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Sunitinib brings Adult Acute Lymphoblastic Leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Health Economics and Outcomes Research, Interviews with Scientific Leaders, Medical and Population Genetics, Nephrology, Nephrology & Regenerative medicine, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, tagged Acute lymphoblastic leukemia, Cancer - General, Chromosome 13, compassionate use program, DNA, DNA Sequencing, FLT3 gene on CHromosome 13, FLT3 receptor blockage, kidney cancer, New York Times, progression-free survival, RNA sequencing, sequencing, Sunitinib, Washington University in St. Louis on July 9, 2012| 12 Comments »

Sunitinib brings Adult Acute Lymphoblastic Leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade

Curator: Aviva Lev-Ari, PhD, RN

Article ID #1: Sunitinib brings Adult Acute Lymphoblastic Leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade. Published on 7/9/2012

WordCloud Image Produced by Adam Tubman

Word Cloud by Daniel Menzin

Updated 11/13/2013

Pazopanib versus Sunitinib in Renal Cancer

N Engl J Med 2013; 369:1968-1970November 14, 2013DOI: 10.1056/NEJMc1311795

Article

To the Editor:

Cancer treatments are expensive. The estimation of the total cost can be challenging because of several factors such as efficacy, toxicity, and the costs and duration of supportive care and end-of-life care. Motzer et al. (Aug. 22 issue)1 report similar efficacy but a favorable safety and quality-of-life profile and less medical resource utilization with pazopanib as compared with sunitinib in first-line therapy for metastatic renal cancer. Since oncology is becoming an increasingly value-based specialty, we wanted to highlight another important aspect of this trial. Pazopanib appears to be favorable not only in terms of safety and quality of life, but also in terms of overall cost. A 30-day supply of pazopanib (at a dose of 800 mg daily) ranges from $3,500 to $8,556, whereas a 30-day supply of sunitinib (at a dose of 50 mg daily) ranges from $4,500 to $13,559.2 The total cost of pazopanib during the median progression-free survival of 8.4 months is $29,400 to $71,870, and the total cost of sunitinib during the median progression-free survival of 9.5 months is $42,750 to $127,454. Less toxicity and less medical resource utilization with pazopanib will most likely further lower the overall costs of treatment with this agent. Comparative-effectiveness trials hold great promise for maximizing patient safety, improving treatment outcomes, and reducing costs.

Ryan Ramaekers, M.D.
Mark Tharnish, Pharm.D.
M. Sitki Copur, M.D.
Saint Francis Cancer Treatment Center, Grand Island, NE
mcopur@sfmc-gi.org

No potential conflict of interest relevant to this letter was reported.

2 References

To the Editor:

Motzer et al. report a combined analysis of two open-label noninferiority trials (927 patients in the original trial and 183 patients in a second trial), each of which compared pazopanib with sunitinib with respect to progression-free survival in renal-cell carcinoma. Quality-of-life outcomes were subjective.

Analysis of noninferiority trials is notoriously difficult.1,2 The authors’ analysis of the trials, which was open-label because of the different administration schedules of the drugs, presents problems in interpreting progression-free survival and quality of life. The studies define disease progression differently. The larger study defined progression-free survival according to independent review. The protocol for the smaller study states that progression-free survival “will be summarized . . . based on the investigator assessment.” Inference from subjective outcomes in unmasked trials (e.g., quality of life in both studies and progression-free survival in the smaller study and therefore in the combined analysis) is subject to well-known bias. Moreover, the article does not state how many of the 379 participants (34%) who discontinued the intervention before death or disease progression (see Fig. S2 in the Supplementary Appendix, available with the full text of the article at NEJM.org) were assessed for progression-free survival. A fair comparison must use rigorous methods to handle missing data.3 Since the article did not deal appropriately with missing data, its conclusions regarding noninferiority are uninterpretable.

Janet Wittes, Ph.D.
Statistics Collaborative, Washington, DC
janet@statcollab.com

Dr. Wittes reports that her company, Statistics Collaborative, has consulting agreements with both GlaxoSmithKline and Pfizer, the manufacturers of the drugs discussed in the article by Motzer et al. In addition, Statistics Collaborative has contracts with several other companies that produce drugs for patients with cancer. No other potential conflict of interest relevant to this letter was reported.

3 References

To the Editor:

Motzer et al. state that “the results of the progression-free survival analysis in the per-protocol population were consistent with the results of the primary analysis.” However, the predefined margin of noninferiority (<1.25) was not met. The upper limit of the confidence interval (1.255) was clearly above the defined threshold.1 In a noninferiority trial, the use of the intention-to-treat population is generally nonconservative,2 the full analysis set and the per-protocol analysis set are considered to have equal importance, and the use of the intention-to-treat population should lead to similar conclusions for a robust interpretation.3 Thus, it is surprising that the authors did not come to or discuss the same conclusions as that of the French National Authority for Health4: “serious doubt exists about the noninferiority result of pazopanib compared to sunitinib” and “the clinical significance of the noninferiority threshold defined in the protocol was an efficacy loss of 2.2 months in the median progression-free survival. This is too large for patients.”

Jochen Casper, M.D.
Silke Schumann-Binarsch, M.D.
Claus-Henning Köhne, M.D.
Klinikum Oldenburg, Oldenburg, Germany
casper.jochen@klinikum-oldenburg.de

Dr. Casper reports receiving consulting fees from Bayer, Novartis, and Pfizer and speaking fees from Novartis and Pfizer. No other potential conflict of interest relevant to this letter was reported.

4 References

The authors reply: In reply to Ramaekers et al.: we agree that decisions regarding the provision of health care include economic evaluations to identify treatments that provide the best clinical benefit at an acceptable cost.

To clarify a point in the letter by Wittes: the primary end point of this phase 3 trial was progression-free survival evaluated by an independent review committee; these data were assessed for all 1110 patients from both trials. This is specified in the protocol. The consistency of the quality-of-life results with the observed differences in the safety profiles for the two drugs speaks to the absence of bias in the quality-of-life outcome. The number of patients in whom follow-up ended before progression was assessed by the independent review committee was balanced between the two groups: 156 patients in the pazopanib group (28%) and 168 patients in the sunitinib group (30%). To Wittes’s final point regarding rigorous methods to handle missing data: the algorithm for assigning disease-progression and censoring dates followed the Guidance for Industry of the Food and Drug Administration1 and is included in the protocol of our article.

In reply to Casper et al.: there is no consensus regarding whether the per-protocol population is more conservative than the intention-to-treat population for the noninferiority analysis.2,3Reviews of noninferiority trials indicate that the per-protocol population is not generally more conservative than the intention-to-treat population, and there are scenarios in which the per-protocol analysis itself could introduce bias.3 A systematic review indicated that more than 70% of published findings from noninferiority trials in oncology show results in only the intention-to-treat population and not in the per-protocol population.4 Our phase 3 trial had a single primary analysis in the intention-to-treat population, with the per-protocol population included as a key sensitivity analysis, as supported by Fleming et al.5 No formal hypothesis testing was planned for the per-protocol population, nor was the trial powered for this. Consistency of the point estimates was desired to show an absence of bias due to the analysis population. This absence of bias was shown by the consistency of the hazard ratios (1.07 in the per-protocol analysis vs. 1.05 in the primary analysis). For an underpowered per-protocol comparison, it is inappropriate for Casper et al. to interpret that the upper bound that barely exceeded 1.25 in our per-protocol analysis is an indication of inconsistency of results across the two populations. The noninferiority margin was selected in consultation with oncology experts, and justification of the margin is in the protocol.

Robert J. Motzer, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY
motzerr@mskcc.org

Lauren McCann, Ph.D.
Keith Deen, M.S.
GlaxoSmithKline, Collegeville, PA

Since publication of their article, the authors report no further potential conflict of interest.

REFERENCES

Food and Drug Administration. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. May 2007 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf).

Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996;313:36-39[Erratum, BMJ 1996;313:550.]
CrossRef | Web of Science | Medline

Brittain E, Lin D. A comparison of intent-to-treat and per-protocol results in antibiotic non-inferiority trials. Stat Med 2005;24:1-10
CrossRef | Web of Science | Medline

Tanaka S, Kinjo Y, Kataoka Y, Yoshimura K, Termukai S. Statistical issues and recommendations for noninferiority trials in oncology: a systematic review. Clin Cancer Res 2012;18:1837-1847
CrossRef | Web of Science | Medline

Fleming TR, Odem-Davis K, Rothmann MD, Li Shen Y. Some essential considerations in the design and conduct of non-inferiority trials. Clin Trials2011;8:432-439
CrossRef | Web of Science | Medline

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMc1311795?query=TOC

Original Article Published on 7/9/2012

July 6, 2012 NY Times reports on a new approach based on DNA and RNA sequencing and a cancer drug for kidney cancer to bring REMISSION to Adult acute lymphoblastic leukemia (ALL).

On the lower left corner of this page – Watch the VIDEO

second-chance.html

Dr. Lukas Wartman, is a Cancer Researcher specializing in Leukemia. He suspected he had Leukemia, the very disease he had devoted his medical career to studying.

After years of treatment and two relapses of ALL, he has exhaused all conventional approaches to his disease. At Washington University in St. Louis, his colleagues in the lab, decoded Dr. Wartman’s genetic information by genome sequencing techniques t determine the genetic cause of his ALL. The team found an overactive gne, FLT3 on Chromosome 13. The gene was treated with pfizer’s Suntinib drug for advanced kidney cancer.

Blood samples free of ALL found in days after using the drug. As results were very promising, Pfizer, the drug’s maker who has turned down Dr. Wartman’s request for the drug under their compassionate use program, though he explained that his entire salary was only enough to pay for 7 1/2 months of Sutent (Suntinib). While he does not know why Pfizer gave him the drug finally, he suspects it was the plea of his Nurse Practitioner, Stephanie Bauer, NP.

Identification of the genetic cause for his ALL, thus discovering a breakthough in understanding and treatment for ALL in other patients, involved the following steps:

SAMPLE

two tissue samples taken from Dr. Wartman’s Bone marrow and skin cells

SEQUENCE

Extracts of DNA and RNA from Dr. Wartman’s cells, two types of genetic material tested

COMPARISON

DNA sequesnces showed genetic mutations possibly related to his ALL, none seemed treatable. However, RNA sequencing revealed that a normal Gene, FLT3, on cheomozome 13, was overactive in his leukemia cells

TARGETING

The FLT3 gene helps create new white blod cells in the bone marrow. Dr. Wartman’s marrow bone cells were covered with an extreme number of FLT3 receptors which possibly caused the growth of his leukemia.

TREATMENT – Receptor Blockade 

Drug known to block FLT3 receptor, Sunitinib, used for kedney cancer treatment, was given to Dr. Wartman. Two weeks after Dr, Wartman began taking the drug, tests revealed that his leukenia was in remission.

NEW MARKETS FOR FLT3  GENE BLOCKADE DRUG  – KIDNEY CANCER AND LEUKEMIA

Pfizer has NOW a NEW market for Sunitinib — All CANCER PATIENTS DIAGNOSED WITH Adult acute lymphoblastic leukemia (ALL) where an overactive FLT3 gene on chomosome 13 is found.

NEW TREATMENT OPTIONS FOR Adult acute lymphoblastic leukemia (ALL)

Thus, any (ALL) diagnosed patient needs to be tested for Chromosome 13, ONLY rather then the entire genome sequencing of the Patient. If FLT3 is not found overactive, THEN proceed with entire genome sequencing of the Patient. IF another gene is overactive FIND DRUG FOR RECEPTOR BLOCKADE.

SIZING THE MARKET FOR FLT3 BLOCKADE DRUGS: KIDNEY CANCER vs LEUKEMIA

The Market for Adult ALL is much bigger than the market for kidney cancer. Thus, this discovery regarding the remission of Dr. Wartman’s remission following two relapses is so significant for Pfizer and for any patient with the diagnosis of Adult ALL.

I recommend the reader to click on the links and follow the reactions of the public to this article in The New York Times.

http://www.nytimes.com/2012/07/08/health/in-gene-sequencing-treatment-for-leukemia-glimpses-of-the-future.html?pagewanted=all

Read HUNDREDS of Comments by Cancer Patients and the readers of The New York Times Health Section

http://www.nytimes.com/2012/07/08/health/in-gene-sequencing-treatment-for-leukemia-glimpses-of-the-future.html?pagewanted=all#commentsContainer

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History of medicine, science, and society: 200 Years of the New England Journal of Medicine

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Infectious Disease & New Antibiotic Targets, Medical and Population Genetics, Population Health Management, Genetics & Pharmaceutical, tagged Allan M. Brandt, Ether Dome, John Collins Warren, Massachusetts General Hospital, Massachusetts Medical Society, Medical Knowledge, New England, New England Journal of Medicine, Science and Medicine, Therapeutic innovations on July 2, 2012| 1 Comment »

New England Journal of Medicine an Interview with Allan M. Brandt, Ph.D.

N Engl J Med 2012; 366:1-7 January 5, 2012

http://www.nejm.org/doi/full/10.1056/NEJMp1112812

Reporter: Aviva Lev-Ari PhD, RN

With this issue, the New England Journal of Medicine marks its 200th anniversary. In January 1812, as the first issue came off the handset letterpress, few of its founders could have predicted such continuity and success. (See Figure 1FIGURE 1Illustration from “Cases of Organic Diseases of the Heart and Lungs,” by John C. Warren, April 1, 1812, Issue of the Journal., from an 1812 issue.) John Collins Warren, the renowned Boston surgeon, his colleague James Jackson, a founder of Massachusetts General Hospital, and the small group of distinguished colleagues who joined them in starting the New England Journal of Medicine and Surgery, and the Collateral Branches of Science expressed modest and largely local aspirations for the enterprise. Boston, a growing urban center, and the wider New England environs had no medical journal of their own, although much medical knowledge and practice was considered region-specific. Although the name and format of the Journal would vary until 1928, 7 years after its ownership passed to the Massachusetts Medical Society, it remains the longest continuously published medical periodical in the world. The prospectus for the Journal, a call for papers issued in late 1811, explained the goals of Warren and his collaborators: “The editors have been encouraged to attempt this publication by the opinion, that a taste for medical literature has greatly increased in New England within a few years past. New methods of practice, good old ones which are not sufficiently known, and occasional investigations of the modes in common use, when thus distributed among our medical brethren in the country, will promote a disposition for inquiry and reflection, which cannot fail to produce the most happy results.”1

At a time of intense debate and controversy regarding the causes of disease, the nature of therapeutics, and the basis of professional authority, the young Journal worked to steer a middle course. This was certainly advisable from a commercial point of view, since it could easily alienate diverse medical readers by endorsing a particular therapeutic system or theory. But this approach also established the ecumenical temper of theJournal, which based its early publications on a commitment to empirical observation and an outlook skeptical of conventional medical wisdoms. As the editors explained in 1837, “It has been a point of ambition with us . . . to make these pages the vehicle of useful intelligence, rather than the field of warfare. . . . The Journal is to all intents and purposes, designed to be a record of medical and surgical facts. It is the medium through which the profession may interchange sentiments and publish the results of their experience” (see Historical Journal Articles Cited).

THE ENDURING PROBLEM OF DISEASE

The observation and investigation of disease is perhaps the most salient consistent feature of theJournal. From the meticulous description of angina pectoris in the first issue to the early descriptions of AIDS in the early 1980s, there has been an ongoing recognition that therapeutic approaches must await the sharp articulation of symptoms. The first decades of the Journal‘s history reflected the intensive concern with the epidemics affecting New England and the new nation, and it was not unusual during the early years for authors to direct attention to the environment as a critical variable in the production of disease. John Gorham, an editor writing in 1828, offered a “Medical Report of the Weather and Prevalent diseases for the last Three months.” Such articles may appear both quaint and humorous from our contemporary scientific perch, but they reveal a serious commitment to understanding more fully the vagaries of epidemic disease that could devastate town and country in short order. Furthermore, they offer a complex notion of causality that characterized much 19th-century medicine, in which disease was seen as the result of interactions of the patient’s individual “constitution” with an ever-changing and often dangerous environment.2 By the late 20th century, many observers would renew concerns voiced more than a century earlier about the environment’s relationship to disease.

DOCUMENTING THERAPEUTIC INNOVATION

The Journal provides a powerful record of the course taken by medical science and its applications over a 200-year period. It quickly became a conduit for reporting new investigations and findings and for summarizing and disseminating evolving medical knowledge across the widest range of practice. After issuing favorable reports on bloodletting, herbal treatments, and other “heroic” practices of the early 19th century, the Journal began to reflect a growing skepticism toward such approaches. Authors increasingly pointed to the benefits of the healing powers of nature — vis medicatrix naturae — as physicians came to recognize some of the iatrogenic effects of their interventions that had previously been difficult to differentiate from the course of serious disease.3Therapeutics based on ancient notions of humoral excess and depletion gave way to a renewed emphasis on empirical observation and experiment. The first demonstration of surgical anesthesia, conducted at Massachusetts General Hospital in 1846 in an amphitheater soon to be renamed the “Ether Dome,” was first reported in the Journal (Figure 2FIGURE 2“First Operation under Ether,” 1846, with Related Journal Report.). Others quickly began using ether in their practices. One surgeon wrote in the Journal, “I performed the amputation of an arm, the second under the use of ether, while the patient was dreaming of her harvest labors in Ireland, and felt grating but not painful sensations, `as if a reaping-hook was in her arm’” (1850).

EDUCATION AND THE DISSEMINATION OF MEDICAL KNOWLEDGE

From the beginning, the Journal has critically covered essential debates about the character and quality of medical education. The editors considered one of their primary goals to be educating the profession, so assessment of medical school programs was in harmony with their mission; after all, these schools produced their readers. In the late 19th century, the Journal frequently noted the great inconsistencies in educational standards and quality. A decade before the publication of the Flexner reforms, prominent Boston physician Henry Bowditch anticipated many key aspects of the report when he called for linking medical education to universities, lengthening the course of study, and demanding deeper preparation in the sciences and wider domains of knowledge (1900). He argued for active learning to replace didactics, a theme that would echo through the debates about medical education. As late as 1900, when Bowditch proposed his reforms in the Journal, less than half the students at Harvard Medical School had completed a college education. After the publication of the Flexner Report in 1910 and the massive changes that followed, the Journalapplauded the consolidation of medical education on a new scientific foundation.

TOO MUCH TO KNOW

With the radical expansion and shifting of the scientific basis of medicine at the turn of the 20th century, the Journal recorded growing interest in and concern about specialization. From a largely undifferentiated notion of medical training and expertise, many new and specific divisions of the medical profession developed.6 Whereas the Journal came to view specialization as the inevitable result of exploding medical knowledge, the creation of medical “specializm” was viewed with considerable skepticism and lamentation, if not outright hostility. Much ink was spilled in attempts to determine the relationship of general knowledge and practice to increasingly specific (and limited) areas of expertise. How would the “whole patient” be treated when specialties had divided the body into organ systems and medicine into categories of disease and authority over various technologies and techniques?

THE PERMEABLE BOUNDARIES OF SCIENCE AND MEDICINE

Despite the Journal‘s deep commitment to empirical reasoning and scientific rationality, cultural and political beliefs and values are ever apparent in its pages. In some instances, professional prerogatives and social assumptions are exposed. For example, when the introduction of women students at Harvard Medical School was debated in 1878, the Journal expressed concern: “It would . . . be impossible to avoid an indiscriminate mingling of the sexes in the dissecting or autopsy rooms, and in the amphitheatres, to witness exercises which justly have hitherto been thought of a character to be witnessed by one sex alone.” Harvard would ultimately admit women in 1945, when the war caused a shortage of male candidates. In the 1950s, the Journal expressed regret that some women physicians with children “have found it impossible to carry on their practices” (1954).

REFLECTIONS ON THE JOURNAL AT 200

While the Journal embraced new science and the critical apparatus of peer review, it rejected a narrow notion of specialism, continuing to cover the widest range of contributions to medical knowledge. In an increasingly atomized medical world, the commitment to publish on cross-cutting educational, professional, ethical, and policy issues pulled together diverse readers, including physicians and other health care providers, public health experts, and policymakers, around issues that were often beyond their immediate expertise. The radical growth of teaching hospitals, federal funding for basic science and clinical research, and academic medical centers (all developments reflected in the Journal) have been crucially linked to the Journal‘s growth, stability, and success.

During the Journal’s first 200 years of publication, medicine and health care moved from the social periphery to become dominant aspects of our science, culture, and economy. The Journalunquestionably owes its success and stability to this monumental shift in the status, authority, and impact of biomedicine. But the Journal has also played a critical role in these developments. By combining a commitment to publishing papers of scrupulous scientific merit across wide-ranging domains, with a recognition of the central questions and values uniting the profession, the Journalhas remained true to its founders’ vision. It has recognized that advances in medical science can finally be assessed only in the context of delivery, care, and outcome. The Journal reflects today, as at its inception, a view that medical science and its applications are fundamentally tied to patient care and public health. It therefore continues to draw a range of readers wider than Warren could have imagined. Today, the ability to disseminate publications so widely through digital technologies promises to bring innovations in medical knowledge to a new set of global constituents. The first hundred issues of Warren’s journal were, of course, distributed on horseback.

HISTORICAL JOURNAL ARTICLES CITED.

New England Journal of Medicine and Surgery, and the Collateral Branches of Science

1812. Warren J. Remarks on Angina Pectoris. 1:1-11.

The Boston Medical and Surgical Journal

1828. Gorham J. Medical report of the weather and prevalent diseases for the last three months. 1:10-12.

1832. Editorials and Medical Intelligence. 6:401-2.

1837. Editorials and Medical Intelligence. 16:16-17.

1846. Bigelow HJ. Insensibility during surgical operations produced by inhalation. 35:309-17.

1850. Peirson AL. Anæsthetic agents. 42:229-32.

1871. Seaverns J. Recent advances in medicine and their influence on therapeutics. 85:113-20.

1878. Reports of Meetings. Female medical students at Harvard. 98:786-7.

1891. Ernst HC. Records for cases of tuberculosis treated with Koch’s parataloid. 124:75.

1900. Bowditch HP. The medical school of the future. 142:445-53.

1919. Editorial. Science and medical teaching. 180:108-9.

1923. Phippen WG. The relation of the specialist to the general practitioner. 189:204-6.

1924. Specialism versus Competence. 190:475-6.

1926. Editorial. The teaching of medicine. 195:1124-5.

1928. Appel KE. Medical education: the retrospect of a recent graduate. 197:1265-7.

The New England Journal of Medicine

1928. Lombard HL, Doering CR. Cancer studies in Massachusetts: habits, characteristics and environment of individuals with and without cancer. 198:481-7.

1928. Editorial. Sterilization of defectives. 199:1225-6.

1934. Editorial. Sterilization and its possible accomplishments. 211:379-80.

1935. Henderson LJ. Physician and patient as a social system. 212:819-23.

1939. Mallory TB. Richard Clarke Cabot and the clinicopathologic conference. 220:880.

1948. The Case Records of the Massachusetts General Hospital. 239:690.

1949. Alexander L. Medical science under dictatorship. 241:39-47.

1954. Editorial. Practice of medicine by married women. 250:486.

1966. Beecher HK. Ethics and clinical research. 274:1354-60.

1970. Swan HJC, Ganz W, Forrester J, et al. Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter. 283:447-51.

1981. Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men. 305:1425-31.

1981. Masur H, Michelis MA, Greene JB, et al. An outbreak of community-acquired Pneumocystis carinii pneumonia. 305:1431-8.

1981. Siegal FP, Lopez C, Hammer GS, et al. Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. 305:1439-44.

Special Anniversary Articles

We are publishing a series of engaging Review and Perspective articles from established authors who are preeminent in their fields. Each article explores a story of progress in medicine over the past 200 years. These articles will appear every other week during 2012 and be collected here. Check the News & Eventssection of this site for announcements about upcoming articles.

http://nejm200.nejm.org/explore/special-anniversary-articles/

Two Hundred Years of Surgery

Atul Gawande, M.D., M.P.H.

N Engl J Med 2012; 366:1716-1723 May 3, 2012

Two Hundred Years of Cancer Research

Vincent T. DeVita, Jr., M.D., and Steven A. Rosenberg, M.D., Ph.D.

N Engl J Med 2012; 366:2207-2214 June 7, 2012

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