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Archive for the ‘Automated Cell Processing’ Category


Reporter: Irina Robu, PhD

Using the century-old cutting method, it would take a researcher five hours to cut 100 cells, and by the time they were done, the cells they cut first would be well on their way to healing.

In an effort to comprehend how a single cell heal, mechanical engineer Sing Tand developed a microscopic guillotine that proficiently cuts cells into two.

Tang, who is an assistant professor of mechanical engineering at Stanford University knew that finding a way to competently slice the cell in two could lead to engineering self-healing materials and machines. In order, to efficiently slice a cell in two he developed a tool that could cut 150 cells in just over 2 minutes, and the cuts were much more standardized and synchronized in the stage of their repair process. They attained this rate by creating a scaled-up version of their tool with eight identical parallel channels that run simultaneously. Being able to efficiently study cell healing could eventually help scientists study and treat a variety of human diseases such as cancer and neurodegenerative diseases. Prior to Tang’s cellular guillotine, scientists used to slice cells by hand under a microscope using a glass needle which is a method that can lead to errors.

Tang’s method can be the Holy Grail of engineering self-healing materials and machines.

SOURCE

http://news.stanford.edu/2017/06/26/stanford-scientists-create-cellular-guillotine-studying-single-cell-wound-repair/

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Treatment of Lymphomas [2.4.4C]

Larry H. Bernstein, MD, FCAP, Author, Curator, Editor

http://pharmaceuticalinnovation.com/2015/8/11/larryhbern/Treatment-of-Lymphomas-[2.4.4C]

 

Lymphoma treatment

Overview

http://www.emedicinehealth.com/lymphoma/page8_em.htm#lymphoma_treatment

The most widely used therapies are combinations of chemotherapyand radiation therapy.

  • Biological therapy, which targets key features of the lymphoma cells, is used in many cases nowadays.

The goal of medical therapy in lymphoma is complete remission. This means that all signs of the disease have disappeared after treatment. Remission is not the same as cure. In remission, one may still have lymphoma cells in the body, but they are undetectable and cause no symptoms.

  • When in remission, the lymphoma may come back. This is called recurrence.
  • The duration of remission depends on the type, stage, and grade of the lymphoma. A remission may last a few months, a few years, or may continue throughout one’s life.
  • Remission that lasts a long time is called durable remission, and this is the goal of therapy.
  • The duration of remission is a good indicator of the aggressiveness of the lymphoma and of the prognosis. A longer remission generally indicates a better prognosis.

Remission can also be partial. This means that the tumor shrinks after treatment to less than half its size before treatment.

The following terms are used to describe the lymphoma’s response to treatment:

  • Improvement: The lymphoma shrinks but is still greater than half its original size.
  • Stable disease: The lymphoma stays the same.
  • Progression: The lymphoma worsens during treatment.
  • Refractory disease: The lymphoma is resistant to treatment.

The following terms to refer to therapy:

  • Induction therapy is designed to induce a remission.
  • If this treatment does not induce a complete remission, new or different therapy will be initiated. This is usually referred to as salvage therapy.
  • Once in remission, one may be given yet another treatment to prevent recurrence. This is called maintenance therapy.

Chemotherapy

Many different types of chemotherapy may be used for Hodgkin lymphoma. The most commonly used combination of drugs in the United States is called ABVD. Another combination of drugs, known as BEACOPP, is now widely used in Europe and is being used more often in the United States. There are other combinations that are less commonly used and not listed here. The drugs that make up these two more common combinations of chemotherapy are listed below.

ABVD: Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), and dacarbazine (DTIC-Dome). ABVD chemotherapy is usually given every two weeks for two to eight months.

BEACOPP: Bleomycin, etoposide (Toposar, VePesid), doxorubicin, cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), and prednisone (multiple brand names). There are several different treatment schedules, but different drugs are usually given every two weeks.

The type of chemotherapy, number of cycles of chemotherapy, and the additional use of radiation therapy are based on the stage of the Hodgkin lymphoma and the type and number of prognostic factors.

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/Patient/page1

Key Points for This Section

Adult non-Hodgkin lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

Because lymph tissue is found throughout the body, adult non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.

Non-Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information on the treatment of non-Hodgkin lymphoma during pregnancy

Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children, however, is different than treatment for adults. (See the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information.)

There are many different types of lymphoma.

Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult non-Hodgkin lymphoma. For information about other types of lymphoma, see the following PDQ summaries:

Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin lymphoma.

If cancer is found, the following tests may be done to study the cancer cells:

  • Immunohistochemistry : A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.
  • Cytogenetic analysis : A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
  • Immunophenotyping : A process used to identify cells, based on the types of antigens ormarkers on the surface of the cell. This process is used to diagnose specific types of leukemia and lymphoma by comparing the cancer cells to normal cells of the immune system.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer.
  • The type of non-Hodgkin lymphoma.
  • The amount of lactate dehydrogenase (LDH) in the blood.
  • The amount of beta-2-microglobulin in the blood (for Waldenström macroglobulinemia).
  • The patient’s age and general health.
  • Whether the lymphoma has just been diagnosed or has recurred (come back).

Stages of adult non-Hodgkin lymphoma may include E and S.

Adult non-Hodgkin lymphoma may be described as follows:

E: “E” stands for extranodal and means the cancer is found in an area or organ other than the lymph nodes or has spread to tissues beyond, but near, the major lymphatic areas.

S: “S” stands for spleen and means the cancer is found in the spleen.

Stage I adult non-Hodgkin lymphoma is divided into stage I and stage IE.

  • Stage I: Cancer is found in one lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen).
  • Stage IE: Cancer is found in one organ or area outside the lymph nodes.

Stage II adult non-Hodgkin lymphoma is divided into stage II and stage IIE.

  • Stage II: Cancer is found in two or more lymph node groups either above or below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIE: Cancer is found in one or more lymph node groups either above or below the diaphragm. Cancer is also found outside the lymph nodes in one organ or area on the same side of the diaphragm as the affected lymph nodes.

Stage III adult non-Hodgkin lymphoma is divided into stage III, stage IIIE, stage IIIS, and stage IIIE+S.

  • Stage III: Cancer is found in lymph node groups above and below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIIE: Cancer is found in lymph node groups above and below the diaphragm and outside the lymph nodes in a nearby organ or area.
  • Stage IIIS: Cancer is found in lymph node groups above and below the diaphragm, and in the spleen.
  • Stage IIIE+S: Cancer is found in lymph node groups above and below the diaphragm, outside the lymph nodes in a nearby organ or area, and in the spleen.

In stage IV adult non-Hodgkin lymphoma, the cancer:

  • is found throughout one or more organs that are not part of a lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen), and may be in lymph nodes near those organs; or
  • is found in one organ that is not part of a lymphatic area and has spread to organs or lymph nodes far away from that organ; or
  • is found in the liver, bone marrow, cerebrospinal fluid (CSF), or lungs (other than cancer that has spread to the lungs from nearby areas).

Adult non-Hodgkin lymphomas are also described based on how fast they grow and where the affected lymph nodes are in the body.  Indolent & aggressive.

The treatment plan depends mainly on the following:

  • The type of non-Hodgkin’s lymphoma
  • Its stage (where the lymphoma is found)
  • How quickly the cancer is growing
  • The patient’s age
  • Whether the patient has other health problems
  • If there are symptoms present such as fever and night sweats (see above)

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Treatment for Chronic Leukemias [2.4.4B]

Larry H. Bernstein, MD, FCAP, Author, Curator, Editor

https://pharmaceuticalintelligence.com/2015/8/11/larryhbern/Treatment-for-Chronic-Leukemias-[2.4.4B]

2.4.4B1 Treatment for CML

Chronic Myelogenous Leukemia Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/page4

Treatment Option Overview

Key Points for This Section

There are different types of treatment for patients with chronic myelogenous leukemia.

Six types of standard treatment are used:

  1. Targeted therapy
  2. Chemotherapy
  3. Biologic therapy
  4. High-dose chemotherapy with stem cell transplant
  5. Donor lymphocyte infusion (DLI)
  6. Surgery

New types of treatment are being tested in clinical trials.

Patients may want to think about taking part in a clinical trial.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Follow-up tests may be needed.

There are different types of treatment for patients with chronic myelogenous leukemia.

Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information about new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Six types of standard treatment are used:

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia.

Imatinib mesylate, nilotinib, dasatinib, and ponatinib are tyrosine kinase inhibitors that are used to treat CML.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Biologic therapy

Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

High-dose chemotherapy with stem cell transplant

High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Donor lymphocyte infusion (DLI)

Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant.Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.

Surgery

Splenectomy

What`s new in chronic myeloid leukemia research and treatment?

http://www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-new-research

Combining the targeted drugs with other treatments

Imatinib and other drugs that target the BCR-ABL protein have proven to be very effective, but by themselves these drugs don’t help everyone. Studies are now in progress to see if combining these drugs with other treatments, such as chemotherapy, interferon, or cancer vaccines (see below) might be better than either one alone. One study showed that giving interferon with imatinib worked better than giving imatinib alone. The 2 drugs together had more side effects, though. It is also not clear if this combination is better than treatment with other tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib. A study going on now is looking at combing interferon with nilotinib.

Other studies are looking at combining other drugs, such as cyclosporine or hydroxychloroquine, with a TKI.

New drugs for CML

Because researchers now know the main cause of CML (the BCR-ABL gene and its protein), they have been able to develop many new drugs that might work against it.

In some cases, CML cells develop a change in the BCR-ABL oncogene known as a T315I mutation, which makes them resistant to many of the current targeted therapies (imatinib, dasatinib, and nilotinib). Ponatinib is the only TKI that can work against T315I mutant cells. More drugs aimed at this mutation are now being tested.

Other drugs called farnesyl transferase inhibitors, such as lonafarnib and tipifarnib, seem to have some activity against CML and patients may respond when these drugs are combined with imatinib. These drugs are being studied further.

Other drugs being studied in CML include the histone deacetylase inhibitor panobinostat and the proteasome inhibitor bortezomib (Velcade).

Several vaccines are now being studied for use against CML.

2.4.4.B2 Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Treatment (PDQ®)

General Information About Chronic Lymphocytic Leukemia

Key Points for This Section

  1. Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
  2. Leukemia may affect red blood cells, white blood cells, and platelets.
  3. Older age can affect the risk of developing chronic lymphocytic leukemia.
  4. Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
  5. Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
  6. Certain factors affect treatment options and prognosis (chance of recovery).
  7. Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is one of the most common types of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children.

http://www.cancer.gov/images/cdr/live/CDR755927-750.jpg

Anatomy of the bone; drawing shows spongy bone, red marrow, and yellow marrow. A cross section of the bone shows compact bone and blood vessels in the bone marrow. Also shown are red blood cells, white blood cells, platelets, and a blood stem cell.

Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Leukemia may affect red blood cells, white blood cells, and platelets.

Normally, the body makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell becomes one of three types of mature blood cells:

  1. Red blood cells that carry oxygen and other substances to all tissues of the body.
  2. White blood cells that fight infection and disease.
  3. Platelets that form blood clots to stop bleeding.

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

  1. B lymphocytes that make antibodies to help fight infection.
  2. T lymphocytes that help B lymphocytes make antibodies to fight infection.
  3. Natural killer cells that attack cancer cells and viruses.
Blood cell development. CDR526538-750

Blood cell development. CDR526538-750

http://www.cancer.gov/images/cdr/live/CDR526538-750.jpg

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

In CLL, too many blood stem cells become abnormal lymphocytes and do not become healthy white blood cells. The abnormal lymphocytes may also be called leukemia cells. The lymphocytes are not able to fight infection very well. Also, as the number of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding.

This summary is about chronic lymphocytic leukemia. See the following PDQ summaries for more information about leukemia:

  • Adult Acute Lymphoblastic Leukemia Treatment.
  • Childhood Acute Lymphoblastic Leukemia Treatment.
  • Adult Acute Myeloid Leukemia Treatment.
  • Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
  • Chronic Myelogenous Leukemia Treatment.
  • Hairy Cell Leukemia Treatment

Older age can affect the risk of developing chronic lymphocytic leukemia.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for CLL include the following:

  • Being middle-aged or older, male, or white.
  • A family history of CLL or cancer of the lymph system.
  • Having relatives who are Russian Jews or Eastern European Jews.

Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.

Usually CLL does not cause any signs or symptoms and is found during a routine blood test. Signs and symptoms may be caused by CLL or by other conditions. Check with your doctor if you have any of the following:

  • Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
  • Feeling very tired.
  • Pain or fullness below the ribs.
  • Fever and infection.
  • Weight loss for no known reason.

Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.

The following tests and procedures may be used:

Physical exam and history : An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.

Complete blood count (CBC) with differential : A procedure in which a sample of blood is drawn and checked for the following:

The number of red blood cells and platelets.

The number and type of white blood cells.

The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.

The portion of the blood sample made up of red blood cells.

Results from the Phase 3 Resonate™ Trial

Significantly improved progression free survival (PFS) vs ofatumumab in patients with previously treated CLL

  • Patients taking IMBRUVICA® had a 78% statistically significant reduction in the risk of disease progression or death compared with patients who received ofatumumab1
  • In patients with previously treated del 17p CLL, median PFS was not yet reached with IMBRUVICA® vs 5.8 months with ofatumumab (HR 0.25; 95% CI: 0.14, 0.45)1

Significantly prolonged overall survival (OS) with IMBRUVICA® vs ofatumumab in patients with previously treated CLL

  • In patients with previously treated CLL, those taking IMBRUVICA® had a 57% statistically significant reduction in the risk of death compared with those who received ofatumumab (HR 0.43; 95% CI: 0.24, 0.79; P<0.05)1

Typical treatment of chronic lymphocytic leukemia

http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-treating-treatment-by-risk-group

Treatment options for chronic lymphocytic leukemia (CLL) vary greatly, depending on the person’s age, the disease risk group, and the reason for treating (for example, which symptoms it is causing). Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn’t been shown to help people live longer. Because of this and because treatment can cause side effects, doctors often advise waiting until the disease is progressing or bothersome symptoms appear, before starting treatment.

If treatment is needed, factors that should be taken into account include the patient’s age, general health, and prognostic factors such as the presence of chromosome 17 or chromosome 11 deletions or high levels of ZAP-70 and CD38.

Initial treatment

Patients who might not be able to tolerate the side effects of strong chemotherapy (chemo), are often treated with chlorambucil alone or with a monoclonal antibody targeting CD20 like rituximab (Rituxan) or obinutuzumab (Gazyva). Other options include rituximab alone or a corticosteroid like prednisione.

In stronger and healthier patients, there are many options for treatment. Commonly used treatments include:

  • FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab
  • Bendamustine (sometimes with rituximab)
  • FR: fludarabine and rituximab
  • CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
  • CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
  • Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab
  • PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
  • Alemtuzumab (Campath)
  • Fludarabine (alone)

Other drugs or combinations of drugs may also be also used.

If the only problem is an enlarged spleen or swollen lymph nodes in one region of the body, localized treatment with low-dose radiation therapy may be used. Splenectomy (surgery to remove the spleen) is another option if the enlarged spleen is causing symptoms.

Sometimes very high numbers of leukemia cells in the blood cause problems with normal circulation. This is calledleukostasis. Chemo may not lower the number of cells until a few days after the first dose, so before the chemo is given, some of the cells may be removed from the blood with a procedure called leukapheresis. This treatment lowers blood counts right away. The effect lasts only for a short time, but it may help until the chemo has a chance to work. Leukapheresis is also sometimes used before chemo if there are very high numbers of leukemia cells (even when they aren’t causing problems) to prevent tumor lysis syndrome (this was discussed in the chemotherapy section).

Some people who have very high-risk disease (based on prognostic factors) may be referred for possible stem cell transplant (SCT) early in treatment.

Second-line treatment of CLL

If the initial treatment is no longer working or the disease comes back, another type of treatment may help. If the initial response to the treatment lasted a long time (usually at least a few years), the same treatment can often be used again. If the initial response wasn’t long-lasting, using the same treatment again isn’t as likely to be helpful. The options will depend on what the first-line treatment was and how well it worked, as well as the person’s health.

Many of the drugs and combinations listed above may be options as second-line treatments. For many people who have already had fludarabine, alemtuzumab seems to be helpful as second-line treatment, but it carries an increased risk of infections. Other purine analog drugs, such as pentostatin or cladribine (2-CdA), may also be tried. Newer drugs such as ofatumumab, ibrutinib (Imbruvica), and idelalisib (Zydelig) may be other options.

If the leukemia responds, stem cell transplant may be an option for some patients.

Some people may have a good response to first-line treatment (such as fludarabine) but may still have some evidence of a small number of leukemia cells in the blood, bone marrow, or lymph nodes. This is known as minimal residual disease. CLL can’t be cured, so doctors aren’t sure if further treatment right away will be helpful. Some small studies have shown that alemtuzumab can sometimes help get rid of these remaining cells, but it’s not yet clear if this improves survival.

Treating complications of CLL

One of the most serious complications of CLL is a change (transformation) of the leukemia to a high-grade or aggressive type of non-Hodgkin lymphoma called diffuse large cell lymphoma. This happens in about 5% of CLL cases, and is known as Richter syndrome. Treatment is often the same as it would be for lymphoma (see our document called Non-Hodgkin Lymphoma for more information), and may include stem cell transplant, as these cases are often hard to treat.

Less often, CLL may transform to prolymphocytic leukemia. As with Richter syndrome, these cases can be hard to treat. Some studies have suggested that certain drugs such as cladribine (2-CdA) and alemtuzumab may be helpful.

In rare cases, patients with CLL may have their leukemia transform into acute lymphocytic leukemia (ALL). If this happens, treatment is likely to be similar to that used for patients with ALL (see our document called Leukemia: Acute Lymphocytic).

Acute myeloid leukemia (AML) is another rare complication in patients who have been treated for CLL. Drugs such as chlorambucil and cyclophosphamide can damage the DNA of blood-forming cells. These damaged cells may go on to become cancerous, leading to AML, which is very aggressive and often hard to treat (see our document calledLeukemia: Acute Myeloid).

CLL can cause problems with low blood counts and infections. Treatment of these problems were discussed in the section “Supportive care in chronic lymphocytic leukemia.”

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Treatments other than Chemotherapy for Leukemias and Lymphomas

Author, Curator, Editor: Larry H. Bernstein, MD, FCAP

2.5.1 Radiation Therapy 

http://www.lls.org/treatment/types-of-treatment/radiation-therapy

Radiation therapy, also called radiotherapy or irradiation, can be used to treat leukemia, lymphoma, myeloma and myelodysplastic syndromes. The type of radiation used for radiotherapy (ionizing radiation) is the same that’s used for diagnostic x-rays. Radiotherapy, however, is given in higher doses.

Radiotherapy works by damaging the genetic material (DNA) within cells, which prevents them from growing and reproducing. Although the radiotherapy is directed at cancer cells, it can also damage nearby healthy cells. However, current methods of radiotherapy have been improved upon, minimizing “scatter” to nearby tissues. Therefore its benefit (destroying the cancer cells) outweighs its risk (harming healthy cells).

When radiotherapy is used for blood cancer treatment, it’s usually part of a treatment plan that includes drug therapy. Radiotherapy can also be used to relieve pain or discomfort caused by an enlarged liver, lymph node(s) or spleen.

Radiotherapy, either alone or with chemotherapy, is sometimes given as conditioning treatment to prepare a patient for a blood or marrow stem cell transplant. The most common types used to treat blood cancer are external beam radiation (see below) and radioimmunotherapy.
External Beam Radiation

External beam radiation is the type of radiotherapy used most often for people with blood cancers. A focused radiation beam is delivered outside the body by a machine called a linear accelerator, or linac for short. The linear accelerator moves around the body to deliver radiation from various angles. Linear accelerators make it possible to decrease or avoid skin reactions and deliver targeted radiation to lessen “scatter” of radiation to nearby tissues.

The dose (total amount) of radiation used during treatment depends on various factors regarding the patient, disease and reason for treatment, and is established by a radiation oncologist. You may receive radiotherapy during a series of visits, spread over several weeks (from two to 10 weeks, on average). This approach, called dose fractionation, lessens side effects. External beam radiation does not make you radioactive.

2.5.2  Bone marrow (BM) transplantation

http://www.nlm.nih.gov/medlineplus/ency/article/003009.htm

There are three kinds of bone marrow transplants:

Autologous bone marrow transplant: The term auto means self. Stem cells are removed from you before you receive high-dose chemotherapy or radiation treatment. The stem cells are stored in a freezer (cryopreservation). After high-dose chemotherapy or radiation treatments, your stems cells are put back in your body to make (regenerate) normal blood cells. This is called a rescue transplant.

Allogeneic bone marrow transplant: The term allo means other. Stem cells are removed from another person, called a donor. Most times, the donor’s genes must at least partly match your genes. Special blood tests are done to see if a donor is a good match for you. A brother or sister is most likely to be a good match. Sometimes parents, children, and other relatives are good matches. Donors who are not related to you may be found through national bone marrow registries.

Umbilical cord blood transplant: This is a type of allogeneic transplant. Stem cells are removed from a newborn baby’s umbilical cord right after birth. The stem cells are frozen and stored until they are needed for a transplant. Umbilical cord blood cells are very immature so there is less of a need for matching. But blood counts take much longer to recover.

Before the transplant, chemotherapy, radiation, or both may be given. This may be done in two ways:

Ablative (myeloablative) treatment: High-dose chemotherapy, radiation, or both are given to kill any cancer cells. This also kills all healthy bone marrow that remains, and allows new stem cells to grow in the bone marrow.

Reduced intensity treatment, also called a mini transplant: Patients receive lower doses of chemotherapy and radiation before a transplant. This allows older patients, and those with other health problems to have a transplant.

A stem cell transplant is usually done after chemotherapy and radiation is complete. The stem cells are delivered into your bloodstream usually through a tube called a central venous catheter. The process is similar to getting a blood transfusion. The stem cells travel through the blood into the bone marrow. Most times, no surgery is needed.

Donor stem cells can be collected in two ways:

  • Bone marrow harvest. This minor surgery is done under general anesthesia. This means the donor will be asleep and pain-free during the procedure. The bone marrow is removed from the back of both hip bones. The amount of marrow removed depends on the weight of the person who is receiving it.
  • Leukapheresis. First, the donor is given 5 days of shots to help stem cells move from the bone marrow into the blood. During leukapheresis, blood is removed from the donor through an IV line in a vein. The part of white blood cells that contains stem cells is then separated in a machine and removed to be later given to the recipient. The red blood cells are returned to the donor.

Why the Procedure is Performed

A bone marrow transplant replaces bone marrow that either is not working properly or has been destroyed (ablated) by chemotherapy or radiation. Doctors believe that for many cancers, the donor’s white blood cells can attach to any remaining cancer cells, similar to when white cells attach to bacteria or viruses when fighting an infection.

Your doctor may recommend a bone marrow transplant if you have:

Certain cancers, such as leukemia, lymphoma, and multiple myeloma

A disease that affects the production of bone marrow cells, such as aplastic anemia, congenital neutropenia, severe immunodeficiency syndromes, sickle cell anemia, thalassemia

Had chemotherapy that destroyed your bone

2.5.3 Autologous stem cell transplantation

Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas

O.W Press,  F Appelbaum,  P.J Martin, et al.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(95)92225-3/abstract

25 patients with relapsed B-cell lymphomas were evaluated with trace-labelled doses (2·5 mg/kg, 185-370 MBq [5-10 mCi]) of 131I-labelled anti-CD20 (B1) antibody in a phase II trial. 22 patients achieved 131I-B1 biodistributions delivering higher doses of radiation to tumor sites than to normal organs and 21 of these were treated with therapeutic infusions of 131I-B1 (12·765-29·045 GBq) followed by autologous hemopoietic stem cell reinfusion. 18 of the 21 treated patients had objective responses, including 16 complete remissions. One patient died of progressive lymphoma and one died of sepsis. Analysis of our phase I and II trials with 131I-labelled B1 reveal a progression-free survival of 62% and an overall survival of 93% with a median follow-up of 2 years. 131I-anti-CD20 (B1) antibody therapy produces complete responses of long duration in most patients with relapsed B-cell lymphomas when given at maximally tolerated doses with autologous stem cell rescue.

Autologous (Self) Transplants

http://www.leukaemia.org.au/treatments/stem-cell-transplants/autologous-self-transplants

An autologous transplant (or rescue) is a type of transplant that uses the person’s own stem cells. These cells are collected in advance and returned at a later stage. They are used to replace stem cells that have been damaged by high doses of chemotherapy, used to treat the person’s underlying disease.

In most cases, stem cells are collected directly from the bloodstream. While stem cells normally live in your marrow, a combination of chemotherapy and a growth factor (a drug that stimulates stem cells) called Granulocyte Colony Stimulating Factor (G-CSF) is used to expand the number of stem cells in the marrow and cause them to spill out into the circulating blood. From here they can be collected from a vein by passing the blood through a special machine called a cell separator, in a process similar to dialysis.

Most of the side effects of an autologous transplant are caused by the conditioning therapy used. Although they can be very unpleasant at times it is important to remember that most of them are temporary and reversible.

Procedure of Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient’s own stem cells are used) or allogeneic (the stem cells come from a donor).

Hematopoietic Stem Cell Transplantation

Author: Ajay Perumbeti, MD, FAAP; Chief Editor: Emmanuel C Besa, MD
http://emedicine.medscape.com/article/208954-overview

Hematopoietic stem cell transplantation (HSCT) involves the intravenous (IV) infusion of autologous or allogeneic stem cells to reestablish hematopoietic function in patients whose bone marrow or immune system is damaged or defective.

The image below illustrates an algorithm for typically preferred hematopoietic stem cell transplantation cell source for treatment of malignancy.

An algorithm for typically preferred hematopoietic stem cell transplantation cell source for treatment of malignancy: If a matched sibling donor is not available, then a MUD is selected; if a MUD is not available, then choices include a mismatched unrelated donor, umbilical cord donor(s), and a haploidentical donor.

Supportive Therapies

2.5.4  Blood transfusions – risks and complications of a blood transfusion

  • Allogeneic transfusion reaction (acute or delayed hemolytic reaction)
  • Allergic reaction
  • Viruses Infectious Diseases

The risk of catching a virus from a blood transfusion is very low.

HIV. Your risk of getting HIV from a blood transfusion is lower than your risk of getting killed by lightning. Only about 1 in 2 million donations might carry HIV and transmit HIV if given to a patient.

Hepatitis B and C. The risk of having a donation that carries hepatitis B is about 1 in 205,000. The risk for hepatitis C is 1 in 2 million. If you receive blood during a transfusion that contains hepatitis, you’ll likely develop the virus.

Variant Creutzfeldt-Jakob disease (vCJD). This disease is the human version of Mad Cow Disease. It’s a very rare, yet fatal brain disorder. There is a possible risk of getting vCJD from a blood transfusion, although the risk is very low. Because of this, people who may have been exposed to vCJD aren’t eligible blood donors.

  • Fever
  • Iron Overload
  • Lung Injury
  • Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is a condition in which white blood cells in the new blood attack your tissues.

2.5.5 Erythropoietin

Erythropoietin, (/ɨˌrɪθrɵˈpɔɪ.ɨtɨn/UK /ɛˌrɪθr.pˈtɪn/) also known as EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine (protein signaling molecule) for erythrocyte (red blood cell) precursors in the bone marrow. Human EPO has a molecular weight of 34 kDa.

Also called hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. In addition to erythropoiesis, erythropoietin also has other known biological functions. For example, it plays an important role in the brain’s response to neuronal injury.[1] EPO is also involved in the wound healing process.[2]

Exogenous erythropoietin is produced by recombinant DNA technology in cell culture. Several different pharmaceutical agents are available with a variety ofglycosylation patterns, and are collectively called erythropoiesis-stimulating agents (ESA). The specific details for labelled use vary between the package inserts, but ESAs have been used in the treatment of anemia in chronic kidney disease, anemia in myelodysplasia, and in anemia from cancer chemotherapy. Boxed warnings include a risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence.[3]

2.5.6  G-CSF (granulocyte-colony stimulating factor)

Granulocyte-colony stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

There are different types, including

  • Lenograstim (Granocyte)
  • Filgrastim (Neupogen, Zarzio, Nivestim, Ratiograstim)
  • Long acting (pegylated) filgrastim (pegfilgrastim, Neulasta) and lipegfilgrastim (Longquex)

Pegylated G-CSF stays in the body for longer so you have treatment less often than with the other types of G-CSF.

2.5.7  Plasma Exchange (plasmapheresis)

http://emedicine.medscape.com/article/1895577-overview

Plasmapheresis is a term used to refer to a broad range of procedures in which extracorporeal separation of blood components results in a filtered plasma product.[1, 2] The filtering of plasma from whole blood can be accomplished via centrifugation or semipermeable membranes.[3] Centrifugation takes advantage of the different specific gravities inherent to various blood products such as red cells, white cells, platelets, and plasma.[4] Membrane plasma separation uses differences in particle size to filter plasma from the cellular components of blood.[3]

Traditionally, in the United States, most plasmapheresis takes place using automated centrifuge-based technology.[5] In certain instances, in particular in patients already undergoing hemodialysis, plasmapheresis can be carried out using semipermeable membranes to filter plasma.[4]

In therapeutic plasma exchange, using an automated centrifuge, filtered plasma is discarded and red blood cells along with replacement colloid such as donor plasma or albumin is returned to the patient. In membrane plasma filtration, secondary membrane plasma fractionation can selectively remove undesired macromolecules, which then allows for return of the processed plasma to the patient instead of donor plasma or albumin. Examples of secondary membrane plasma fractionation include cascade filtration,[6] thermofiltration, cryofiltration,[7] and low-density lipoprotein pheresis.

The Apheresis Applications Committee of the American Society for Apheresis periodically evaluates potential indications for apheresis and categorizes them from I to IV based on the available medical literature. The following are some of the indications, and their categorization, from the society’s 2010 guidelines.[2]

  • The only Category I indication for hemopoietic malignancy is Hyperviscosity in monoclonal gammopathies

2.5.8  Platelet Transfusions

Indications for platelet transfusion in children with acute leukemia

Scott Murphy, Samuel Litwin, Leonard M. Herring, Penelope Koch, et al.
Am J Hematol Jun 1982; 12(4): 347–356
http://onlinelibrary.wiley.com/doi/10.1002/ajh.2830120406/abstract;jsessionid=A6001D9D865EA1EBC667EF98382EF20C.f03t01
http://dx.doi.org:/10.1002/ajh.2830120406

In an attempt to determine the indications for platelet transfusion in thrombocytopenic patients, we randomized 56 children with acute leukemia to one of two regimens of platelet transfusion. The prophylactic group received platelets when the platelet count fell below 20,000 per mm3 irrespective of clinical events. The therapeutic group was transfused only when significant bleeding occurred and not for thrombocytopenia alone. The time to first bleeding episode was significantly longer and the number of bleeding episodes were significantly reduced in the prophylactic group. The survival curves of the two groups could not be distinguished from each other. Prior to the last month of life, the total number of days on which bleeding was present was significantly reduced by prophylactic therapy. However, in the terminal phase (last month of life), the duration of bleeding episodes was significantly longer in the prophylactic group. This may have been due to a higher incidence of immunologic refractoriness to platelet transfusion. Because of this terminal bleeding, comparison of the two groups for total number of days on which bleeding was present did not show a significant difference over the entire study period.

Clinical and Laboratory Aspects of Platelet Transfusion Therapy
Yuan S, Goldfinger D
http://www.uptodate.com/contents/clinical-and-laboratory-aspects-of-platelet-transfusion-therapy

INTRODUCTION — Hemostasis depends on an adequate number of functional platelets, together with an intact coagulation (clotting factor) system. This topic covers the logistics of platelet use and the indications for platelet transfusion in adults. The approach to the bleeding patient, refractoriness to platelet transfusion, and platelet transfusion in neonates are discussed elsewhere.

Pooled Platelets – A single unit of platelets can be isolated from every unit of donated blood, by centrifuging the blood within the closed collection system to separate the platelets from the red blood cells (RBC). The number of platelets per unit varies according to the platelet count of the donor; a yield of 7 x 1010 platelets is typical [1]. Since this number is inadequate to raise the platelet count in an adult recipient, four to six units are pooled to allow transfusion of 3 to 4 x 1011 platelets per transfusion [2]. These are called whole blood-derived or random donor pooled platelets.

Advantages of pooled platelets include lower cost and ease of collection and processing (a separate donation procedure and pheresis equipment are not required). The major disadvantage is recipient exposure to multiple donors in a single transfusion and logistic issues related to bacterial testing.

Apheresis (single donor) Platelets – Platelets can also be collected from volunteer donors in the blood bank, in a one- to two-hour pheresis procedure. Platelets and some white blood cells are removed, and red blood cells and plasma are returned to the donor. A typical apheresis platelet unit provides the equivalent of six or more units of platelets from whole blood (ie, 3 to 6 x 1011 platelets) [2]. In larger donors with high platelet counts, up to three units can be collected in one session. These are called apheresis or single donor platelets.

Advantages of single donor platelets are exposure of the recipient to a single donor rather than multiple donors, and the ability to match donor and recipient characteristics such as HLA type, cytomegalovirus (CMV) status, and blood type for certain recipients.

Both pooled and apheresis platelets contain some white blood cells (WBC) that were collected along with the platelets. These WBC can cause febrile non-hemolytic transfusion reactions (FNHTR), alloimmunization, and transfusion-associated graft-versus-host disease (ta-GVHD) in some patients.

Platelet products also contain plasma, which can be implicated in adverse reactions including transfusion-related acute lung injury (TRALI) and anaphylaxis. (See ‘Complications of platelet transfusion’ .)

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Hematological Cancer Classification

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

 

 

Introduction to leukemias and lymphomas

 

2.4.1 Ontogenesis of the blood elements: hematopoiesis

http://www.britannica.com/EBchecked/topic/69747/blood-cell-formation

Blood cells are divided into three groups: the red blood cells (erythrocytes), the white blood cells (leukocytes), and the blood platelets (thrombocytes). The white blood cells are subdivided into three broad groups: granulocytes, lymphocytes, and monocytes.

Blood cells do not originate in the bloodstream itself but in specific blood-forming organs, notably the marrow of certain bones. In the human adult, the bone marrow produces all of the red blood cells, 60–70 percent of the white cells (i.e., the granulocytes), and all of the platelets. The lymphatic tissues, particularly the thymus, the spleen, and the lymph nodes, produce the lymphocytes (comprising 20–30 percent of the white cells). The reticuloendothelial tissues of the spleen, liver, lymph nodes, and other organs produce the monocytes (4–8 percent of the white cells). The platelets, which are small cellular fragments rather than complete cells, are formed from bits of the cytoplasm of the giant cells (megakaryocytes) of the bone marrow.

In the human embryo, the first site of blood formation is the yolk sac. Later in embryonic life, the liver becomes the most important red blood cell-forming organ, but it is soon succeeded by the bone marrow, which in adult life is the only source of both red blood cells and the granulocytes. Both the red and white blood cells arise through a series of complex, gradual, and successive transformations from primitive stem cells, which have the ability to form any of the precursors of a blood cell. Precursor cells are stem cells that have developed to the stage where they are committed to forming a particular kind of new blood cell.

In a normal adult the red cells of about half a liter (almost one pint) of blood are produced by the bone marrow every week. Almost 1 percent of the body’s red cells are generated each day, and the balance between red cell production and the removal of aging red cells from the circulation is precisely maintained.

Cells-in-the-Bone-Marrow-1024x747

http://interactive-biology.com/wp-content/uploads/2012/07/Cells-in-the-Bone-Marrow-1024×747.png

Erythropoiesis

http://www.interactive-biology.com/3969/erythropoiesis-formation-of-red-blood-cells/

Erythropoiesis – Formation of Red Blood Cells

Because of the inability of erythrocytes (red blood cells) to divide to replenish their own numbers, the old ruptured cells must be replaced by totally new cells. They meet their demise because they don’t have the usual specialized intracellular machinery, which controls cell growth and repair, leading to a short life span of 120 days.

This short life span necessitates the process erythropoiesis, which is the formation of red blood cells. All blood cells are formed in the bone marrow. This is the erythrocyte factory, which is soft, highly cellar tissue that fills the internal cavities of bones.

Erythrocyte differentiation takes place in 8 stages. It is the pathway through which an erythrocyte matures from a hemocytoblast into a full-blown erythrocyte. The first seven all take place within the bone marrow. After stage 7 the cell is then released into the bloodstream as a reticulocyte, where it then matures 1-2 days later into an erythrocyte. The stages are as follows:

  1. Hemocytoblast, which is a pluripotent hematopoietic stem cell
  2. Common myeloid progenitor, a multipotent stem cell
  3. Unipotent stem cell
  4. Pronormoblast
  5. Basophilic normoblast also called an erythroblast.
  6. Polychromatophilic normoblast
  7. Orthochromatic normoblast
  8. Reticulocyte

These characteristics can be seen during the course of erythrocyte maturation:

  • The size of the cell decreases
  • The cytoplasm volume increases
  • Initially there is a nucleus and as the cell matures the size of the nucleus decreases until it vanishes with the condensation of the chromatin material.

Low oxygen tension stimulates the kidneys to secrete the hormone erythropoietin into the blood, and this hormone stimulates the bone marrow to produce erythrocytes.

Rarely, a malignancy or cancer of erythropoiesis occurs. It is referred to as erythroleukemia. This most likely arises from a common myeloid precursor, and it may occur associated with a myelodysplastic syndrome.

Summary of erythrocyte maturation

White blood cell series: myelopoiesis

http://www.nlm.nih.gov/medlineplus/ency/presentations/100151_3.htm

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/15220.jpg

There are various types of white blood cells (WBCs) that normally appear in the blood: neutrophils (polymorphonuclear leukocytes; PMNs), band cells (slightly immature neutrophils), T-type lymphocytes (T cells), B-type lymphocytes (B cells), monocytes, eosinophils, and basophils. T and B-type lymphocytes are indistinguishable from each other in a normal slide preparation. Any infection or acute stress will result in an increased production of WBCs. This usually entails increased numbers of cells and an increase in the percentage of immature cells (mainly band cells) in the blood. This change is referred to as a “shift to the left” People who have had a splenectomy have a persistent mild elevation of WBCs. Drugs that may increase WBC counts include epinephrine, allopurinol, aspirin, chloroform, heparin, quinine, corticosteroids, and triamterene. Drugs that may decrease WBC counts include antibiotics, anticonvulsants, antihistamine, antithyroid drugs, arsenicals, barbiturates, chemotherapeutic agents, diuretics and sulfonamides.   (Updated by: David C. Dugdale, III, MD)

https://www.med-ed.virginia.edu/courses/path/innes/nh/wcbmaturation.cfm

Note that the mature forms of the myeloid series (neutrophils, eosinophils, basophils), all have lobed (segmented) nuclei. The degree of lobation increases as the cells mature.

The earliest recognizable myeloid cell is the myeloblast (10-20m dia) with a large round to oval nucleus. There is fine diffuse immature chromatin (without clumping) and a prominant nucleolus.

The cytoplasm is basophilic without granules. Although one may see a small golgi area adjacent to the nucleus, granules are not usually visible by light microscopy. One should not see blast cells in the peripheral blood.

myeloblast x100b

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20myeloblast%20x100b.jpeg

The promyelocyte (10-20m) is slightly larger than a blast. Its nucleus, although similar to a myeloblast shows slight chromatin condensation and less prominent nucleoli. The cytoplasm contains striking azurophilic granules or primary granules. These granules contain myeloperoxidase, acid phosphatase, and esterase enzymes. Normally no promyelocytes are seen in the peripheral blood.

At the point in development when secondary granules can be recognized, the cell becomes a myelocyte.

promyelocyte x100

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20promyelocyte%20×100%20a.jpeg

Myelocytes (10-18m) are not normally found in the peripheral blood. Nucleoli may not be seen in the late myelocyte. Primary azurophilic granules are still present, but secondary granules predominate. Secondary granules (neut, eos, or baso) first appear adjacent to the nucleus. In neutrophils this is the “dawn” of neutrophilia.

Metamyelocytes (10-18m) have kidney shaped indented nuclei and dense chromatin along the nuclear membrane. The cytoplasm is faintly pink, and they have secondary granules (neutro, eos, or baso). Zero to one percent of the peripheral blood white cells may be metamyelocytes (juveniles).

metamyelocyte x100

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20metamyelocyte%20×100.jpeg

Bands, slightly smaller than juveniles, are marked by a U-shaped or deeply indented nucleus.

band neutrophilx100a

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20band%20x100a.jpeg

Segmented (segs) or polymorphonuclear (PMN) leukocytes (average 14 m dia) are distinguished by definite lobation with thin thread-like filaments of chromatin joining the 2-5 lobes. 45-75% of the peripheral blood white cells are segmented neutrophils.

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20neutrophil%20×100%20d.jpeg

Thrombocytogenesis

The incredible journey: From megakaryocyte development to platelet formation

Kellie R. Machlus1,2 and Joseph E. Italiano Jr
JCB 2013; 201(6): 785-796
http://dx.doi.org:/10.1083/jcb.201304054

Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. MKs release platelets through a series of fascinating cell biological events. During maturation, they become polyploid and accumulate massive amounts of protein and membrane. Then, in a cytoskeletal-driven process, they extend long branching processes, designated proplatelets, into sinusoidal blood vessels where they undergo fission to release platelets.

megakaryocyte production of platelets

http://dm5migu4zj3pb.cloudfront.net/manuscripts/26000/26891/medium/JCI0526891.f4.jpg

platelets and the immune continuum nri2956-f3

http://www.nature.com/nri/journal/v11/n4/images/nri2956-f3.jpg

2.4.2 Classification of hematological malignancies
Practical Diagnosis of Hematologic Disoreders. 4th edition. Vol 2.
Kjeldsberg CR, Ed.  ASCP Press.  2006. Chicago, IL.

2.4.2.1 Primary Classification

Acute leukemias

Myelodysplastic syndromes

Acute myeloid leukemia

Acute lymphoblastic leukemia

Myeloproliferative Disorders

Chronic myeloproliferative disorders

Chronic myelogenous leukemia and related disorders

Myelofibrosis, including chronic idiopathic

Polycythemia, including polycythemia rubra vera

Thrombocytosis, including essential thrombocythemia

Chronic lymphoid leukemia and other lymphoid leukemias

Lymphomas

Non-Hodgkin Lymphoma

Hodgkin lymphoma

Lymphoproliferative disorders associated with immunodeficiency

Plasma Cell dyscrasias

Mast cell disease and Histiocytic neoplasms

2.4.2.2 Secondary Classification

2.4.2.3 Nuance – PathologyOutlines
Nat Pernick, Ed.

Leukemia – Acute

Primary referencesacute leukemia-generalAML generalAML classificationtransient abnormal myelopoiesis

Recurrent genetic abnormalities: AML with t(6;9)AML with t(8;21)AML with 11q23 abnormalitiesAML with inv(16) or t(16;16)AML with Down syndromeAML with FLT3 mutationsAML with myelodysplastic related changesAML therapy relatedAPL microgranular variantAPL with t(15;17)APL with t(V;17)APL therapy related

AML not otherwise categorized: minimally differentiated (M0)without maturation (M1)with maturation (M2)M3myelomonocyticmonoblastic and monocyticerythroidmegakaryoblasticCD13/CD33 negativebasophilicmyeloid sarcomaacute panmyelosis with myelofibrosiswith Philadelphia chromosomewith pseudo Chediak-Higashi anomalyhypocellular

ALL: generalWHO classificationwith eosinophilia

PreB ALL: generalt(9;22)t(v;11q23)t(1;19)t(5;14)t(12;21)hyperdiploidyhypodiploidymature B ALL/Burkitt

Other ALL: T ALLambiguous lineagemixed phenotype

AML and related malignancies

Acute myeloid leukemias with recurrent genetic abnormalities:

  • AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
  • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBF&beta-MYH11
  • Acute promyelocytic leukemia with t(15;17)(q22;q12); PML/RAR&alpha and variants
  • AML with t(9;11)(p22;q23); MLLT3-MLL
  • AML with t(6;9)(p23;q34); DEK-NUP214
  • AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
  • AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
  • AML with mutated NPM1*
  • AML with mutated CEBPA*

* provisional

Acute myeloid leukemia with myelodysplasia related changes

Therapy related acute myeloid leukemia

  • Alkylating agent related
  • Topoisomerase II inhibitor related (some maybe lymphoid)

Acute myeloid leukemia not otherwise categorized:

  • AML minimally differentiated (M0)
  • AML without maturation (M1)
  • AML with maturation (M2)
  • Acute myelomonocytic leukemia (M4)
  • Acute monoblastic and monocytic leukemia (M5a, M5b)
  • Acute erythroid leukemia (M6)
  • Acute megakaryoblastic leukemia (M7)
  • Acute basophilic leukemia
  • Acute panmyelosis with myelofibrosis

Myeloid Sarcoma

Myeloid proliferations related to Down syndrome:

  • Transient abnormal myelopoeisis
  • Myeloid leukemia associated with Down syndrome

Blastic plasmacytoid dentritic cell neoplasm:

Acute leukemia of ambiguous lineage:

  • Acute undifferentiated leukemia
  • Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1
  • Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged
  • Mixed phenotype acute leukemia, B/myeloid, NOS
  • Mixed phenotype acute leukemia, T/myeloid, NOS
  • Mixed phenotype acute leukemia, NOS, rare types
  • Other acute leukemia of ambiguous lineage
  • References: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue (IARC, 2008), Discovery Medicine 2010, eMedicine

Acute lymphocytic leukemia

General
=================================================================

  • WHO classification system includes former FAB classifications ALL-L1 and L2
    ● FAB L3 is now considered Burkitt lymphoma

WHO classification of acute lymphoblastic leukemia
=================================================================

Precursor B lymphoblastic leukemia / lymphoblastic lymphoma:
● ALL with t(9;22)(q34;q11.2); BCR-ABL (Philadelphia chromosome)
● ALL with t(v;11q23) (MLL rearranged)
● ALL with t(1;19)(q23;p13.3); TCF3-PBX1 (E2A-PBX1)
● ALL with t(12;21)(p13;q22); ETV6-RUNX1 (TEL-AML1)
● Hyperdiploid > 50
● Hypodiploid
● t(5;14)(q31;q32); IL3-IGH

Precursor T lymphoblastic leukemia / lymphoma

Additional references
=================================================================

Mixed phenotype acute leukemia (MPAL)

General
=================================================================

  • De novo acute leukemia containing separate populations of blasts of more than one lineage (bilineal or bilineage), or a single population of blasts co-expressing antigens of more than one lineage (biphenotypic)Excludes:
    ● Acute myeloid leukemia (AML) with recurrent translocations t(8;21), t(15;17) or inv(16)
    ● Leukemias with FGFR1 mutations
    ● Chronic myelogenous leukemia (CML) in blast crisis
    ● Myelodysplastic syndrome (MDS)-related AML and therapy-related AML, even if they have MPAL immunophenotypeCriteria for biphenotypic leukemia:
    ● Score of 2 or more for each of two separate lineages:The European Group for the Immunological Classification of Leukemias (EGIL) scoring system2008 WHO classification of acute leukemias of ambiguous lineage 

Prognosis
=================================================================

  • Poor, overall survival of 18 months
    ● Young age, normal karyotype and ALL induction therapy are associated with favorable survival
    ● Ph+ is a predictor for poor prognosis
    ● Bone marrow transplantation should be considered in first remission

Major Categories

MPAL with t(9;22)(q34;q11.2); BCR-ABL1
=================================================================

  • 20% of all MPAL
    ● Blasts with t(9;22)(q34;q11.2) translocation or BCR-ABL1 rearrangement (Ph+) without history of CML
    ● Majority in adults
    ● High WBC counts● Most of the cases B/myeloid phenotype
    ● Rare T/myeloid, B and T lineage, or trilineage leukemiasMorphology:
    ● Many cases show a dimorphic blast population, one resembling myeloblasts and the other lymphoblastsCytogenetic abnormalities:
    ● Conventional karyotyping for t(9;22), FISH or PCR for BCR-ABL1 translocation
    ● Additional complex karyotypes
    ● Ph+ is a poor prognostic factor for MPAL, with a reported median survival of 8 months
    ● Worse than patients of all other types of MPAL

MPAL with t(v;11q23); MLL rearranged
=================================================================

  • Meeting the diagnostic criteria for MPAL with blasts bearing a translocation involving the 11q23 breakpoint (MLL gene)
    ● MPAL with MLL rearranged rare
    ● More often seen in children and relatively common in infancy
    ● High WBC counts
    ● Poor prognosis
    ● Dimorphic blast population, with one resembling monoblasts and the other resembling lymphoblasts
    ● Lymphoblast population often shows a CD19+, CD10- B precursor immunophenotype, frequently CD15+
    ● Expression of other B markers usually weak
    ● Translocations involving MLL gene include t(4;11)(q21;q23), t(11;19)(q23;p13), and t(9;11)(p22;q23)
    ● Cases with chromosome 11q23 deletion should not be classified in this category

B cell acute lymphoblastic leukemia (ALL) / lymphoblastic lymphoma (LBL)

General

=================================================================

  • Current 2008 WHO classification: B lymphoblastic leukemia / lymphoma, NOS or B lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities
  • See also lymphomas: B cell chapter
  • Also called B cell acute lymphoblastic leukemia / lymphoblastic lymphoma, pre B ALL / LBL
  • Usually children
  • B acute lymphoblastic leukemia presents with pancytopenia due to extensive marrow involvement, stormy onset of symptoms, bone pain due to marrow expansion, hepatosplenomegaly due to neoplastic infiltration, CNS symptoms due to meningeal spread and testicular involvement
  • B acute lymphoblastic lymphoma often presents with cutaneous nodules, bone or nodal involvement, < 25% lymphoblasts in bone marrow and peripheral blood; aleukemic cases are usually asymptomatic
  • Depending on specific leukemia, arises in either hematopoietic stem cell or B-cell progenitor
  • Tumors are derived from pre-germinal center naive B cells with unmutated VH region genes
  • Have multiple immunophenotyping aberrancies relative to normal B cell precursors (hematogones); at relapse, 73% show loss of 1+ aberrance and 60% show new aberrancies (Am J Clin Pathol 2007;127:39)

Prognostic features

=================================================================

  • Favorable prognosis: age 1-10 years, female, white; preB phenotype, hyperdiploidy>50, t(12,21), WBC count at presentation <50×108/L, non-traumatic tap with no blasts in CNS, rapid response to chemotherapy < 5% blasts on morphology on day 15, remission status after induction <5% blasts on morphology and <0.01% blast on flow or PCR, CD10+
  • Intermediate prognosis: hyperdiploidy 47-50, diploid, 6q- and rearrangements of 8q24
  • Unfavorable prognosis: under age 1 (usually have 11q23 translocations) or over age 10; t(9;22) (but not if age 59+ years, Am J Clin Pathol 2002;117:716); male, > 50×108/L WBC at presentation, hypodiploidy, near tetraploidy, 17p- and MLL rearrangements t(v;11q23); CD10-; non-traumatic tap with > 5% blasts or traumatic tap (7%); also increased microvessel staining using CD105 in children (Leuk Res 2007;31:1741), MDR1 expression in children (Oncol Rep 2004;12:1201) and adults (Blood 2002;100:974), 25%+ blasts on morphology on day 15, remission status after induction ≥ 5% blasts on morphology and ≥ 0.1% blasts on flow or PCR

Case reports

=================================================================

  • 12 month old girl and 13 month old boy with mature phenotype but no translocations (Arch Pathol Lab Med 2003;127:1340)
  • 56 year old man with ALL arising from follicular lymphoma (Arch Pathol Lab Med 2002;126:997)
  • 76 year old man with basal cell carcinoma (Diagn Pathol 2007;2:32)
  • With hemophagocytic lymphohistiocytosis (Pediatr Blood Cancer 2008;50:381)

Treatment

================================================================

  • Chemotherapy cures more children than adults; adolescents benefit from intensive regimens (Hematology Am Soc Hematol Educ Program 2005:123)

Micro description

=================================================================

  • Bone marrow smears: small to intermediate blast-like cells with scant, variably basophilic cytoplasm, round / oval or convoluted nuclei, fine chromatin and indistinct nucleoli; frequent mitotic figures; may have “starry sky” appearance similar to Burkitt lymphoma; may have large lymphoblasts with 1-4 prominent nucleoli resembling myeloblasts; usually no sclerosis
  • Bone marrow biopsy: usually markedly hypercellular with reduction of trilinear maturation; cells have minimal cytoplasm, medium sized nuclei that are often convoluted, moderately dense chromatin and indistinct nucleoli, brisk mitotic activity
  • Other tissues: may have “starry sky” appearance similar to Burkitt lymphoma; collagen dissection, periadipocyte growth pattern and single cell linear filing

Chronic Leukemia

Chronic Myeloid Neoplasms

Myelodysplastic syndromes (MDS): general, WHO classification, childhood, refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, 5q-syndrome, therapy related, unclassified, arsenic toxicity

Myeloproliferative neoplasms (MPN): general, WHO classification, chronic eosinophilic leukemia, chronic myelogenous leukemia, chronic neutrophilic leukemia, essential thrombocythemia, hypereosinophilic syndrome, mast cell disease, polycythemia vera, primary myelofibrosis, unclassifiable

MDS/MPN: general, WHO classification, atypical CML, chronic myelomonocytic leukemia (CMML), chronic myelomonocytic leukemia with eosinophilia, juvenile myelomonocytic leukemia, unclassifiable

Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1: PDGFRA, PDGFRB, FGFR1

Miscellaneous: transient myeloproliferative disorder of Downís syndrome

Lymphoma and plasma cell neoplasms

Lymph nodes: normal development-generalB cellsT cellsNK cellsnormal histologygrossing lymph nodesfeatures to report

Molecular testing: theoryFISHnorthern blotPCRsouthern blot

Non-Hodgkin lymphoma: generalcytogeneticsstagingstaging-pediatricmorphologic clueshemophagocytic syndromechemotherapeutic atypia

B cell disorders: generalpost-rituximabbone marrow biopsyclassification-historicalWHO classification

B cell lymphoma subtypes: age-related EBV-associatedALK positive large cellBurkittunclassifiable-intermediate between Burkitt and diffuse large B cell lymphomaCLL
diffuse large B cell: 
diffuse-NOSCD5+T cell / histiocyte richprimary cutaneous-generalprimary cutaneous-legprimary sites-other
follicular: 
generalchildhoodcutaneousGI
hairy cell leukemiaHCL variantintravascular large B celllymphomatoid granulomatosislymphoplasmacyticmantle cell-classicmantle cell-blastoidmarginal zone-generalmarginal zone-MALTMALT-primary sitesmarginal zone-nodalmediastinal (thymic)plasmablasticpre B lymphoblastic leukemia/lymphomaprimary effusionprolymphocytic leukemiapyothorax associatedSLLsplenic marginal zonesplenic lymphoma with villous lymphocytes

Plasma cell neoplasms: generalmyelomaplasmacytomaheavy chain diseaseprimary amyloidosisMGUSOsteosclerotic myeloma (POEMS)cryoglobulinemia

T/NK cell disorders: generalWHO classificationadult T cellaggressive NK cell leukemiaanaplastic large cell ALK+ALK-angioimmunoblastic T cellblastic plasmacytoidchronic lymphoproliferative disorders of NK cellscutaneous CD4+ small/medium sized T cell lymphomacutaneous CD30 positive T cell lymphoproliferative disorderscutaneous gamma delta T cell lymphomaenteropathyepidermotropic CD8+ T cell lymphomahepatosplenicindolent T cell proliferationsmycosis fungoidesNK/T cell lymphoma-nasal typenodal CD8+ cytotoxic T cellnonB nonT lymphoblasticperipheral T cell lymphoma, NOSprimary effusion lymphomaSezary syndromestagingsubcutaneous panniculitis-likeT cell large granular lymphocytic leukemiaT cell lymphoblastic leukemia/lymphomaT cell prolymphocytic leukemia

Hodgkin lymphoma: general/stagingclassiclymphocyte depletedlymphocyte rich classicalmixed cellularitynodular lymphocyte predominantnodular sclerosis

Post-transplantation: generalWHO classificationplasmacytic hyperplasia/IM-like lesionspolymorphic B cell lymphoproliferative disordersmonomorphic B cell lymphoproliferative disordersothergraft versus host disease

Other: AIDS associated-generalAIDS associated-examplesEBV+ T cell lymphoproliferative disorders of childhoodprimary immune disorders related

Myeloproliferative neoplasms (MPN)

WHO 2008 – Myeloproliferative neoplasms (MPN) 

General
=================================================================

  • Chronic myelogenous leukemia
    ● Polycythemia vera
    ● Essential thrombocythemia
    ● Primary myelofibrosis
    ● Chronic neutrophilic leukemia
    ● Chronic eosinophilic leukemia, not otherwise categorized
    ● Mast cell disease
    ● MPNs, unclassifiable

WHO 2001 – Chronic myeloproliferative diseases 

Definition
=================================================================

  • Chronic myelogenous leukemia (Philadelphia chromosome, t(9;22)(q34;q11), BCR-ABL positive)
    ● Chronic neutrophilic leukemia
    ● Chronic eosinophilic leukemia (and the hypereosinophilic syndrome)
    ● Polycythemia vera
    ● Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)
    ● Essential thrombocythemia
    ● Chronic myeloproliferative disease, unclassifiable

Additional references
=================================================================

The World Health Organization (WHO) classification of the myeloid neoplasms  James W. Vardiman, Nancy Lee Harris, and Richard D. Brunning
Blood 2002; 100(7)  http://dx.doi.org/10.1182/blood-2002-04-1199

Lymphoma – Non B cell neoplasms

T/NK cell disorders/WHO classification (2008)

Principles of classification
=================================================================

  • Based on all available information (morphology, immunophenotype, genetics, clinical)
    ● No one antigenic marker is specific for any neoplasm (except ALK1)
    ● Immune profiling less helpful in subclassification of T cell lymphomas then B cell lymphomas
    ● Certain antigens commonly associated with specific disease entities but not entirely disease specific
    ● CD30: common in anaplastic large cell lymphoma but also classic Hodgkin lymphoma and other B and T cell lymphomas
    ● CD56: characteristic for nasal NK/T cell lymphoma, but also other T cell neoplasms and plasma cell disorders
    ● Variation of immunophenotype within a given disease (hepatosplenic T cell lymphoma: usually γδ but some are αβ)
    ● Recurrent genetic alterations have been identified for many B cell lymphomas but not for most T cell lymphomas
    ● No attempt to stratify lymphoid malignancies by grade
    ● Recognize the existence of grey zone lymphomas
    ● This multiparameter approach has been validated in international studies as highly reproducible

WHO 2008 classification of tumors of hematopoietic and lymphoid tissues (T/NK)
=================================================================

Precursor T-lymphoid neoplasms
● T lymphoblastic leukemia/lymphoma, 9837/3

Mature T cell and NK cell neoplasms
● T cell prolymphocytic leukemia, 9834/3
● T cell large granular lymphocytic leukemia, 9831/3
● Chronic lymphoproliferative disorder of NK cells, 9831/3
● Aggressive NK cell leukemia, 9948/3
● Systemic EBV-positive T cell lymphoproliferative disease of childhood, 9724/3
● Hydroa vacciniforme-like lymphoma, 9725/3
● Adult T cell leukemia/lymphoma, 9827/3
● Extranodal NK/T cell lymphoma, nasal type, 9719/3
● Enteropathy-associated T cell lymphoma, 9717/3
● Hepatosplenic T cell lymphoma, 9716/3
● Subcutaneous panniculitis-like T cell lymphoma, 9708/3
● Mycosis fungoides, 9700/3
● Sézary syndrome, 9701/3
● Primary cutaneous CD30-positive T cell lymphoproliferative disorders
● Lymphomatoid papulosis, 9718/1
● Primary cutaneous anaplastic large cell lymphoma, 9718/3
● Primary cutaneous gamma-delta T cell lymphoma, 9726/3
● Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T cell lymphoma, 9709/3
● Primary cutaneous CD4-positive small/medium T cell lymphoma, 9709/3
● Peripheral T cell lymphoma, NOS, 9702/3
● Angioimmunoblastic T cell lymphoma, 9705/3
● Anaplastic large cell lymphoma, ALK-positive, 9714/3
● Anaplastic large cell lymphoma, ALK-negative, 9702/3

Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Staging
Author: Sandy D Kotiah, MD; Chief Editor: Jules E Harris, MD
Medscape Sep 6, 2013
http://emedicine.medscape.com/article/2006578-overview

General considerations in the staging of chronic lymphocytic leukemia (CLL) and the revised Rai (United States) and Binet (Europe) staging systems for CLL are provided below.[1, 2, 3]

See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.

General considerations

  • CLL and small lymphocytic lymphoma (SLL) are different manifestations of the same disease; SLL is diagnosed when the disease is mainly nodal, and CLL is diagnosed when the disease is seen in the blood and bone marrow
  • CLL is diagnosed by > 5000 monoclonal lymphocytes/mm3 for longer than 3mo; the bone marrow usually has more than 30% monoclonal lymphocytes and is either normocellular or hypercellular
  • Monoclonal B lymphocytosis is a precursor form of CLL that is defined by a monoclonal B cell lymphocytosis < 5000 monoclonal lymphocytes/mm3; all lymph nodes smaller than 1.5 cm; no anemia; and no thrombocytopenia

Revised Rai staging system (United States)

Low risk (formerly stage 0)[1] :

  • Lymphocytosis, lymphocytes in blood > 15000/mcL, and > 40% lymphocytes in the bone marrow

Intermediate risk (formerly stages I and II):

  • Lymphocytosis as in low risk with enlarged node(s) in any site, or splenomegaly or hepatomegaly or both

High risk (formerly stages III and IV):

  • Lymphocytosis as in low risk and intermediate risk with disease-related anemia (hemoglobin level < 11.0 g/dL or hematocrit < 33%) or platelets < 100,000/mcL

Binet staging system (Europe)

Stage A:

  • Hemoglobin ≥ 10 g/dL, platelets ≥ 100,000/mm3, and < 3 enlarged areas

Stage B:

  • Hemoglobin ≥ 10 g/dL, platelets ≥ 100,000/mm3, and ≥ 3 enlarged areas

Stage C:

  • Hemoglobin < 10 g/dL, platelets < 100,000/mm3, and any number of enlarged areas

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Why did this occur? The matter of Individual Actions Undermining Trust, The Patent Dilemma and The Value of a Clinical Trials


Why did this occur? The matter of Individual Actions Undermining Trust, The Patent Dilemma and The Value of a Clinical Trials

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

 

he large amount of funding tied to continued research and support of postdoctoral fellows leads one to ask how following the money can lead to discredited work in th elite scientific community.

Moreover, the pressure to publish in prestigious journals with high impact factors is a road to academic promotion.  In the last twenty years, it is unusual to find submissions for review with less than 6-8 authors, with the statement that all contributed to the work.  These factors can’t be discounted outright, but it is easy for work to fall through the cracks when a key investigator has over 200 publications and holds tenure in a great research environment.  But that is where we find ourselves today.

There is another issue that comes up, which is also related to the issue of carrying out research, and then protecting the work for commercialization.  It is more complicated in the sense that it is necessary to determine whether there is prior art, and then there is the possibility that after the cost of filing patent and a 6 year delay in obtaining protection, there is as great a cost in bringing the patent to finasl production.

I.  Individual actions undermining trust.

II. The patent dilemma.

III. The value of a clinical trial.

IV. The value contributions of RAP physicians
(radiologists, anesthesiologists, and pathologists – the last for discussion)
Those who maintain and inform the integrity of medical and surgical decisions

 

I. Top heart lab comes under fire

Kelly Servick

Science 18 July 2014: Vol. 345 no. 6194 p. 254 DOI: 10.1126/science.345.6194.25

 

In the study of cardiac regeneration, Piero Anversa is among the heavy hitters. His research into the heart’s repair mechanisms helped kick-start the field of cardiac cell therapy (see main story). After more than 4 decades of research and 350 papers, he heads a lab at Harvard Medical School’s Brigham and Women’s Hospital (BWH) in Boston that has more than $6 million in active grant funding from the National Institutes of Health (NIH). He is also an outspoken voice in a field full of disagreement.

So when an ongoing BWH investigation of the lab came to light earlier this year, Anversa’s colleagues were transfixed. “Reactions in the field run the gamut from disbelief to vindication,” says Mark Sussman, a cardiovascular researcher at San Diego State University in California who has collaborated with Anversa. By Sussman’s account, Anversa’s reputation for “pushing the envelope” and “challenging existing dogma” has generated some criticism. Others, however, say that the disputes run deeper—to doubts about a cell therapy his lab has developed and about the group’s scientific integrity. Anversa told Science he was unable to comment during the investigation.

“People are talking about this all the time—at every scientific meeting I go to,” says Charles Murry, a cardiovascular pathologist at the University of Washington, Seattle. “It’s of grave concern to people in the field, but it’s been frustrating,” because no information is available about BWH’s investigation. BWH would not comment for this article, other than to say that it addresses concerns about its researchers confidentially.

In April, however, the journal Circulation agreed to Harvard’s request to retract a 2012 paper on which Anversa is a corresponding author, citing “compromised” data. The Lancet also issued an “Expression of Concern” about a 2011 paper reporting results from a clinical trial, known as SCIPIO, on which Anversa collaborated. According to a notice from the journal, two supplemental figures are at issue.

For some, Anversa’s status has earned him the benefit of the doubt. “Obviously, this is very disconcerting,” says Timothy Kamp, a cardiologist at the University of Wisconsin, Madison, but “I would be surprised if it was an implication of a whole career of research.”

Throughout that career, Anversa has argued that the heart is a prolific, lifelong factory for new muscle cells. Most now accept the view that the adult heart can regenerate muscle, but many have sparred with Anversa over his high estimates for the rate of this turnover, which he maintained in the retracted Circulation paper.

Anversa’s group also pioneered a method of separating cells with potential regenerative abilities from other cardiac tissue based on the presence of a protein called c-kit. After publishing evidence that these cardiac c-kit+cells spur new muscle growth in rodent hearts, the group collaborated in the SCIPIO trial to inject them into patients with heart failure. In The Lancet, the scientists reported that the therapy was safe and showed modest ability to strengthen the heart—evidence that many found intriguing and provocative. Roberto Bolli, the cardiologist whose group at the University of Louisville in Kentucky ran the SCIPIO trial, plans to test c-kit+ cells in further clinical trials as part of the NIH-funded Cardiovascular Cell Therapy Research Network.

But others have been unable to reproduce the dramatic effects Anversa saw in animals, and some have questioned whether these cells really have stem cell–like properties. In May, a group led by Jeffery Molkentin, a molecular biologist at Cincinnati Children’s Hospital Medical Center in Ohio, published a paper in Nature tracing the genetic lineage of c-kit+ cells that reside in the heart. He concluded that although they did make new muscle cells, the number is “astonishingly low” and likely not enough to contribute to the repair of damaged hearts. Still, Molkentin says that he “believe[s] in their therapeutic potential” and that he and Anversa have discussed collaborating.

Now, an anonymous blogger claims that problems in the Anversa lab go beyond controversial findings. In a letter published on the blog Retraction Watch on 30 May, a former research fellow in the Anversa lab described a lab culture focused on protecting the c-kit+ cell hypothesis: “[A]ll data that did not point to the ‘truth’ of the hypothesis were considered wrong,” the person wrote. But another former lab member offers a different perspective. “I had a great experience,” says Federica Limana, a cardiovascular disease researcher at IRCCS San Raffaele Pisana in Rome who spent 2 years of her Ph.D. work with the group in 1999 and 2000, as it was beginning to investigate c-kit+ cells. “In that period, there was no such pressure” to produce any particular result, she says.

Accusations about the lab’s integrity, combined with continued silence from BWH, are deeply troubling for scientists who have staked their research on theories that Anversa helped pioneer. Some have criticized BWH for requesting retractions in the midst of an investigation. “Scientific reputations and careers hang in the balance,” Sussman says, “so everyone should wait until all facts are clearly and fully disclosed.”

 

II.  Trolling Along: Recent Commotion About Patent Trolls

July 17, 2014

PriceWaterhouseCoopers recently released a study about 2014 Patent Litigation. PwC’s ultimate conclusion was that case volume increased vastly and damages continue a general decline, but what’s making headlines everywhere is that “patent trolls” now account for 67% of all new patent lawsuits (see, e.g., Washington Post and Fast Company).

Surprisingly, looking at PwC’s study, the word “troll” is not to be found. So, with regard to patent trolls, what does this study really mean for companies, patent owners and casual onlookers?

First of all, who are these trolls?

“Patent Troll” is a label applied to patent owners who do not make or manufacture a product, or offer a service. Patent trolls live (and die) by suing others for allegedly practicing an invention that is claimed by their patents.

The politically correct term is Non-practicing Entity (NPE). PwC solely uses the term NPE, which it defines as an entity that does not have the capability to design, manufacture, or distribute products with features protected by the patent.

So, what’s so bad about them?

The common impression of an NPEs is a business venture looking to collect and monetize assets (i.e., patents). In the most basic strategy, an NPE typically buys patents with broad claims that cover a wide variety of technologies and markets, and then sues a large group of alleged patent infringers in the hope to collect a licensing royalty or a settlement. NPEs typically don’t want to spend money on a trial unless they have to, and one tactic uses settlements with smaller businesses to build a “war chest” for potential suits with larger companies.

NPEs initiating a lawsuit can be viewed positively, such as a just defense of the lowly inventor who sold his patent to someone (with deeper pockets) who could fund the litigation to protect the inventor’s hard work against a mega-conglomerate who ripped off his idea.

Or NPE litigation can be seen negatively, such as an attorney’s demand letter on behalf of an anonymous shell corporation to shake down dozens of five-figure settlements from all the local small businesses that have ever used a fax machine.

NPEs can waste a company’s valuable time and resources with lawsuits, yet also bring value to their patent portfolios by energizing a patent sales and licensing market. There are unscrupulous NPEs, but it’s hardly the black and white situation that some media outlets are depicting.

What did PwC say about trolls?

Well, the PwC study looked at the success rates and awards of patent litigation decisions. One conclusion is that damages awards for NPEs averaged more than triple those for practicing entities over the last four years. We’ll come back to this statistic.

Another key observation is that NPEs have been successful 25% of the time overall, versus 35% for practicing entities. This makes sense because of the burden of proof the NPEs carry as a plaintiff at trial and the relative lack of success for NPEs at summary judgment. However, PwC’s report states that both types of entities win about two-thirds of their trials.

But what about this “67% of all patent trials are initiated by trolls” discussion?

The 67% number comes from the RPX Corporation’s litigation report (produced January 2014) that quantified the percentage of NPE cases filed in 2013 as 67%, compared to 64% in 2012, 47% in 2011, 30% in 2010 and 28% in 2009.

PwC refers to the RPX statistics to accentuate that this new study indicates that only 20% ofdecisions in 2013 involved NPE-filed cases, so the general conclusion would be that NPE cases tend to settle or be dismissed prior to a court’s decision. Admittedly, this is indicative of the prevalent “spray and pray” strategy where NPEs prefer to collect many settlement checks from several “targets” and avoid the courtroom.

In this study, who else is an NPE?

If someone were looking to dramatize the role of “trolls,” the name can be thrown around liberally (and hurtfully) to anyone who owns and asserts a patent without offering a product or a service. For instance, colleges and universities fall under the NPE umbrella as their research and development often ends with a series of published papers rather than a marketable product on an assembly line.

In fact, PwC distinguishes universities and non-profits from companies and individuals within their NPE analysis, with only about 5% of the NPE cases from 1995 to 2013 being attributed to universities and non-profits. Almost 50% of the NPE cases are attributed to an “individual,” who could be the listed inventor for the patent or a third-party assignee.

The word “troll” is obviously a derogatory term used to connote greed and hiding (under a bridge), but the term has adopted a newer, meme-like status as trolls are currently depicted as lacking any contribution to society and merely living off of others’ misfortunes and fears. [Three Billy Goats Gruff]. This is not always the truth with NPEs (e.g., universities).

No one wants to be called a troll—especially in front of a jury—so we’ve even recently seen courts bar defendants from referring to NPEs as such colorful terms as a “corporate shell,” “bounty hunter,” “privateer,” or someone “playing the lawsuit lottery.” [Judge Koh Bans Use Of Term ” Patent Troll” In Apple Jury Trial]

Regardless of the portrayal of an NPE, most people in the patent world distinguish the “trolls” by the strength of the patent, merits of the alleged infringement and their behavior upon notification. Often these are expressed as “frivolity” of the case and “gamesmanship” of the attorneys. Courts are able to punish plaintiffs who bring frivolous claims against a party and state bar associations are tasked with monitoring the ethics of attorneys. The USPTO is tasked with working to strengthen the quality of patents.

What’s the take-away from this study regarding NPEs?

The study focuses on patent litigation that produced a decision, therefore the most important and relevant conclusion is that, over the last four years, average damages awards for NPEs are more than triple the damages for practicing entities. Everything else in these articles, such as the initiation of litigation by NPEs, settlement percentages, and the general behavior of patent trolls is pure inference beyond the scope of the study.

This may sound sympathetic to trolls, but keep in mind that the study highlights that NPEs have more than triple the damages on average compared to practicing entities and it is meant to shock the reader a bit. One explanation for this is that NPEs are in the best position to choose the patents they want to assert and choose the targets they wish to sue—especially when the NPE is willing to ride that patent all the way to the end of a long, expensive trial. Sometimes settling is not an option. Chart 2b indicates that the disparity in the damages awarded to NPEs relative to practicing entities has always been big (since 2000), but perhaps going from two-fold from 2000 – 2009 to three times as much in the past 4 years indicates that NPEs are improving at finding patents and/or picking battles to take all the way to a court decision. More than anything, this seems to reflect the growth in the concept of patents as a business asset.

The PwC report is chock full of interesting patterns and trends of litigation results, so it’s a shame that the 67% number makes the headlines—far more interesting are the charts comparing success rates by 4-year periods (Chart 6b) or success rates for NPEs and practicing entities in front of a jury verusin front of a bench (Chart 6c), as well as other tables that reveal statistics for specific districts of the federal courts. Even the stats that look at the success rates of each type of NPE are telling because the reader sees that universities and non-profits have a higher success rate than non-practicing companies or individuals.

What do we do about the trolls?

The White House has recently called for Congress to do something about the trolls as horror stories of scams and shake-downs are shared. A bill was gaining momentum in the Senate, when Senator Leahy took it off the agenda in early July. That bill had miraculously passed 325-91 in the House and President Obama was willing to sign it if the Senate were to pass it. The bill was opposed by trial attorneys, universities, and bio-pharmaceutical businesses who felt as though the law would severely inhibit everyone’s access to the courts in order to hinder just the trolls. Regardless, most people think that the sitting Congressmen merely wanted a “win” prior to the mid-term elections and that patent reform is unlikely to reappear until next term.

In the meantime, the Supreme Court has recently reiterated rules concerning attorney fee-shifting on frivolous patent cases, as well as clarifying the validity of software patents. Time will tell if these changes have any effects on the damages awards that PwC’s study examined or even if they cause a chilling of the number of patent lawsuit filings.

Furthermore, new ways to challenge the validity of asserted patents have been initiated via the America Invents Act. For example, the Inter Partes Review (IPR) has yielded frightening preliminary statistics as to slowing, if not killing, patents that have been asserted in a suit. While these administrative trials are not cheap, many view these new tools at the Patent Trial and Appeals Board as anti-troll measures. It will be interesting to watch how the USPTO implements these procedures in the near future, especially while former Google counsel, Acting Director Michelle K. Lee, oversees the office.

In the private sector, Silicon Valley has recently seen a handful of tech companies come together as the License on Transfer Network, a group hoping to disarm the “Patent Assertion Entities.” Joining the LOT Network comes via an agreement that creates a license for use of a patent by anyone in the LOT network once that patent is sold. The thought is that the NPEs who consider purchasing patents from companies in the LOT Network will have fewer companies to sue since the license to the other active LOT participants will have triggered upon the transfer and, thus, the NPE will not be as inclined to “troll.” For instance, if a member-company such as Google were to sell a patent to a non-member company and an NPE bought that patent, the NPE would not be able to sue any members of the LOT Network with that patent.

Other notes

NPEs are only as evil as the people who run them—that being said, there are plenty of horror stories of small businesses receiving phantom demand letters that threaten a patent infringement suit without identifying themselves or the patent. This is an out-and-out scam and a plague on society that results in wasted time and resource, and inevitably higher prices on the consumer end.

It is a sin and a shame that patent rights can be misused in scams and shake-downs of businesses around us, but there is a reason that U.S. courts are so often used to defend patent rights. The PwC study, at minimum, reflects the high stakes of the patent market and perhaps the fragility. Nevertheless, merely monitoring the courts may not keep the trolls at bay.

I’d love to hear your thoughts.

*This is provided for informational purposes only, and does not constitute legal or financial advice. The information expressed is subject to change at any time and should be checked for completeness, accuracy and current applicability. For advice, consult a suitably licensed attorney or patent agent.

 

III. Large-scale analysis finds majority of clinical trials don’t provide meaningful evidence

Ineffective TreatmentsMedical Ethics • Tags: Center for Drug Evaluation and ResearchClinical trialCTTIDuke University HospitalFDAFood and Drug AdministrationNational Institutes of HealthUnited States National Library of Medicine

04 May 2012

DURHAM, N.C.— The largest comprehensive analysis of ClinicalTrials.gov finds that clinical trials are falling short of producing high-quality evidence needed to guide medical decision-making. The analysis, published today in JAMA, found the majority of clinical trials is small, and there are significant differences among methodical approaches, including randomizing, blinding and the use of data monitoring committees.

“Our analysis raises questions about the best methods for generating evidence, as well as the capacity of the clinical trials enterprise to supply sufficient amounts of high quality evidence to ensure confidence in guideline recommendations,” said Robert Califf, M.D., first author of the paper, vice chancellor for clinical research at Duke University Medical Center, and director of the Duke Translational Medicine Institute.

The analysis was conducted by the Clinical Trials Transformation Initiative (CTTI), a public private partnership founded by the Food and Drug Administration (FDA) and Duke. It extends the usability of the data in ClinicalTrials.gov for research by placing the data through September 27, 2010 into a database structured to facilitate aggregate analysis. This publically accessible database facilitates the assessment of the clinical trials enterprise in a more comprehensive manner than ever before and enables the identification of trends by study type.

 

The National Library of Medicine (NLM), a part of the National Institutes of Health, developed and manages ClinicalTrials.gov. This site maintains a registry of past, current, and planned clinical research studies.

“Since 2007, the Food and Drug Administration Amendment Act has required registration of clinical trials, and the expanded scope and rigor of trial registration policies internationally is producing more complete data from around the world,” stated Deborah Zarin, MD, director, ClinicalTrials.gov, and assistant director for clinical research projects, NLM. “We have amassed over 120,000 registered clinical trials. This rich repository of data has a lot to say about the national and international research portfolio.”

This CTTI project was a collaborative effort by informaticians, statisticians and project managers from NLM, FDA and Duke. CTTI comprises more than 60 member organizations with the goal of identifying practices that will improve the quality and efficiency of clinical trials.

“Since the ClinicalTrials.gov registry contains studies sponsored by multiple entities, including government, industry, foundations and universities, CTTI leaders recognized that it might be a valuable source for benchmarking the state of the clinical trials enterprise,” stated Judith Kramer, MD, executive director of CTTI.

The project goal was to produce an easily accessible database incorporating advances in informatics to permit a detailed characterization of the body of clinical research and facilitate analysis of groups of studies by therapeutic areas, by type of sponsor, by number of participants and by many other parameters.

“Analysis of the entire portfolio will enable the many entities in the clinical trials enterprise to examine their practices in comparison with others,” says Califf. “For example, 96% of clinical trials have ≤1000 participants, and 62% have ≤ 100. While there are many excellent small clinical trials, these studies will not be able to inform patients, doctors and consumers about the choices they must make to prevent and treat disease.”

The analysis showed heterogeneity in median trial size, with cardiovascular trials tending to be twice as large as those in oncology and trials in mental health falling in the middle. It also showed major differences in the use of randomization, blinding, and data monitoring committees, critical issues often used to judge the quality of evidence for medical decisions in clinical practice guidelines and systematic overviews.

“These results reinforce the importance of exploration, analysis and inspection of our clinical trials enterprise,” said Rachel Behrman Sherman, MD, associate director for the Office of Medical Policy at the FDA’s Center for Drug Evaluation and Research. “Generation of this evidence will contribute to our understanding of the number of studies in different phases of research, the therapeutic areas, and ways we can improve data collection about clinical trials, eventually improving the quality of clinical trials.”

Related articles

 

IV.  Lawmakers urge CMS to extend MU hardship exemption for pathologists

 

Eighty-nine members of Congress have asked the Centers for Medicare & Medicaid Services to give pathologists a break and extend the hardship exemption they currently enjoy for all of Stage 3 of the Meaningful Use program.In the letter–dated July 10 and addressed to CMS Administrator Marilyn Tavenner–the lawmakers point out that CMS had recognized in its 2012 final rule implementing Stage 2 of the program that it was difficult for pathologists to meet the Meaningful Use requirements and granted a one year exception for 2015, the first year that penalties will be imposed. They now are asking that the exception be expanded to include the full five-year maximum allowed under the American Recovery and Reinvestment Act.

“Pathologists have limited direct contact with patients and do not operate in EHRs,” the letter states. “Instead, pathologists use sophisticated computerized laboratory information systems (LISs) to support the work of analyzing patient specimens and generating test results. These LISs exchange laboratory and pathology data with EHRs.”

Interestingly, the lawmakers’ exemption request is only on behalf of pathologists, even though CMS had granted the one-year hardship exception to pathologists, radiologists and anesthesiologists.

Rep. Tom Price (R-Ga.), one of the members spearheading the letter, had also introduced a bill (H.R. 1309) in March 2013 that would exclude pathologists from the incentives and penalties of the Meaningful Use program. The bill, which has 31 cosponsors, is currently sitting in committee. That bill also does not include relief for radiologists or anesthesiologists.

CMS has provided some flexibility about the hardship exceptions in the past, most recently by allowing providers to apply for one due to EHR vendor delays in upgrading to Stage 2 of the program.

However, CMS also noted in the 2012 rule granting the one-year exception that it was granting the exception in large part because of the then-current lack of health information exchange and that “physicians in these three specialties should not expect that this exception will continue indefinitely, nor should they expect that we will grant the exception for the full 5-year period permitted by statute.”

To learn more:
– read the letter (.pdf)

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A Great University engaged in Drug Discovery: University of Pittsburgh

 

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

 

The US-based pharmaceutical companies have been consolidating and now are moving offshore to reduce taxes and other costs.  A part of the problem has been the large cost of clinical trials, the failure to detect toxicities in the early phases, and late phase failure or drug resistance conferring short term success.  This has been at a rate above 60%.  The result is that Big Pharma is looking to recycling old drugs for repurposing. Whatever success can be obtained from this, there is a larger problem in not having a comprehensive biological understanding of the problems imposed by the complexity on a deeper understanding.  I present here a major university, very well recognized in genetics, proteomics, and experimental pathology engaged in the drug development effort with reasonable promise of successes.

 

Perspective On: A Drug Discovery Lab

As lab manager at the University of Pittsburgh Drug Discovery Institute (UPDDI), Celeste Reese and her team use high-content imaging strategies and work with many other labs both within the university and outside the university on a wide range of projects.

By Rachel Muenz | July 03, 2014

 

We try to use new technologies and approaches and quantitative systems pharmacology (QSP) to complement the traditional drug discovery strategies

We try to use new technologies and approaches and quantitative systems pharmacology (QSP) to complement the traditional drug discovery strategies

 

 

Finding Clinically Relevant Solutions

Hard work, teamwork, and a whole lot of multitasking help this lab overcome a tough economic environment

“We try to use new technologies and approaches and quantitative systems pharmacology (QSP) to complement the traditional drug discovery strategies that are used by the large pharmacy companies,” she explains, adding that, on average, they have seven to ten active projects going on at any given time. “Right now we have a metastatic breast cancer program, a head and neck cancer project, and a Huntington’s disease project. We do some zebra fish modeling, some development of novel HIV diagnostics, liver modeling, and a variety of other things.”

Those projects take place in the institute’s 11,000 square feet of space, which covers two floors of the building the institute occupies and includes a large open lab on the top floor and an imaging lab, automation lab, and tissue culture facility on the floor below. Working in that space are 34 staff, including seven faculty, four graduate students, and five undergraduates, with the rest made up of technical specialists, administrative staff, and Reese herself. As in many other labs, staff members have a wide range of education levels—from high school for the undergrads all the way up to extensive post-doctoral experience for the faculty, Reese says, adding that staff receive quite a bit of training when they begin.

“The university has a lot of training modules that we send people to for such things as chemical hygiene, safety, and blood-borne pathogens, even things like safe shipping,” she says. “Then there are modules like conflict of interest training and research integrity training, which are also provided by the university. In-house, we train everyone on our equipment and on the procedures and protocols that we use within our institute.”

Training the grads and undergrads on those lab procedures is a big part of Reese’s role as lab manager, a task that she considers one of the highlights of the position.

“I really like working with the graduate students who come into the lab,” Reese says. “They always have a fresh perspective and they’re always challenging established protocols. They’re fresh and enthusiastic.”

The Catalyst Express robot is used to load plates onto a high-content imaging platform.It was a similar enthusiasm for science that led Reese to pursue the field in university, which led to a job in a pharmacology lab after graduation, getting her interested in the drug discovery field and—after 14 years staying home to raise her children—eventually brought her to the UPDDI, where she has worked for the past eight years.

“I’ve always loved science in general but then after college I got the job in the pharmacology lab and I just really liked experimental design and problem solving and implementation—which eventually led into the lab management position,” says Reese, who has now been lab manager at the UPDDI for four years.

Because of her enjoyment of experimenting, along with her other management duties of looking after supplies and equipment, Reese also likes to keep a hand in what’s going on in the lab.

“I keep an active role in at least one of the research projects that we have going on,” she explains. “I find that that’s very helpful in the lab management area as well, because I see key things while I’m doing experiments that I normally wouldn’t see on a walkthrough.”

Blocking out the day

Liquid nitrogen cell bank.

Liquid nitrogen cell bank.

 

 

Liquid nitrogen cell bank.For Reese, scheduling chunks of time for certain tasks is critical in ensuring she meets her goals for the day.

“Time management’s key when you’re trying to cover as many roles as it takes to do this job,” she says. “I try to keep the mornings for the lab management tasks and then the afternoons are usually taken up with meetings, experimental design and implementation, or data analysis.”

That means Reese’s mornings typically involve coming in, checking on what’s happening in the lab, looking after the ordering of supplies for the week, and attending to any equipment problems and emails. Along with meetings, her afternoons are usually taken up with running or designing experiments or analyzing data. Of course, the rest of the staff have a variety of different roles.

A few programs and regular inventory checks help keep everything organized.

“One of the big tools we have is a purchasing program that we have developed in-house—an access program that we use and a similar one for equipment reservations and things like that,” Reese says. “We do a weekly inventory. We have two stockroom areas and we have two student workers who go out and stock all the individual work areas for people every day. And then we also have written protocols and established procedures for things like routine equipment maintenance and buffer preparations and such.”

She adds that the main challenge her lab faces is the same one that many other labs face—doing more with less in the current tough economic climate. For her lab, multitasking and teamwork are a big part of solving that issue.

“We just have really talented people here,” Reese says of her staff. “Everybody takes on a variety of roles. Everybody pitches in with things like routine equipment maintenance and … rather than having one person in each job, everybody covers a variety of tasks.” Because of that strong teamwork, Reese finds she doesn’t need to do much to motivate members of the lab.

“I don’t manage people—I just try to lead by example and try to take care of any issues that come up promptly rather than put things off,” she explains. “Everybody’s pretty self-motivated and hardworking here.”

An automated compound storage system is used to store the institute’s screening libraries.

An automated compound storage system is used to store the institute’s screening libraries.

 

six separate tissue culture facilities

six separate tissue culture facilities

 

 

 

 

 

 

 

 

 

 

 

An automated compound storage system is used to store the institute’s screening libraries. The UPDDI has six separate tissue culture facilities equipped with biosafety cabinets, incubators, and microscopes.

The tech side

Along with the aforementioned high-content imaging, Reese’s lab also uses automated liquid handling platforms, biosensors, microfluidics, and immunofluorescence and fluorescence microscopy, and they are starting to implement 3D cell culture strategies to tackle their many projects.

“These fluorescent proteins react to the physiological changes in the cell in real time,” Reese says of the lab’s work with biosensors. “And [with] microfluidics you actually have a moving system. The system is more clinically relevant— it’s a better model for the in vivo systems.”

By “clinically relevant” Reese says she basically means the center is trying to more closely model what is actually going on in the human body, rather than relying on traditional 2D cell culture models or high throughput methods. That focus on clinically relevant methods is a result of big changes in the pharmaceutical industry in recent years.

Top 5 Instruments in the Lab

  • GE InCell6000 Imaging System
  • Agilent (Velocity 11) Bravo Liquid Handling Platform
  • Thermo Scientific Multidrop Combi Dispenser
  • PerkinElmer EnVision 2103 Multilabel Plate Reader
  • Brooks (Matrical) Ministore Automated Compound  Management System

“In the drug discovery field in general, big pharma has been using the mass-scale high throughput screening for a long time and of course now we’re coming to the patent cliff for a lot of the pharmaceutical companies, when a lot of their moneymakers are going off patent,” Reese explains. “So here, we’re trying to move away from that high throughput screening toward a more high-content [screening] where we’re looking at more clinically relevant methods and QSP approaches for drug discovery.”

And the most interesting work the lab is doing right now?

“I would say the coolest thing we have going on is a liver microphysiology project,” Reese says. “We’re making a liver biomimetic, which will be integrated with other organ biomimetics to create a human-on-a-chip for use as a model for drug toxicity and other kinds of organ analysis.”

Categories: Research-Specific Labs

Tags: Drug Discovery Labs

 

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