zeke—Emanuel was right: Never let a crisis go to waste. When the word “cancer” was uttered or written, hair lit on fire and something had to be done, right or wrong.

That is my opinion. I’m Dr George Lundberg.

Medscape Medical News Conference News

New Clue as to Why Only Some Breast Cancers Relapse

Zosia Chustecka

UPDATED September 26, 2015 // VIENNA — A new clue as to why only some breast cancers recur comes from the largest study of genetic sequencing of breast cancer tissue to date.

While most breast cancer is cured after treatment, about 20% of cases recur. The new study shows that the cases that recur have a different genetic profile, and suggests that some of the genetic drivers of relapse are targetable with drugs.

“We demonstrate that there are clear differences within the driver landscapes of relapsed cancers. This probably reflects a combination of predisposition to relapse and of differences in the mutations acquired during the relapse and metastasis phase,” say the researchers, led by Lucy Yates, MD, a clinical research oncologist from the Wellcome Trust Sanger Institute in Cambridge, United Kingdom.

The finding raises the hope that breast cancer patients who are most at risk for relapse can be identified when they are first diagnosed, they suggest.

In addition, as the newly identified genetic drivers of relapse are targetable with drugs, there is also hope that eventually women who are identified as being at high risk for relapse could be treated with such drugs to prevent recurrence, they suggest.

The study is due to be presented European Cancer Congress (ECC) 2015, but details were released early by the ECC press office.

The finding comes from a study that compared the genetic make-up of breast cancer from 836 tissue samples taken from women on primary diagnosis with 161 samples of tissue taken from recurrences or metastases.

The study is the largest and most comprehensive carried out to date, say the researchers, both in terms of the number of samples from relapsed breast cancers and in terms of the wide-ranging genetic sequencing carried out, which looked at 365 genes involved in cancer-related pathways.

The researchers performed de novo driver mutation discovery, and individual mutations were annotated with likely driver status based upon recurrence and known driver status in previously published, well-curated datasets and databases. The incidence of each driver mutation in the primary and relapse datasets was compared using Fisher’s exact test and using the Benjamini–Hochberg correction for multiple testing.

The team found 11 genes that were significantly enriched in the relapsed cohort compared with the primary tumor cohort. The most heavily enriched were TP53 and ARID1B. Multiple samples were available for 66 patients, including local or distant relapse samples in all cases and a sample from the primary tumor in 21 cases. This multisample analysis allowed the team to trace the evolution of mutations.

“We have found that some of the genetic mutations that drive breast cancers that relapse are relatively uncommon amongst cancers that do not relapse at the point of primary diagnosis,” Dr Yates said in a statement.

“We believe that the differences we have seen reflect genetic differences that can predispose a cancer to return, combined with mutations acquired throughout the period from first diagnosis to the subsequent relapse,” she added.

However, in a discussion of this paper, Fabrice André, MD, PhD, from the Gustave Roussy Institute, in Villejuif, France, questioned whether all the genes that were found to be enriched in the relapsed samples were driving the relapse and whether any could be identified as recurrent markers. He noted that although Dr Yates and colleagues found 11 genes that were highly enriched in the relapsed tissue samples, another study (which analyzed 183 samples) found only one of these genes to be highly enriched.

Dr Andre also wondered whether the late mutations that were identified are clinically relevant ― could they explain the development of resistance to therapy? This has been seen in other cancers, he noted.

Extreme Heterogeneity ― Need for Multiple Biopsies

“Our data reveal extreme heterogeneity and indicate that genomic analysis of primary, relapsed, and matched normal tissue are needed,” Dr Yates concluded.

“We need to do biopsies again and again and again,” said Anne-Lise Borresen-Dale, MD, from the Institute for Cancer Research, Oslo University Hospital, Norway, who chaired the session. But Dr Andre wondered whether circulating tumor cells, the so-called “liquid biopsy,” could be used.

Multiple samples were available for 66 subjects, including local or distant relapse samples in all cases and a sample from the primary tumor in 21 cases. This multisample analysis permitted relative temporal ordering of driver mutation accumulation to be determined, the researchers explain.

“We have found that some of the genetic mutations that drive breast cancers that relapse are relatively uncommon amongst cancers that do not relapse at the point of primary diagnosis,” Dr Yates said in a statement.

“This study highlights the differences between genetic alterations that drive relapsed and metastatic disease as opposed to primary breast cancers, and underlines the importance of analyzing the genetic features of metastases when making treatment decisions,” said Jorge Reis-Filho, MD, from the Memorial Sloan Kettering Cancer Center in New York City, who was acting as a spokesperson for the European Society of Medical Oncology, which is cohosting the meeting. He was not involved with this work.

However, Dr Reis-Filho also cautioned that “the extent of the differences in the repertoire of mutations among different metastatic sites within individual patients remains to be determined, however, as does the best way to obtain tumor-derived genetic material in patients with metastatic disease. We also need to know more about whether single or multiple metastatic sites should be analyzed in this context.”

Also commenting on the study, Peter Naredi, MD, PhD, professor of surgery at Sahlgrenska University Hospital in Gothenburg, Sweden, who is the European CanCer Organization scientific cochair of the congress, said: “Information such as that which Dr Yates will present is very important in the era of precision medicine.”

“This study also underlines the fact that we should consider a recurrence of a cancer as a new event, and carefully select the right treatment for the recurrent tumor as opposed to just relying on information from the first occurrence,” Dr Naredi said in a statement.

JAK Inhibitors in Breast Cancer

Some of the genetic changes that were found in the relapsed/metastatic breast cancer samples appeared at a late stage when the cancer recurred, and were not seen in samples taken at primary diagnosis. Among these later-stage mutations, the researchers say they found “compelling evidence” for the tumor suppression activity of two related genes, called JAK2 and STAT3, that operate within the same signaling pathway.

“Within some breast cancers, a disruption in this signaling pathway seems to be advantageous for survival of the cancer,” Dr Yates said in a statement.

“Interestingly, this is in contrast to the role of JAK2 in some other cancers, where overactivity of the gene drives malignancy rather than suppresses it,” she added.

The JAK (Janus-associated kinase) enzymes JAK1 and JAK2 are involved in regulating blood and immunologic functioning, and a dysregulation of these enzymes is thought to be a driver in the development of myelofibrosis. The first JAK inhibitor, ruxolitinib (Jakafi, Incyte Corp), was approved for the treatment of myelofibrosis in 2011.

Dr Yates and colleagues note that enhanced JAK-STAT signaling is known to play an important role in breast cancer stem cell development and cancerous cell line survival, and preclinical evidence seems to suggest that inhibiting the gene would be therapeutically advantageous. These findings have led to the development of clinical trials for breast cancer using JAK inhibitors in the hope that they will slow cancer progression.

“However, our findings suggest that, in a subset of cancers, inhibiting this pathway may have the opposite effect, and this requires further investigation. In general, the observation highlights the importance of understanding the diverse nature of breast cancers in the era of precision medicine,” Dr Yates said.

The work was funded by the Wellcome Trust. Dr Yates has disclosed no relevant financial relationships.

European Cancer Congress (ECC) 2015: Abstract 1804.

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Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle


Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle

Reporter: Stephen J Williams, PhD

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series C: e-Books on Cancer & Oncology

Volume One: Cancer Biology and Genomics for Disease Diagnosis

CancerandOncologyseriesCcoverwhich is now available on Amazon Kindle at                          http://www.amazon.com/dp/B013RVYR2K.

This e-Book is a comprehensive review of recent Original Research on Cancer & Genomics including related opportunities for Targeted Therapy written by Experts, Authors, Writers. This ebook highlights some of the recent trends and discoveries in cancer research and cancer treatment, with particular attention how new technological and informatics advancements have ushered in paradigm shifts in how we think about, diagnose, and treat cancer. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon. All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations
  • on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Cancer Biology and Genomics for Disease Diagnosis

Preface

Introduction  The evolution of cancer therapy and cancer research: How we got here?

Part I. Historical Perspective of Cancer Demographics, Etiology, and Progress in Research

Chapter 1:  The Occurrence of Cancer in World Populations

Chapter 2.  Rapid Scientific Advances Changes Our View on How Cancer Forms

Chapter 3:  A Genetic Basis and Genetic Complexity of Cancer Emerge

Chapter 4: How Epigenetic and Metabolic Factors Affect Tumor Growth

Chapter 5: Advances in Breast and Gastrointestinal Cancer Research Supports Hope for Cure

Part II. Advent of Translational Medicine, “omics”, and Personalized Medicine Ushers in New Paradigms in Cancer Treatment and Advances in Drug Development

Chapter 6:  Treatment Strategies

Chapter 7:  Personalized Medicine and Targeted Therapy

Part III.Translational Medicine, Genomics, and New Technologies Converge to Improve Early Detection

Chapter 8:  Diagnosis                                     

Chapter 9:  Detection

Chapter 10:  Biomarkers

Chapter 11:  Imaging In Cancer

Chapter 12: Nanotechnology Imparts New Advances in Cancer Treatment, Detection, &  Imaging                                 

Epilogue by Larry H. Bernstein, MD, FACP: Envisioning New Insights in Cancer Translational Biology

 

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Examples of Surgical Procedures [4.4]

Writer and Curator: Larry H. Bernstein, MD, FCAP 

It is not possible to discuss surgical procedures without a firsthand knowledge of the principles of surgical, radiation and medical oncology and the current interdisciplinary approach to the care of the patient with cancer with respect to the type of cancer, the stage, the patient health status, the preoperative preparation, the assessment of treatment for cure or of palliation, and the postoperative plan for management of the patient.

Cancer surgery has evolved over the decades from a radical ‘one size fits all’ approach to a patient-specific, cancer-specific direction, which means that surgeons rely on their multidisciplinary partners in the assessment of patients. As surgeons are frequently the first specialists involved with most solid tumors, familiarity with pre-operative imaging, pathological biopsy and patient-selection, careful surgical technique and staging are fundamental to the surgeon’s armamentarium.

Surgical resection of cancers remains the cornerstone of treatment for many types of cancers. Historically, surgery was the only effective form of cancer treatment, but developments in radiation therapy and chemotherapy have demanded that surgeons work with the other disciplines of medicine in order to achieve best results for the patient with cancer.

This type of interaction between the medical disciplines together with the supportive care groups required by cancer patients is defined as multidisciplinary care. It is now widely recognized that for optimal treatment of cancer a multidisciplinary team with the surgeon as part of this team is essential.

Surgery is effective treatment for cancer if the disease is localized. Defining the extent of the cancer before surgery has become much more accurate with modern imaging methods including computed tomography (CT), positron emission tomography (PET) scanning and high resolution ultrasound. The exploratory operation to determine the extent of disease, or attempting a ‘curative’ resection when the disease has already spread beyond the bounds of a ‘surgical’ cure, is not part of the modern surgical treatment of cancer. Oncological trained surgeons are now distinguished from more general surgeons because of the particular needs of the cancer patients.

Clinical trials are required to evaluate new treatments and treatment combinations. The struggle against the scourge of cancer has seen an explosion in basic research directed towards cancer. This academic element to cancer care is a constant feature as all those involved in cancer care endeavor to advance the understanding of the management of cancer patients.

Three main questions to consider are implied from the preceding:

What is the type of cancer?

In most cases, this requires a tissue diagnosis. In modern oncology, it is unusual or inappropriate to start treatment based on clinical diagnosis alone without tissue diagnosis. Tissue diagnosis is also important to perform molecular studies to select appropriate targeted therapies.

What is the extent of the spread of the cancer?

This is answered by staging scans including CT scans, bone scans and PET scans.

Is it curable or not curable?

This depends on the type of cancer and the presence or absence of and the extent of metastasis.

For curable cancers, rate of cure is determined by prognostic factors (for example: tumor size and nodal status in breast cancer).

For incurable cancers, duration of survival is expressed in median survival rather than in absolute time frame.

Most solid tumors require adequate and site-specific imaging. This facilitates diagnosis and staging of the primary tumor and staging for distal metastases. Not all modalities are appropriate for all sites. For example mammography using the BIRADS system and ultrasound are used in breast cancers to assess a primary breast cancer. Meanwhile, an esophageal cancer requires a CT and a low rectal cancer will be best assessed with MRI or endorectal ultrasound, while a thyroid cancer is best evaluated with neck ultrasound.

One of the biggest challenges for the surgeon is to choose the correct surgery for the correct patient and with the tumor type and biology in mind. Although surgery removes a tumor and provides further pathological information to estimate prognosis and influence adjuvant therapies, the surgery cannot cause more morbidity than the cancer and must achieve surgical goals without compromising tumor biology.

The TNM staging system (American Joint Commission on Cancer AJCC) is devised for cancers to allow an assessment of T- tumor, N- nodal metastases and M- distal metastases. The goal of having a site-specific staging system is to estimate prognosis, facilitate treatment planning including the sequence of treatments and allow comparisons of treatment for different stages. Generally, a combination of different ‘T’, ‘N’, and ‘M’ allows the cancer to be grouped into stages. Stages I-IV usually depict a tumor in the following state: Stage 1- early and superficial cancer, Stage 2- locally advanced, Stage 3- regionally advanced with lymph node metastases and Stage 4- distant metastatic disease.

Despite suggestive imaging, a cancer is not diagnosed until histopathological biopsy. Biopsies where tissue (as opposed to cells) are provided to the pathologist increase the accuracy of the pre-operative diagnosis but may not always be feasible. Biopsies may be undertaken percutaneously — for example, a core biopsy of the breast, fine needle aspiration of thyroid or endoscopically such as in gastric cancer or colon cancer.

A biopsy should confirm the tumor type, grade, may show lymphovascular invasion and in some cases, special immunohistochemical stains may be performed to assess hormone receptor status such as in breast cancer or flow cytometry may be performed to assess subtypes such as in lymphoma. Staging may also require a biopsy of draining lymph nodes.

The aims of any cancer surgery are to remove the cancer with an adequate margin of normal tissue with minimal morbidity. Clear margins have an impact on local control.  Many solid tumors require removal of the draining lymph nodes for the purpose of staging and/or to achieve local control. Surgery has become more conservative with the advent of sentinel node biopsy, and is frequently used in breast cancer and melanoma. The sentinel node biopsy is a  staging tool to predict prognosis and influence use of adjuvant therapies. Surgery is performed for cure by removing the primary cancer and lymph nodes.

When tumors are locally advanced, a neoadjuvant approach with chemotherapy, radiotherapy or targeted therapies may be important to ‘control’ the growth of a tumor, down-stage a tumor to render it operable, or because the impact of systemic disease risk may outweigh those of local control. Similarly, patients with metastatic disease may still require surgery to prevent complications of the primary tumor, such as bowel obstruction from a colon cancer.

The preceding paragraphs define the discipline of surgical oncology. In summary, surgical oncology is the involvement of a specialty trained surgeon as part of a multidisciplinary team program, the use of appropriate surgery in an adequately staged patient and the involvement of the surgeon in academic programs particularly involved with clinical trials.

The use of effective techniques in the operating theater, the careful management of the patient undergoing surgery and supportive post-operative care are similar requirements to those of all other disciplines of surgery.

Communication with the patient and family, the obtaining of informed consent and the careful honest, realistic but where possible optimistic explanation of the results of surgery, are all matters of high importance to all surgical practice. However, the ability to talk sympathetically to cancer patients and their family is particularly important in the field of surgical oncology.

Multidisciplinary care

Surgeons need to understand the principles and practical consequences of the treatment offered by radiation oncologists, medical oncologists and the paramedical disciplines in order to be able to work in a team to treat cancer patients.

Principles of cancer surgery
Dr. Anita Skandarajah MBBS MD FRACS — Author
Cancer Council Australia Oncology Education Committee — Co-author
http://wiki.cancer.org.au/oncologyformedicalstudents/Principles_of_cancer_surgery

http://www.surgwiki.com/wiki/Principles_of_surgical_oncology

Principles of surgery for malignant disease
http://www.surgwiki.com/wiki/Principles_of_surgical_oncology#Principles_of_surgery_for_malignant_disease

Screening

Surgical resection has the potential to cure early or localized cancers which have not metastasized. In general early cancers equate with curability. For example, a malignant polyp in the colon is usually curable by surgery. However, this does not always hold true. Small breast cancers may metastasize early with cure not inevitable from surgical excision alone. Screening for cancer to detect early asymptomatic cancers is now commonplace.

For screening to be effective, the test must be able to detect a common cancer at a stage when it can be cured by treatment. For screening to be effective it must be introduced on a population basis. The most effective screening program has been cervical screening where, since its introduction, there has been a substantial fall in mortality from cervical cancer in all age groups. Similar less dramatic effect is seen with breast cancer screening by mammography.

Surgeons are involved in screening programs performing endoscopies and biopsies (e.g. abnormal Barrett’s mucosa), excising polyps from the colons at colonoscopy and biopsying mammographically detected breast lesions.

Diagnosis

A tissue diagnosis is essential prior to the creation of any management plan for a cancer patient. The consequences of many cancer treatments are so severe that only rarely can treatment be commenced without a pathological diagnosis. Tissue is obtained by fine needle aspiration, core biopsy or by excisional biopsy.

Assessment of the patient

An important early part of the assessment of a patient with cancer is to determine the psychological and physical fitness of the patient. An idea of the ‘health’ of the patient can be gained from a simple clinical assessment, the Eastern Cooperative Oncology Group (ECOG) status. Patients who are ECOG 3 or lower will usually have a poor outcome from any treatment including major surgery.

All patients undergoing major surgery need assessment of the clinical status including, where appropriate, tests of cardiac function, for example scans and angiography if indicated, respiratory status by lung function tests and renal function tests including creatinine clearance.

Staging of malignant disease

Accurate staging of the extent of disease is of great importance in formulating a treatment plan. Clinical stage is that defined by clinical examination and imaging of the patient. It is often not accurate but with the use of high quality CT and PET scanning the accuracy is improved. Pathological staging is that defined after excisional surgery by the anatomical pathologist. It is accurate in defining the extent of disease associated with a primary tumor. The staging system is varied according to the primary site of the tumor.

Rectal cancers have a long-standing clinical and pathological staging system known as the Cuthbert-Dukes staging system. Dukes A is local disease in the rectum not invading muscularis propria; Dukes B, the tumour has extended through the wall of the bowel; and Dukes C, where there is lymph node involvement. Dukes D is when distant metastases are present. The Dukes system is commonly used alongside the TNM system.

Methods of clinical staging include radiological methods such as CT, MRI and ultrasound. Within the area of nuclear medicine are PET scanning and nuclear scanning generally (e.g. bone scanning). Laparoscopy is an added staging method which detects intra-abdominal tumors.

Decision about treatment at the multidisciplinary conference

Armed with information about the diagnosis of the cancer, the extent of the disease, that is the clinical stage of the disease and the fitness of the patient, decisions can be made about the most appropriate treatment program. Ideally consultation with a multidisciplinary team occurs at this stage, however if the decision regarding surgery is straightforward, the multidisciplinary conference usually occurs after the surgery when a pathological stage has been determined. However many cancers require down-staging with radiotherapy or chemotherapy prior to surgery, and multidisciplinary consultations early are important to facilitate this process.

The provision of written information to the patient and family, with careful and repeated discussions, is necessary to ensure that the patient can give informed consent to any treatment plan offered. Patients have the right to refuse all or some of the treatment plan and they are encouraged to be part of the decision making process.

At this stage discussions regarding involvement in research projects, use of resected tissues and involvement in clinical trials need to be commenced.

Principles of operative surgical oncology

The technical issues in surgical oncology are not different from other surgical intervention. Open surgery, laparoscopic surgery, robotic surgery, ablative interventions and other technical interventions all have a place in modern surgical oncology. However some important oncological principles exist which must be followed by the surgeon for a satisfactory outcome.

Definition of curative surgery

Despite modern staging methods, occult tumor spread is still discovered by the surgeon, for example small-volume peritoneal disease or unsuspected nodal disease. Frozen section examination of the disease is necessary to confirm the diagnosis. So-called curative surgery is only performed when a total excision of the tumor is possible. The primary tumor and the associated lymph node drainage fields are excised in continuity. A measure of the adequacy of the oncological surgical operation is demonstrated by the findings on pathological examination of the specimen. The operative specimens need to be correctly orientated by the surgeon to allow the pathologist to carefully examine and interpret the specimen given to him. The key issues are:

  • whether the margins of the specimen removed are clear of tumor
  • the total number of lymph nodes excised together with the number of involved lymph nodes.
  • Standards exist for the adequacy of the surgical excision to be assessed in many tumors.

Palliative surgery

Here the operation is performed to overcome some symptom-producing consequence of the tumor either by resection or bypass. This is to remove a potentially symptomatic lesion even though a cure is known to be impossible.
Examples include the following:

In case of pyloric obstruction from an advanced cancer of the stomach, a gastrojejunostomy will provide good palliation of vomiting.

Resection of a bleeding cancer of the colon is justified even in the presence of metastases.

Many other examples exist. ‘Tailoring’ this type of surgery to the needs of the patient without undue morbidity or loss of quality of life is an important role for an oncological surgeon.

Margins of surgical excision

The degree to which normal tissues should be removed with the primary tumor is a subject constantly being researched. A universal rule is not possible to formulate. In general a margin of 2-5 cm is suggested. Particular examples follow:

For excision of melanomas the depth of excision is more important than the extent of surrounding skin. A margin of 2 cm usually suffices in contrast to the 5 cm previously practiced.

However for esophageal resection the majority of the esophagus needs to be resected because the tumor does spread up and down in the submucosal plane.

Soft tissue sarcomas may spread along aponeurotic planes so that complete excision requires the resection of the entire muscle group and fascial compartment to encompass this type of spread.

The recognition that spread of rectal cancer occurs into perirectal tissues has led to the use of the total mesorectal excision of the rectum to improve the completeness of resection.

The principle of complete local excision with an adequate margin is paramount in surgical oncology and it needs to be achieved in different ways depending on the type of tumor being resected.

Lymph node resection

Traditionally the draining lymph nodes from a primary tumor are excised with the local lesion. The main benefit of this removal is increased staging information, which will affect the decisions regarding post-operative adjuvant therapy. In some situations there may be a survival benefit from removal of early-involved lymph nodes. However prophylactic excision of uninvolved nodes does not provide a survival advantage to the patient and exposes the patient to increased morbidity from the node removal. An example is the prophylactic removal of groin lymph nodes (radical groin dissection), when these glands are not involved. This operation is nowadays not performed when the glands are clinically not involved as randomized controlled trials have shown that survival rates have not improved but the morbidity from the operation is significant. Poor skin healing and swelling of the affected leg are two such complications.

Rehabilitation

It is necessary to undertake rehabilitation of the cancer patient who has undergone major a resection. This usually involves the allied health disciplines, part of the oncology team. The type and duration of the process will vary according to the type of tumor and surgery performed.

Follow-up of patient after initial treatment

A program of follow-up is required for cancer patients after their initial treatment. This is for two main reasons. This is to observe the patient and investigate when appropriate to detect recurrent disease, which can then be treated effectively. By definition this is only likely to be useful to the patient when strong effective postoperative therapies are available which will have a real impact on the control of cancer.

Conclusion

The principles of surgical oncology can be applied to many of the systemic practices of surgery. In simple terms the surgeon operating on cancer patients in the 21st century must have some understanding of the malignant process, be prepared to work as part of a team and offer multidisciplinary care, communicate well with a very concerned sometimes desperate group of patients, operate with a high level of skill and perform an adequate cancer operation, help the patient rehabilitate from the treatment and finally be prepared to be involved in the advancing area of surgical science as applied to cancer patients. As God knows, surgeons cannot cure all cancers on their own.

Principles of Surgical Oncology    (Apr 08, 2009)
http://www.cancernetwork.com/articles/principles-surgical-oncology-2 Lawrence D. Wagman, MD, FACS

Surgical oncology, as its name suggests, is the specific application of surgical principles to the oncologic setting. These principles adapt standard surgical approaches to the unique situations that arise when treating cancer patients.

The surgical oncologist must be knowledgeable about all of the available surgical and adjuvant therapies, both standard and experimental, for a particular cancer. This enables the surgeon not only to explain the various treatment options to the patient but also to facilitate and avoid interfering with future therapeutic options.

Invasive diagnostic modalities

As the surgeon approaches the patient with a solid malignancy or abnormal nodal disease or the rare individual with a tissue-based manifestation of a leukemia, selection of a diagnostic approach that will have a high likelihood of a specific, accurate diagnosis is paramount. The advent of high-quality invasive diagnostic approaches guided by radiologic imaging modalities has limited the open surgical approach to those situations where the disease is inaccessible, a significant amount of tissue is required for diagnosis, or a percutaneous approach is too dangerous (due, for example, to a bleeding diathesis, critical intervening structures, or the potential for unacceptable complications, such as pneumothorax).

Lymph node biopsy

The usual indication for biopsy of the lymph node is to establish the diagnosis of lymphoma or metastatic carcinoma. Each situation should be approached in a different manner.

Lymphoma The initial diagnosis of lymphoma should be made on a completely excised node that has been minimally manipulated to ensure that there is little crush damage. When primary lymphoma is suspected, the use of needle aspiration does not consistently allow for the complete analyses described above and can lead to incomplete or inaccurate diagnosis and treatment delays.

Carcinoma The diagnosis of metastatic carcinoma often requires less tissue than is needed for lymphoma. Fine-needle aspiration (FNA), core biopsy, or subtotal removal of a single node will be adequate in this situation. The use of immunocytochemical analyses can be successful in defining the primary site, even on small amounts of tissue.

Head and neck adenopathy The head and neck region is a common site of palpable adenopathy that poses a significant diagnostic dilemma. Nodal zones in this area serve as the harbinger of lymphoma (particularly Hodgkin lymphoma) and as sites of metastasis from the mucosal surfaces of the upper digestive tract; nasopharynx; thyroid; lungs; and, occasionally, intra-abdominal sites, such as the stomach, liver, and pancreas. The surgical oncologist must consider the most likely source of the disease prior to performing the biopsy. FNA or core biopsy becomes a valuable tool in this situation, as the tissue sample is usually adequate for basic analysis (cytologic or histologic), and special studies (eg, immunocytochemical analyses) can be performed as needed.

Biopsy of a tissue-based mass

Several principles must be considered when approaching the seemingly simple task of taking a tissue biopsy. As each of the biopsy methods has unique risks, yields, and costs, the initial choice can be a critical factor in the timeliness and expense of the diagnostic process.

Mass in the digestive tract In the digestive tract, biopsy of a lesion should include a representative amount of tissue taken preferably from the periphery of the lesion, where the maximum amount of viable malignant cells will be present. The biopsy must be of adequate depth to determine penetration of the tumors. This is particularly true for carcinomas of the oral cavity, pharynx, and larynx.

Breast mass Although previously a common procedure, an open surgical biopsy of the breast is rarely indicated today. Palpable breast masses that are highly suspicious (as indicated by physical findings and mammography) can be diagnosed as malignant with close to 100% accuracy with FNA. However, because the distinction between invasive and noninvasive diseases is often required prior to the initiation of treatment, a core biopsy, performed either under image guidance (ultrasonography or mammography) or directly for palpable lesions, is the method of choice.

An excellent example of the interdependence of the method of tissue diagnosis and therapeutic options is the patient with a moderate-sized breast tumor considering breast conservation who chooses preoperative chemotherapy for downsizing of the breast lesion. The core biopsy method establishes the histologic diagnosis, provides adequate tissue for analyses of hormone-receptor levels and other risk factors, causes little or no cosmetic damage, does not perturb sentinel node analyses, and does not require extended healing prior to the initiation of therapy. In addition, a small radio-opaque clip can be placed in the tumor to guide the surgical extirpation. This step is important because excellent treatment responses can make it difficult for the surgeon to localize the original tumor site.

Mass in the trunk or extremities For soft-tissue or bony masses of the trunk or extremities, the biopsy technique should be selected on the basis of the planned subsequent tumor resection. The incision should be made along anatomic lines in the trunk or along the long axis of the extremity. When a sarcoma is suspected, FNA can establish the diagnosis of malignancy, but a core biopsy will likely be required to determine the histologic type and plan neoadjuvant therapy.

Specific Surgical References

Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data
AJ Breugom, M Swets, Jean-François Bosset, L Collette, ..CJH van de Velde
Lancet (Oncology) 2015; 16: 200-207.
http://dx.doi.org/10.1016/S1470-2045(14)71199-4

Background The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. Methods We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomized, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. Findings We analyzed data from four eligible trials, including data from 1196 patients with TNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumor located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0·97, 95% CI 0·81–1·17; p=0·775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0·91, 95% CI 0·77–1·07; p=0·230) or distant recurrences (0·94, 0·78–1·14; p=0·523) compared with observation. However, in subgroup analyses, patients with a tumor 10–15 cm from the anal verge had improved disease-free survival (0·59, 0·40–0·85; p=0·005, p interaction=0·107) and fewer distant recurrences (0·61, 0·40–0·94; p=0·025, p interaction=0·126) when treated with adjuvant chemotherapy compared with patients undergoing observation. Interpretation Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumor 10–15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted.

Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial
IH Kunkler, LJ Williams, WJL Jack, DA Cameron, JM Dixon, et al.
Lancet Oncol 2015; 16: 266–73
http://dx.doi.org/10.1016/S1470-2045(14)71221-5

Background For most older women with early breast cancer, standard treatment after breast-conserving surgery is adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. We aimed to assess the effect omission of whole-breast radiotherapy would have on local control in older women at low risk of local recurrence at 5 years. Methods Between April 16, 2003, and Dec 22, 2009, 1326 women aged 65 years or older with early breast cancer judged low-risk (ie, hormone receptor-positive, axillary node-negative, T1–T2 up to 3 cm at the longest dimension, and clear margins; grade 3 tumor histology or lympho-vascular invasion, but not both, were permitted), who had had breast conserving surgery and were receiving adjuvant endocrine treatment, were recruited into a phase 3 randomized controlled trial at 76 centers in four countries. Eligible patients were randomly assigned to either whole-breast radiotherapy (40–50 Gy in 15–25 fractions) or no radiotherapy by computer-generated permuted block randomization, stratified by center, with a block size of four. The primary endpoint was ipsilateral breast tumor recurrence. Follow-up continues and will end at the 10-year anniversary of the last randomized patient. Analyses were done by intention to treat. The trial is registered on ISRCTN.com, number ISRCTN95889329.n Findings 658 women who had undergone breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and 668 were allocated to no further treatment. After median follow-up of 5 years (IQR 3·84–6·05), ipsilateral breast tumor recurrence was 1·3% (95% CI 0·2–2·3; n=5) in women assigned to whole-breast radiotherapy and 4·1% (2·4–5·7; n=26) in those assigned no radiotherapy (p=0·0002). Compared with women allocated to whole-breast radiotherapy, the univariate hazard ratio for ipsilateral breast tumor recurrence in women assigned to no radiotherapy was 5·19 (95% CI 1·99–13·52; p=0·0007). No differences in regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between groups. 5-year overall survival was 93·9% (95% CI 91·8–96·0) in both groups (p=0·34). 89 women died; eight of 49 patients allocated to no radiotherapy and four of 40 assigned to radiotherapy died from breast cancer. Interpretation Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer 5 years after randomization. However, the 5-year rate of ipsilateral breast tumor recurrence is probably low enough for omission of radiotherapy to be considered for some patients.
Disease-free survival after complete mesocolic excision compared with conventional colon cancer surgery: a retrospective, population-based study   CA Bertelsen, AU Neuenschwander, JE Jansen, M Wilhelmsen, et al.
Lancet Oncol 2015; 16: 161–68
http://dx.doi.org/10.1016/S1470-2045(14)71168-4

Background Application of the principles of total mesorectal excision to colon cancer by undertaking complete mesocolic excision (CME) has been proposed to improve oncological outcomes. We aimed to investigate whether implementation of CME improved disease-free survival compared with conventional colon resection. Methods Data for all patients who underwent elective resection for Union for International Cancer Control (UICC) stage I–III colon adenocarcinomas in the Capital Region of Denmark between June 1, 2008, and Dec 31, 2011, were retrieved for this population-based study. The CME group consisted of patients who underwent CME surgery in a centre validated to perform such surgery; the control group consisted of patients undergoing conventional colon resection in three other hospitals. Data were collected from the Danish Colorectal Cancer Group (DCCG) database and medical charts. Patients were excluded if they had stage IV disease, metachronous colorectal cancer, rectal cancer (≤15 cm from anal verge) in the absence of synchronous colon adenocarcinoma, tumor of the appendix, or R2 resections. Survival data were collected on Nov 13, 2014, from the DCCG database, which is continuously updated by the National Central Office of Civil Registration. Findings The CME group consisted of 364 patients and the non-CME group consisted of 1031 patients. For all patients, 4-year disease-free survival was 85·8% (95% CI 81·4–90·1) after CME and 75·9% (72·2–79·7) after non-CME surgery (log-rank p=0·0010). 4-year disease-free survival for patients with UICC stage I disease in the CME group was 100% compared with 89·8% (83·1–96·6) in the non-CME group (log-rank p=0·046). For patients with UICC stage II disease, 4-year disease-free survival was 91·9% (95% CI 87·2–96·6) in the CME group compared with 77·9% (71·6–84·1) in the non-CME group (log-rank p=0·0033), and for patients with UICC stage III disease, it was 73·5% (63·6–83·5) in the CME group compared with 67·5% (61·8–73·2) in the non-CME group (log-rank p=0·13). Multivariable Cox regression showed that CME surgery was a significant, independent predictive factor for higher disease-free survival for all patients (hazard ratio 0·59, 95% CI 0·42–0·83), and also for patients with UICC stage II (0·44, 0·23–0·86) and stage III disease (0·64, 0·42–1·00). After propensity score matching, disease-free survival was signifi cantly higher after CME, irrespective of UICC stage, with 4-year disease-free survival of 85·8% (95% CI 81·4–90·1) after CME and 73·4% (66·2–80·6) after non-CME (log-rank p=0·0014). Interpretation Our data indicate that CME surgery is associated with better disease-free survival than is conventional colon cancer resection for patients with stage I–III colon adenocarcinoma. Implementation of CME surgery might improve outcomes for patients with colon cancer.

Biomolecular and clinical practice in malignant pleural mesothelioma and lung cancer: what thoracic surgeons should know
I Opitza, R Bueno, E Lim, H Pass, U Pastorino, M Boeri, G Rocco, et al.
European J Cardio-Thor Surg 46(2014):602–606
http://dx.doi.org:/10.1093/ejcts/ezu048

Today, molecular-profile-directed therapy is a guiding principle of modern thoracic oncology. The knowledge of new biomolecular technology applied to the diagnosis, prognosis, and treatment of lung cancer and mesothelioma should be part of the 21st century thoracic surgeons’ professional competence. The European Society of Thoracic Surgeons (ESTS) Biology Club aims at providing a comprehensive insight into the basic biology of the diseases we are treating. During the 2013 ESTS Annual Meeting, different experts of the field presented the current knowledge about diagnostic and prognostic biomarkers in malignant pleural mesothelioma including new perspectives as well as the role and potential application of microRNA and genomic sequencing for lung cancer, which are summarized in the present article.

 

Principles of Surgical Therapy in Oncology
Michael S. Sabel, Kathleen M. Diehl, and Alfred E. Chang
With the expansion of the multidisciplinary approach to cancer, the role of the surgeon has changed significantly. In addition to the well-established curative role, surgeons are often asked to obtain tissue for diagnosis and staging, debulk tumors as part of multimodality therapy, palliate incurable patients, or prevent cancer by the surgical removal of nonessential organs. As the management of cancer is altered by new discoveries in genetics, molecular biology, immunology, and improved therapeutics, so too will the functions of the surgical oncologist change. With our increased understanding of the genetic predisposition to cancer, the surgeon is increasingly being asked to remove healthy organs to prevent malignancy. However, as other effective methods of prevention are developed, such as chemoprevention or gene therapy, this role will certainly diminish. Improving imaging technologies may have diminished the need for surgical intervention for staging (such as in Hodgkin’s lymphoma), but the expanded use of neoadjuvant therapies often requires interventions to accurately assess response to therapy. In addition, harvesting tumors may become increasingly important for molecular staging as well as identifying molecular targets for specific therapies. It is therefore imperative for surgical oncologists to remain up-to-date on the newest approaches to cancer therapy, both multidisciplinary and experimental, and be prepared to adapt to the changing requirements for surgery.

The major objective for surgery of the primary cancer is to achieve optimal local control of the lesion. Local control is defined as the elimination of the neoplastic process and establishing a milieu in which local tumor recurrence is minimized. Historically, this was achieved with radical extirpative surgeries that shaped the surgical oncologists’ major objective, namely, avoiding a local recurrence. Before William Halsted’s description of the radical mastectomy, surgical

treatment of breast cancer resulted in a dismal local control rate of less than 30%. The reason why Halsted’s procedure was adopted as a standard approach was because he achieved greater than 90% local control, despite the fact that the overall survival of his patients was not improved.4 The latter was due to the locally advanced stage of the patients who were treated in those days. This consideration ushered in the concept of en bloc removal of adjacent tissue when removing a primary cancer. Halsted’s mastectomy involved the removal of adjacent skin (often necessitating a skin graft), underlying pectoral muscles, and axillary lymph nodes (Figure 4.1). One of the major principles of surgical therapy of the primary tumor is to obtain adequate negative margins around the primary tumor, which could mean different operative approaches depending on the tumor type and its local involvement with adjacent structures. For example, the removal of a primary colon cancer that involves an adjacent loop of small bowel or bladder requires the en bloc resection of the primary tumor along with removal of the involved segment of small bowel and bladder wall. This approach avoids violation of the primary tumor margins that could lead to tumor spillage and possible implantation of malignant cells in the surrounding normal tissues. Aside from biopsies of the primary tumor, the lesion should not be entered during a definitive resection. In fact, any biopsy tract or incision that was performed before the tumor resection should be included in the procedure to reduce the risk of local recurrence (Figure 4.2). The risk of local recurrence for all solid malignancies is clearly increased if negative margins are not achieved. The adequacy of the negative margin has been defined for most tumor types either from retrospective clinical experience or prospective clinical trials. For example, a 5-cm margin is an adequate bowel margin for primary colon cancers that has been established from clinical experience. Likewise, it is accepted that a 2-cm distal margin for rectal cancers results in adequate local control. Through several prospective, randomized clinical trials, the margins of excision for primary cutaneous melanomas differ according to the thickness of the primary (see Chapter 60). It was a commonly held notion that the development of a local recurrence would in itself result in metastatic disease with decreased overall survival. However, this has not been borne out in the context of prospective trials as described here. The emergence of multimodal therapy has dramatically affected the surgical approach to many primary cancers, especially when surgical resection of the tumor is combined with radiotherapy. Local control is significantly improved after surgical resection of breast, rectal, sarcoma, head and neck, and pancreatic primary cancers. In fact, the addition of radiation therapy as an adjunctive therapy has allowed for less-radical procedures to be performed with an improvement in the quality of life of patients. A prime example of this is in breast cancer. Several clinical trials have demonstrated that the overall survival of patients with invasive breast cancer was comparable if treated by mastectomy versus lumpectomy plus adjuvant radiotherapy.

The regional lymph nodes represent the most prevalent site of metastasis for solid tumors. Because of this, the involvement of the regional lymph nodes represents an important prognostic factor in the staging of the cancer patient. For this reason, the removal of the regional lymph nodes is often performed at the time of resection of the primary cancer. Besides staging information, a regional lymphadenectomy provides regional control of the cancer. Examples of this are patients with melanoma who have tumor metastatic to lymph nodes. It is well documented that the removal of these regional lymph nodes can result in long-term survival benefit in approximately 20% to 40% of individuals depending upon the extent of nodal involvement. Hence, the removal of regional lymph nodes can be therapeutic. The controversies regarding regional lymphadenectomy for solid malignancies have related to the timing of the procedure as well as the extent of the procedure. For some visceral solid tumors such as gastric and pancreatic cancers, the extent of lymphadenectomy at the time of primary tumor resection has been hypothesized to be important in optimizing local and regional control and has an impact on improving overall survival. This concept has not been borne out in prospective randomized trials of gastric cancer in which the extent of lymphadenectomy has been examined.

Based on these trials, the more-extended lymphadenectomy appears to result in more accurate staging of patients at a cost of increased morbidity. For nonvisceral solid tumors such as melanoma, breast cancers, and head and neck squamous cancers, the elective removal of regional lymph nodes at the time of primary tumor resection has been postulated to result in better survival outcomes compared to taking the wait-and-watch approach. The latter involves performing a lymphadenectomy only when the patient relapses in a nodal basin that would then necessitate a therapeutic lymph node dissection. In prospective randomized clinical studies evaluating elective versus therapeutic lymph node dissection in various tumor types, there was no survival advantage for performing elective lymph node dissections (Table 4.2). It is apparent from these controversies that the initial removal of regional lymph nodes is most important for its staging impact, rather than its therapeutic effect. The introduction of selective lymphadenectomy based upon the concept of the sentinel lymph node has dramatically improved our ability to stage the regional lymph nodes of certain cancers. This is reviewed in more detail in the Diagnosis and Staging section of this chapter.

One of the earliest examples of surgical prophylaxis is the recommendation for total proctocolectomy for subsets of patients with chronic ulcerative colitis. Patients with pancolitis, onset of disease at a young age, and a long duration of colitis are at high risk of developing colorectal cancer.36 Other clinical diseases of the large intestine also illustrate the role of proctocolectomy in cancer prevention. Familial adenomatous polyposis coli (FAP) syndrome, defined by the diffuse involvement of the colon and rectum with adenomatous polyps often in the second or third decade of life, almost always predisposes to colorectal cancer if the large intestine is left in place. However, the role of screening and prophylactic proctocolectomy changed dramatically with the identification of the gene responsible for FAP, the adenomatous polyposis coli (APC) gene, located on the long arm of chromosome 5 (5q21).37 Now, children of families in which an APC mutation has been identified can have genetic testing before polyps become evident. Carriers can have screening and surgical resection once polyps appear, usually in the late teens or early twenties. Although not ideal, the palatability of proctocolectomy in this population was furthered with the description of the total abdominal colectomy, mucosal proctectomy, and ileoanal pouch anastomosis.38

Another example of prophylactic surgery is the bilateral mastectomy for women at high risk of developing breast cancer. Before the identification of the BRCA genes, prophylactic mastectomies were typically reserved as an option for women with lobular carcinoma in situ (LCIS). However, with the identification of BRCA1 and BRCA2, the role of prophylactic mastectomies has been greatly expanded. For women with BRCA1 or BRCA2 mutations, the lifetime probability of breast cancer is between 40% and 85%.41–43 Because mastectomy cannot remove all breast tissue, women can expect a 90% to 94% risk reduction with prophylactic surgery.44 Schrag et al. calculated the estimated gain in life expectancy after prophylactic surgery versus no operation in women with either a BRCA1 or BRCA2 mutation and found a 30-year-old woman would be expected to gain 2.9 to 5.3 years of life, depending on her family history.45 However, potential benefits of prophylactic mastectomy must be weighed against quality of life issues and the morbidity of the surgery.46 In addition, other methods for prophylaxis, such as tamoxifen chemoprevention or bilateral oophorectomy, must be considered. Along with the increased risk of breast cancer with BRCA1/2 mutations, the risk of ovarian cancer is also increased. Bilateral oophorectomy after childbearing is complete not only reduces the risk of ovarian cancer47 but may also decrease the risk of breast cancer.48 A detailed discussion must be held with each patient considering bilateral mastectomies regarding the risks and benefits, the knowns and unknowns. It is becoming increasingly important that today’s surgical oncologist have a clear understanding of genetics and inherited risk.

Increased genetic knowledge has also changed our approach to thyroid cancer. Medullary thyroid cancer (MTC) is a wellestablished component of multiple endocrine neoplasia syndrome type 2a (MEN 2a) or type 2b (MEN 2b). Previously, family members at risk for MEN 2 underwent annual screening for elevated calcitonin levels; however, this only detected MTC after it developed. In 1993 it was identified that mutations in the RET proto-oncogene were present in almost all cases of MEN 2a and 2b. Now family members of MEN patients can be screened for the presence of a RET mutation. Those without the mutation need not undergo additional screening, whereas those with the mutation should undergo total thyroidectomy at a young age (6 years for MEN 2a, infancy for MEN 2b).49

The readers are reminded that older or elderly patients will increasingly make up the population of patients with cancer. Currently 60% of all malignancies, and 70% of all cancer deaths, occur in people over the age of 65.58 In addition to the previously mentioned considerations, assessment of the older patient should include evaluation of activities of daily living, depression, cognitive function, current medications and potential medication interactions, and available social support.59–62

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  12. Fisher B, Remond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822–828.

Quality of surgery: has the time come for colon cancer?
Lancet (Oncology)   Feb 2015; 16  
http://dx.doi.org/10.1016/S1470-2045(14)71223-9

Major improvements in outcomes for rectal cancer have occurred in the 30 years since the introduction of total mesorectal excision and multidisciplinary treatment.1 This situation should continue to improve with more radical surgery for low rectal cancer. Pioneering work by leaders of rectal cancer surgery was initially ignored and it took the independent reproduction of the improved outcomes in single hospital and small regional studies before large-scale regional and national training programs led to major reductions in local recurrence, significant improvements in survival, and major financial savings occurred around the world. Colon cancer accounts for around 70% of bowel cancer and although survival has improved, it has not been to the same extent as that for rectal cancer, with substantial variation remaining between hospitals for operative cases. Historical reports have shown significantly improved survival in colon cancer following surgical standardization,2–4 and excellent results from Japan have largely been ignored.5 The rectal cancer story is repeating itself. Colonic cancer resection in western countries is unfortunately still viewed as a routine procedure with little concern surrounding these major variations in outcome. Indeed the focus has been on laparoscopic surgery rather than optimisation of the surgery. In The Lancet Oncology, a paper by Claus Anders Bertelsen and colleagues,6 and the debate it should generate, is a key step to reproduce the benefits of optimum rectal cancer surgery in colonic cancer, and hints at what could be achievable by the routine adoption of high-quality surgery. In this detailed report, the researchers show that implementation of complete mesocolic excision (CME) with central vascular ligation (CVL) results in a major improvement in survival. By simply visiting and adopting the methods of expert surgeons in Erlangen, led by Werner Hohenberger,4 and by quality controlling their surgery through mesocolic grading, routine specimen photography, and internal and external pathology audit,7 the researchers have independently reproduced results from Erlangen and Japan. The improvement in outcome described could be attributable to two specific variables; first, CME, which comprises the intact removal of the mesocolon and its lymphatic drainage within embryological planes. This procedure should be routine; it does not increase risks to the patient and might seem obvious since careful dissection following anatomical planes is a basic principle of surgery and such planes were described in the early 20th century, but on close scrutiny surgical planes are very variable and must be improved.8,9 Second, but more controversially, is the role of CVL. This procedure entails more radical central dissection, with potential risk to major vessels, nerves, and organs such as the pancreas. In Erlangen, Japan, and now in Hillerød, such surgery seems to be safe, but several important questions remain. How much benefit does it convey in addition to mesocolic surgery? What is the learning curve and is this achievable for all surgeons? Can it be safely achieved laparoscopically? Is the same benefi t derived for all stages of disease?

Radiation therapy in the locoregional treatment of triple-negative breast cancer
Meena S Moran
Lancet Oncol 2015; 16: e113–22

This Review assesses the relevant data and controversies regarding the use of radiotherapy for, and locoregional management of, women with triple-negative breast cancer (TNBC). In view of the strong association between BRCA1 and TNBC, knowledge of baseline mutation status can be useful to guide locoregional treatment decisions. TNBC is not a contraindication for breast conservation therapy because data suggest increased locoregional recurrence risks (relative to luminal subtypes) with breast conservation therapy or mastectomy. Although a boost to the tumour bed should routinely be considered after whole breast radiation therapy, TNBC should not be the sole indication for postmastectomy radiation, and accelerated delivery methods for TNBC should be off ered on clinical trials. Preliminary data implying a relative radioresistance for TNBC do not imply radiation omission because radiation provides an absolute locoregional risk reduction. At present, the integration of subtypes in locoregional management decisions is still in its infancy. Until level 1 data supporting treatment decisions based on subtypes are available, standard locoregional management principles should be adhered to.

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Somatic, germ-cell, and whole sequence DNA in cell lineage and disease profiling

Curator: Larry H Bernstein, MD, FCAP

In humans, mitochondrial DNA spans about 16,500 DNA building blocks (base pairs), representing a small fraction of the total DNA in cells. Mitochondrial DNA contains 37 genes, essential for normal mitochondrial function and thirteen of them provide instructions for making enzymes involved in inner membrane function. The remaining 24 genes are transcribed into transfer RNA (tRNA) and ribosomal RNA (rRNA), which are needed to transfer amino acids into proteins.

Somatic mutations occur in the DNA of certain cells during a person’s lifetime and typically are not passed to future generations.  They differ from germ-line mutations that have a lineal descent from the maternal parent, and they occur later in life.  Mutations in the sperm DNA are not carried on to future generations, as the sperm mitochondria are destroyed after the egg is fertilized.

There is limited evidence linking somatic mutations in mitochondrial DNA with certain cancers, including breast, colon, stomach, liver, and kidney tumors. These mutations might also be associated with cancer of blood-forming tissue (leukemia) and cancer of immune system cells (lymphoma).  There are many heritable diseases that are related to germ-line mutations, and germ-line mutations have a role in many common diseases.  Mitochondrial DNA is particularly vulnerable to the effects of reactive oxygen species (ROS), and with a limited ability of the mitochondrion to repair itself, ROS easily damage mitochondrial DNA.  The repair mechanism is tied to ubiquitinylation system.  A  list of disorders associated with mitochondrial genes  is provided from Wikipedia.

Inherited changes in mitochondrial DNA may be associated with pathologies in growth and development, and multiorgan system disorders, as mutations disrupt the mitochondria’s ability to generate the cell’s energy. The effects of these conditions are most pronounced in organs and tissues with high energy requirements (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, some frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision.

A buildup of somatic mutations in mitochondrial DNA has been considered to have a role in or associated with increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease, and the severity of many mitochondrial disorders is thought to be associated with the percentage of mitochondria affected by a particular genetic change. Consequently, the progressive accumulation of these mutations over a person’s lifetime may play a role in aging.

Mitochondrial DNA is typically diagrammed as a circular structure with genes and regulatory regions labeled.

Mitochondrial DNA

Mitochondrial DNA

http://ghr.nlm.nih.gov/html/images/chromosomeIdeograms/mitochondria/wholeMitochondria.jpg

Additional Resources:

  • Additional NIH Resources – National Institutes of Health

NHGRI Talking Glossary: Mitochondrial DNA

mtDNA : The Eve Gene –  by Stephen Oppenheimer

Mutations are a cumulative dossier of our own maternal prehistory. The main task of DNA is to copy itself to each new generation. We can use these mutations to reconstruct a genetic tree of mtDNA, because each new mtDNA mutation in a prospective mother’s ovum will be transferred in perpetuity to all her descendants down the female line. Each new female line is thus defined by the old mutations as well as the new ones.

By looking at the DNA code in a sample of people alive today, and piecing together the changes in the code that have arisen down the generations, biologists can trace the line of descent back in time to a distant shared ancestor. Because we inherit mtDNA only from our mother, this line of descent is a picture of the female genealogy of the human species.

formation of gene trees

formation of gene trees

The diagram above shows the drawing of gene trees using single mutations

http://www.bradshawfoundation.com/journey/images/gene-diagram3.gif

Not only can we retrace the tree, but by taking into account here the sampled people came from, we can see where certain mutations occurred – for example, whether in Europe, or Asia, or Africa. What’s more, because the changes happen at a statistically consistent (though random) rate, we can approximate the time when they happened.  This has made it possible, during the late 1990s and in the new century, for us to do something that anthropologists of the past could only have dreamt of: we can now trace the migrations of modern humans around our planet.

It turns out that the oldest changes in our mtDNA took place in Africa 150,000 – 190,000 years ago. Then new mutations start to appear in Asia, about 60,000 – 80,000 years ago. This tells us that modern humans evolved in Africa, and that some of us migrated out of Africa into Asia after 80,000 years ago.  A method established in 1996, which dates each branch of the gene tree by averaging the number of new mutations in daughter types of that branch, has stood the test of time.

A final point on the methods of genetic tracking of migrations: it is important to distinguish this new approach to tracing the history of molecules on a DNA tree, known as phylogeography (literally ‘tree-geography’), from the mathematical study of the history of whole human populations, which has been used for decades and is known as classical population genetics.

The two disciplines are based on the same Mendelian biological principles, but have quite different aims and assumptions, and the difference is the source of much misunderstanding and controversy. The simplest way of explaining it is that phylogeography studies the prehistory of individual DNA molecules, while population genetics studies the prehistory of populations. Put another way, each human population contains multiple versions of any particular DNA molecule, each with its own history and different origin.

gene-diagram

gene-diagram

The diagram above shows the tracing of gene spread geographically.
Green disks represent migrant new growth on the tree
http://www.bradshawfoundation.com/journey/images/gene-diagram4.gif

http://www.bradshawfoundation.com/journey/eve.html

David Moskowitz, MD, PhD
Founder and President, GenoMed

 

Germline genes make the best drug targets

  • They operate earliest in the disease pathway
  • Unlike tissue-expressed genes, which operate years after the disease began
  • But which everybody else is using as drug targets

Variation in germline DNA is where all disease starts

  • Cancer patients overexpress oncogenes and underexpress tumor suppressors

beginning in their germline DNA

  • Mutations in tumor DNA are “private”
  • Each tumor is a “snowflake”

Tumor-expressed genes can be compensatory, not causative

  • “Passengers, not drivers”
  • We have the drivers

Tumorigenesis SNPs

Using a SNPnet™ covering only 1/3 of the genome, we found about

2,500 genes associated with each of 6 different cancers in whites

  • Nobody else has found any yet
  • This will change in 2-3 years

We estimate 10,000 genes per cancer

What cellular program takes up 1/3-1/2 of the genome?

What program takes up >1/3 of the genome?

  • Differentiation…

Does sporadic cancer arise when a tissue stem cell fails to differentiate?

  • In the embryo, the surrounding tissue expresses “fields”

Lent C. Johnson published a “field” based hypothesis of bone tumors that coincides with differentiation at the

  1. METAPHYSIS
  2. HYPOPHYSIS

and the type CELL – chondroblast, osteoblast, giant cell (osteoclast), fibroblast

Orthopedic surgeons use magnetic fields for healing

  • of powerful transcription factors.
  • Not so in adult life: a proliferating tissue stem cell is literally on its own.

Germlines hold the key to effective “differentiation therapy”

  • Ideal for patients with stage 3-4 cancer
  • Examples of differentiation therapy:
  1. 1,25-vitamin D and
  2. retinoic acid

Non-toxic but more effective treatment for late stage disease,

GenoMed’s 2,500 cancer-causing genes:

  • ½ are oncogenes,
  • ½ are tumor suppressors

Design inhibitors to oncogenes

  • Screen 1st for toxicity;
  • genomic epidemiology guarantees clinical efficacy

 

Jewish Heritage Written in DNA

By Kate Yandell | Sept 9, 2014

Fully sequenced genomes of more than 100 Ashkenazi people clarify the group’s history and provide a reference for researchers and physicians trying to pinpoint disease-associated genes.

A whole-genome sequence study from 128 healthy Jewish people is aimed at identifying disease-associated variants in the jewish population of Ashkenazi ancestry, according to a study published Sept 9 in Nature Communications. The library of sequences confirms earlier conclusions about Ashkenazi history hinted at by more limited DNA sequencing studies. The sequences point to an approximate 350-person bottleneck in the Ashkenazi population as recently as 700 years ago (1400 A.D.), and suggest that the population has a mixture of European and Middle Eastern ancestry.

The study “provides a very nice reference panel for the very unique population of Ashkenazi Jews,” said Alon Keinan, who studies human population genomics at Cornell University in New York. Keinan
is acknowledged in the study but was not involved in the research.

“One might have thought that, after many years of genetic studies relating to Ashkenazi Jews . . . there would be little room for additional insights,” Karl Skorecki of the Rambam Healthcare Campus
in Israel who also was not involved in the study wrote in an e-mail to The Scientist. The study, he added, provides “a powerful further validation and further resolution of the demographic history of
the Ashkenazi Jews in relation to non-Jewish Europeans that is reassuringly consistent with inferences drawn from two decades of studies using uniparental regions . . . and from array-based data.”

Itsik Pe’er, coauthor of the new study and an associate professor of computer science at Columbia University in New York City, recalled that several years ago, he and his colleagues kept running into the same problem as they tried to understand the genetics of disease in Ashkenazi populations. They were comparing their Ashkenazi samples to the only control genomes that were available, which were of largely non-Jewish European origin. The Ashkenazi genomes had variation that was absent in these general European genomes, making it hard to distinguish rare variants in Ashkenazi people.

“Technology is there to tell us everything in that [Ashkenazi] patient’s genome, but the genome was not there to distinguish the variants that are there and to tell us whether they are normal or whether we should get worried,” said Pe’er. Pe’er’s group teamed up with researchers from additional universities and hospitals in the U.S., Belgium, and Israel to sequence a collection of healthy Ashkenazi people’s genomes. The panel of reference sequences performs better than a group of European genomes at filtering out harmless variants from Ashkenazi Jewish genomes, thereby making it easier to identify potentially harmful ones. According to Pe’er, researchers will also be able to use the panel to infer
more complete sequences from partially sequenced genomes by looking for familiar sequences from the reference genomes.

The team also used its data to better understand the history of the Ashkenazi Jewish people through analyzing both level of similarity within Ashkenazi genomes and between Ashkenazi and non-Jewish
European genomes. By analyzing the length of identical DNA sequences that Ashkenazi individuals share, the researchers were able to estimate that 25 to 32 generations ago, the Ashkenazi Jewish population shrunk to just several hundred people, before expanding rapidly to eventually include the millions of Ashkenazi Jews alive today. Further, the researchers concluded that modern Ashkenazi Jews likely have an approximately even mixture of European and Middle Eastern ancestry. This suggests that after the Jewish people migrated from the Middle East to Europe, they recruited people from local European populations.

These results are compatible with those of prior work on mitochondrial DNA (mtDNA), which is passed on maternally. This prior work suggested that Ashkenazi men from the Middle East intermarried with local European women. The Ashkenazi population “hasn’t been likely as isolated as at least some researchers considered,” said Keinan.

Finally, the newly sequenced genomes shed light on the deeper history of Europe, showing that the European and Middle Eastern portions of Ashkenazi ancestry diverged just around 20,000 years ago.

“This is, I think, the first evidence from whole human genomes that the most important wave of settlement from the Near East was most likely shortly after the Last Glacial Maximum  . . . and, notably, before the Neolithic transitionwhich is what researchers working on mitochondrial DNA have been arguing for some years,” Martin Richards, an archeogeneticist at the University of Huddersfield in the U.K., told The Scientist in an e-mail.

Skorecki noted that the new study “demonstrates the utility of sequencing whole genomes in a diverse population… with sufficient numbers of samples, parent population information, and
computational analytic power, we can expect important and surprising utilities for personal genomic and insights in terms of human demographic history from whole genomes.”

  1. Carmi et al., “Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins,” Nature
    Communications,
    http://dx.doi.org:/10.1038/ncomms5835, 2014.

Added Layers of Proteome Complexity

By Anna Azvolinsky | July 17, 2014

Scientists discover a broad spectrum of alternatively spliced human protein variants within a well-studied family of genes.

There may be more to the human proteome than previously thought. Some genes are known to have several different alternatively spliced protein variants, but the Scripps Research Institute’s Paul Schimmel and his colleagues have now uncovered almost 250 protein splice variants of an essential, evolutionarily conserved family of human genes. The results were published today (July 17) in Science.

Focusing on the 20-gene family of aminoacyl tRNA synthetases (AARSs), the team captured AARS transcripts from human tissues—some fetal, some adult—and showed that many of these messenger RNAs (mRNAs) were translated into proteins. Previous studies have identified
several splice variants of these enzymes that have novel functions, but uncovering so many more variants was unexpected, Schimmel said. Most of these new protein products lack the catalytic domain but retain other AARS non-catalytic functional domains. “The main point is that a vast new area of biology, previously missed, has been uncovered,”
said Schimmel.

“This is an incredible study that fundamentally changes how we look at the protein-synthesis machinery,” Michael Ibba, a protein translation researcher at Ohio State University who was not involved in the work, told The Scientist in an e-mail. “The unexpected and potentially vast
expanded functional networks that emerge from this study have the potential to influence virtually any aspect of cell growth.”

The team—including researchers at the Hong Kong University of Science and Technology, Stanford University, and aTyr Pharma, a San Diego-based biotech company that Schimmel co-founded—comprehensively captured and sequenced the AARS mRNAs from six human tissue types using high-throughput deep sequencing. While many of the transcripts were expressed in each of the tissues, there was also some tissue specificity.

Next, the team showed that a proportion of these transcripts, including those missing the catalytic domain, indeed resulted in stable protein products: 48 of these splice variants associated with polysomes. In vitro translation assays and the expression of more than 100 of these variants in cells confirmed that many of these variants could be made into
stable protein products.

The AARS enzymes—of which there’s one for each of the 20 amino acids—bring together an amino acid with its appropriate transfer RNA (tRNA) molecule. This reaction allows a ribosome to add the amino acid to a growing peptide chain during protein translation. AARS
enzymes can be found in all living organisms and are thought to be among the first proteins to have originated on Earth.

To understand whether these non-catalytic proteins had unique biological activities, the researchers expressed and purified recombinant AARS fragments, testing them in cell-based assays for proliferation, cell differentiation, and transcriptional regulation, among other
phenotypes. “We screened through dozens of biological assays and found that these variants operate in many signaling pathways,” said Schimmel.

“This is an interesting finding and fits into the existing paradigm that, in many cases, a single gene is processed in various ways [in the cell] to have alternative functions,” said Steven Brenner, a computational genomics researcher at the University of California, Berkeley.

The team is now investigating the potentially unique roles of these protein splice variants in greater detail—in both human tissue as well as in model organisms. For example, it is not yet clear whether any of these variants directly bind tRNAs.

“I do think [these proteins] will play some biological roles,” said Tao Pan, who studies the functional roles of tRNAs at the University of Chicago. “I am very optimistic that interesting biological functions will come out of future studies on these variants.”

Brenner agreed. “There could be very different biological roles [for some of these proteins]. Biology is very creative that way, [it’s] able to generate highly diverse new functions using combinations of existing protein domains.” However, the low abundance of these variants
is likely to constrain their potential cellular functions, he noted.

Because AARSs are among the oldest proteins, these ancient enzymes were likely subject to plenty of change over time, said Karin Musier-Forsyth, who studies protein translational
at the Ohio State University. According to Musier-Forsyth, synthetases are already known to have non-translational functions and differential localizations. “Like the addition of post-translational modifications, splicing variation has evolved as another way to repurpose protein function,” she said.

One of the protein variants was able to stimulate skeletal muscle fiber formation ex vivo and upregulate genes involved in muscle cell differentiation and metabolism in primary human skeletal myoblasts. “This was really striking,” said Musier-Forsyth. “This suggests
that, perhaps, peptides derived from these splice variants could be used as protein-based therapeutics for a variety of diseases.”

W.S. Lo et al., “Human tRNA synthetase catalytic nulls with diverse functions,” Science, http://dx.doi.org:/10.1126/science.1252943, 2014.

It’s Not Only in DNA’s Hands

By Ilene Schneider  LabRoots   Aug 22, 2014

Blood stem cells have the potential to turn into any type of blood cell, whether it is the oxygen-carrying red blood cells or the immune system’s many types of white blood cells that help fight infection. How exactly is the fate of these stem cells regulated? Preliminary findings from research conducted by scientists from the Weizmann Institute of Science and the Hebrew University are starting to reshape the conventional understanding of the way blood stem cell fate decisions are controlled, thanks to a new technique for epigenetic analysis developed at these institutions. Understanding epigenetic mechanisms (environmental influences other than genetics) of cell fate could lead to the deciphering of the molecular mechanisms of many diseases,
including immunological disorders, anemia, leukemia, and many more. The study of epigenetics also lends strong support to findings that environmental factors and lifestyle play a more prominent
role in shaping our destiny than previously realized.

 

The process of differentiation – in which a stem cell becomes a specialized mature cell – is controlled by a cascade of events in which specific genes are turned “on” and “off” in a highly regulated and accurate order. The instructions for this process are contained within the DNA itself in short regulatory sequences.

  • These regulatory regions are normally in a “closed” state, masked by special proteins called histones to ensure against unwarranted activation. Therefore, to access and “activate”
    the instructions,
  • this DNA mask needs to be “opened” by epigenetic modifications of the histones so it can be read by the necessary machinery.

In a paper published in Science, Dr. Ido Amit and David Lara-Astiaso of the Weizmann Institute’s Department of Immunology, along with Prof. Nir Friedman and Assaf Weiner of the Hebrew University of Jerusalem, charted – for the first time – histone dynamics during blood development. Thanks to the new technique for epigenetic profiling they developed, in which just a handful of cells – as few as 500 – can be sampled and analyzed accurately, they have identified the exact
DNA sequences, as well as the various regulatory proteins, that are involved in regulating the process of blood stem cell fate.

This research has also yielded unexpected results: As many as

  • 50% of these regulatory sequences are established and opened during intermediate stages of cell development.

The meaning of the research is that epigenetics can be active at stages in which it had been thought that cell destiny was already set. “This changes our whole understanding of the process of blood stem cell fate decisions,” says Lara-Astiaso, “suggesting that the process is more
dynamic and flexible than previously thought.”

Although this research was conducted on mouse blood stem cells, the scientists believe that the mechanism may hold true for other types of cells. “This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” says Weiner.

Largest Cancer Genetic Analysis Reveals New Way of Classifying Cancer

http://www.biosciencetechnology.com/news/2014/08/largest-cancer-genetic-analysis-reveals-new-way-classifying-cancer

Thu, 08/07/2014 – 2:24pm

Researchers with The Cancer Genome Atlas (TCGA) Research Network have completed the largest, most diverse tumor genetic analysis ever conducted, revealing a new approach to classifying cancers. The work, led by researchers at the UNC Lineberger Comprehensive
Cancer Center at the University of North Carolina at Chapel Hill and other TCGA sites, not only

  • revamps traditional ideas of how cancers are diagnosed and treated, but could also have
  • a profound impact on the future landscape of drug development.

“We found that one in 10 cancers analyzed in this study would be classified differently using this new approach,” said Chuck Perou, PhD, professor of genetics and pathology, UNC Lineberger member and senior author of the paper, which appears online Aug. 7 in Cell.
“That means that

  • 10 percent of the patients might be better off getting a different therapy—that’s huge.”

Since 2006, much of the research has identified cancer as not a single disease, but many types and subtypes and has defined these disease types based on the tissue—breast, lung, colon, etc.—in which it originated. In this scenario, treatments were tailored to which
tissue was affected, but questions have always existed because some treatments work, and fail for others, even when a single tissue type is tested.

In their work, TCGA researchers analyzed more than 3,500 tumors across 12 different tissue types to see how they compared to one another — the largest data set of tumor genomics ever assembled, explained Katherine Hoadley, PhD, research assistant professor
in genetics and lead author. They found that

  • cancers are more likely to be genetically similar based on the type of cell in which the cancer originated, compared to the type of tissue in which it originated. 

This is fundamental premise of pathology! (Larry Bernstein)  It goes back to Rudolph Virchow. 

“In some cases, the cells in the tissue from which the tumor originates are the same,” said Hoadley. “But in other cases, the tissue in which the cancer originates is made up of multiple types of cells that can each give rise to tumors. Understanding the cell in which the cancer originates appears to be very important in determining the subtype of a tumor
and, in turn, how that tumor behaves and how it should be treated.”

Perou and Hoadley explain that the new approach may also shift how cancer drugs are developed, focusing more on the development of drugs targeting larger groups of cancers with genomic similarities, as opposed to a single tumor type as they are currently developed.

One striking example of the genetic differences within a single tissue type is breast cancer.
The breast, a highly complex organ with multiple types of cells, gives rise to multiple types of breast cancer; luminal A, luminal B, HER2-enriched and basal-like, which was previously known. In this analysis, the basal-like breast cancers looked more like ovarian cancer
and cancers of a squamous-cell type origin, a type of cell that composes the lower-layer of a tissue, rather than other cancers that arise in the breast.

“This latest research further solidifies that basal-like breast cancer is an entirely unique disease and is completely distinct from other types of breast cancer,” said Perou. In addition, bladder cancers were also quite diverse and might represent at least three different disease types that also showed differences in patient survival.

As part of the Alliance for Clinical Trials in Oncology, a national network of researchers conducting clinical trials, UNC researchers are already testing the effectiveness of carboplatin—a common treatment for ovarian cancer—on top of standard of care chemotherapy for triple-negative breast cancer (TNBC) patients, of which 80 percent are the basal-like subtype. The results of this study (called CALGB40603)
were just published on Aug. 6 in the Journal of Clinical Oncology and showed a benefit of carboplatin in TNBC patients. This new clinical trial result suggests that there may be great value in comparing clinical results across tumor types for which this study highlights as having common genomic similarities.

As participants in TCGA, UNC Lineberger scientists have been involved in multiple individual tissue type studies including most recently an analysis of a comprehensive genomic profile of lung adenocarcinoma. Perou’s seminal work in 2000 led to the first discovery of breast
cancer as not one, but in fact, four distinct subtypes of disease.  These most recent findings should continue to lay the groundwork for what could be the next generation of cancer diagnostics.

Source: University of North Carolina at Chapel Hill School of Medicine

New Gene Tied to Breast Cancer Risk

Wed, 08/06/2014

Marilynn Marchione – AP Chief Medical Writer – Associated Press

It’s long been known that faulty BRCA genes greatly raise the risk for breast cancer. Now, scientists say a more recently identified, less common gene can do the same.

Mutations in the gene can make breast cancer up to nine times more likely to develop, an international team of researchers reports in this week’s New England Journal of Medicine.

About 5 to 10 percent of breast cancers are thought to be due to bad BRCA1 or BRCA2 genes. Beyond those, many other genes are thought to play a role but how much each one raises risk has not been known, said Dr. Jeffrey Weitzel, a genetics expert at City of Hope Cancer Center
in Duarte, Calif.

The new study on the gene- called PALB2 – shows “this one is serious,” and probably is the most dangerous in terms of breast cancer after the BRCA genes, said Weitzel, one of leaders of the study.

It involved 362 members of 154 families with PALB2 mutations – the largest study of its kind. The faulty gene seems to give a woman a 14 percent chance of breast cancer by age 50 and 35 percent by age 70 and an even greater risk if she has two or more close relatives with the disease.

That’s nearly as high as the risk from a faulty BRCA2 gene, Dr. Michele Evans of the National Institute on Aging and Dr. Dan Longo of the medical journal staff write in a commentary in the journal.

The PALB2 gene works with BRCA2 as a tumor suppressor, so when it is mutated, cancer can flourish.

How common the mutations are isn’t well known, but it’s “probably more than we thought because people just weren’t testing for it,” Weitzel said. He found three cases among his own breast cancer
patients in the last month alone.

Among breast cancer patients, BRCA mutations are carried by 5 percent of whites and 12 percent of Eastern European (Ashkenazi) Jews. PALB2 mutations have been seen in up to 4 percent of families with a history of breast cancer.

 Men with a faulty PALB2 gene also have a risk for breast cancer that is eight times greater than men in the general population.

Testing for PALB2 often is included in more comprehensive genetic testing, and the new study should give people with the mutation better information on their risk, Weitzel said. Doctors say that people with faulty cancer genes should be offered genetic counseling and may want to consider more frequent screening and prevention options, which can range from hormone-blocking pills to breast removal.

The actress Angelina Jolie had her healthy breasts removed last year after learning she had a defective BRCA1 gene.

The study was funded by many government and cancer groups around the world and was led by Dr. Marc Tischkowitz of the University of Cambridge in England. The authors include Mary-Clare King, the University of Washington scientist who discovered the first breast
cancer predisposition gene, BRCA1.

Study: http://www.nejm.org/doi/full/10.1056/NEJMoa1400382

Gene info: http://ghr.nlm.nih.gov/gene/PALB2

Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide

Eric S. Fischer, Kerstin Böhm, John R. Lydeard, Haidi Yang, …, J. Wade Harper, Jeremy L. Jenkins & Nicolas H. Thomä

Nature (07 Aug 2014); 512, 49–53  http://dx.doi.org:/10.1038/nature13527

Published online 16 July 2014

In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide,

  • these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for
    multiple myeloma and 5q-deletion-associated dysplasia.
  • IMiDs target the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4CRBN) and
  • promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4CRBN.

Here we present crystal structures of the DDB1–CRBN complex bound to thalidomide,
lenalidomide and pomalidomide. The structure establishes that

  • CRBN is a substrate receptor within CRL4CRBN and enantioselectively binds IMiDs.

Using an unbiased screen, we identified the

  • homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN.

Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN while the ligase complex is recruiting IKZF1 or IKZF3 for degradation.

This dual activity implies that

  • small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.

Curator’s Viewpoint:

The short pieces may not appear to be so closely connected, except for the last subject on the pharmaceutical targeting of an E3 ubiquitin ligase ubiquitination of proteins, but even in that case, we have to keep in mind that protein formation by amino acid transcription, remodeling, and recapture of amino acids are in equilibrium through ubiquitylation. So I put it there.  The DNA in populations ties some mutations to disease that is tied specifically to populations, not only the sephardic population, but in Asia as well.

The next article for consideration is methodological considerations.  The BRCA2 in the sephardic population is one of a number of mutations we can identify, extending to Tay Sachs disease, for instance.  How this might have occurred in the history of the jewish people is not so obvious, except perhaps in the segregation of the jewish population for centuries.  The mutation would be confined within the population with limited marriage outside of the jewish community.  It has been known for some time that there is a Cohen gene that traces back to the priests (Kohanim) of the Holy Temple, the descendents of Aaron (Aharon), the brother of Moses.  The priests would stand at the Ark and bless the congregation in the most holy convocation of Yom Kippur, according to tradition.  Marriages were arranged between the bride and the groom.  Of course, arranged marriages were also the case in other ethnic communities, and between the privileged.

That was dramatically the case during the reign of Queen Victoria of England, with Royal arrangements across Europe.
That would be a factor in the transmission of hemophilia, and in mental disorders in the Royal families. Haemophilia figured prominently in the history of European royalty in the 19th and 20th centuries. Britain’s Queen Victoria, through two of her five daughters (Princess Alice and Princess Beatrice), passed the mutation to various royal houses across the continent, including the royal families of Spain, Germany and Russia. Victoria’s son Prince Leopold, Duke of Albany suffered from the disease.  The Prince Leopold, Duke of Albany KG KT GCSI GCMG GCStJ (Leopold George Duncan Albert; 7 April 1853 – 28 March 1884) was the eighth child and fourth son of Queen Victoria and Prince Albert of Saxe-Coburg and Gotha. Leopold was later created Duke of Albany, Earl of Clarence, and Baron Arklow. He had haemophilia, which led to his death at the age of 30.  The sex-linked X chromosome disorder manifests almost entirely in males, although the gene for the disorder is located on the X chromosome and may be inherited from either mother or father. Expression of the disorder is much more common in males than in females. This is because, although the trait is recessive, males only inherit one X chromosome, from their mothers. Of course, this is classical Mendelian genetics. Victoria appears to have been a spontaneous or de novo mutation and is usually considered the source of the disease in modern cases of haemophilia among royalty. The mutation would probably be assumed today to have occurred at the conception of Princess Alice, as she was the only known carrier among Victoria and Albert’s first seven children. Leopold was a sufferer of haemophilia and her daughters Alice and Beatrice were confirmed carriers of the gene.

Cousin marriage is marriage between people with a common grandparent or other more distant ancestor. In various cultures and legal jurisdictions,  Marriages between first and second cousins account for over 10% of marriages worldwide, and they are common in the Middle East, where in some nations they account for over half of all marriages. Proportions of first-cousin marriage in the United States, Europe and other Western countries like Brazil have declined since the 19th century, though even during that period they were not more than 3.63 percent of all unions in Europe. Cousin marriage is allowed throughout the Middle East for all recorded history, and is used mostly in Syria. It has often been chosen to keep cultural values intact through many generations and preserve familial wealth. In Iraq the right of the cousin has also traditionally been followed and a girl breaking the rule without the consent of the ibn ‘amm could have ended up murdered by him. The Syrian city of Aleppo during the 19th century featured a rate of cousin marriage among the elite of 24% according to one estimate, a figure that masked widespread variation: some leading families had none or only one cousin marriage, while others had rates approaching 70%. Cousin marriage rates were highest among women, merchant families, and older well-established families.  The percentage of Iranian cousin marriages increased from 34 to 44% between the 1940s and 1970s. Cousin marriage among native Middle Eastern Jews is generally far higher than among the European Ashkenazim, who assimilated European marital practices after the diaspora.

The essential elements of the marriage contract were now an offer by the man, an acceptance by the woman, and the performance of such conditions as the payment of dowry. According to anthropologist Ladislav Holý, cousin marriage is not an independent phenomenon but rather one expression of a wider Middle Eastern preference for agnatic solidarity, or solidarity with one’s father’s lineage.

A 2009 study found that many Arab countries display some of the highest rates of consanguineous marriages in the world, and that first cousin marriages which may reach 25-30% of all marriages. Research among Arabs and worldwide has indicated that consanguinity could have an effect on some reproductive health parameters such as postnatal mortality and rates of congenital malformations.

In the terraced streets of Bradford, Yorkshire, a child’s death is anything but rare. At the boy’s inquest, coroner Mark Hinchliffe said Hamza Rehman had died because his Pakistan-born parents (shopkeeper Abdul and housewife Rozina) are first cousins. Muslims have practiced marriages between first cousins in non-prohibited countries since the time of the Quran.

Four years before, Hamza’s older sister, three-month-old Khadeja, had died of the same brain disorder which causes fits, sickness and chest infections. The couple had another baby born with equally devastating neurological problems.

A heartbroken Mr Rehman told the inquest that he and his wife were unsure whether to have any more children. The coroner expressed deep sympathy before saying that Hamza’s death should serve as a warning to others.

I have diverged somewhat onto the genetic risks of consanguinous marriages, which George Darwin, son of Charles Darwin, argues were had a small effect in then English society.  But most importantly, we see the larger factor here of social and familial inheritance, and also the concept of cultural identity.

Insofar as the somatic and mitochondrial mutations are concerned, I call attention to the finding in the GWAS study above discussed that the results were supportive of the conclusions from mtDNA.  This gives some reason to consider whether sufficient information is obtained from the mtDNA, without the more robust GWAS.  One cannot fully consider this without some knowledge of the methodology of specimen preparation.

It is not difficult to prepare mitochondria from cells and obtain a very good preparation before further analysis, whether of the membrane structures, the enzymatic activity, or of the DNA and RNA polynucleotides.  The separation is easily achieved with differential centrifugation.  On the other hand, the finding of the basal layer of epithelium having a different signature than the superficial layer, established by the genomic studies, but known histologically for non-neoplastic tissue, is a matter for cell separation methods that are not easy.  It is from the lower layer of cells that we derive carcinoma in-situ.  These cells were identified in breast, are expected to be found in uterus, and were like the cells in ovarian-cancer, which suggested the use of a common treatment regimen as adjunct in triple negative breast cancer and ovarian cancer.  The importance of a suuficiently prepared cellular specimen as opposed to tissue specimen can’t be taken for granted.

 

 

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