Day: 01/07/2012

Kegel exercises for men: Understand the benefits.

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Think Kegel exercises are just for women? Think again. Kegel exercises for men can strengthen the pelvic floor muscles, which support the bladder and bowel and affect sexual function. With practice, Kegel exercises for men can be done discreetly just about anytime — whether you’re relaxing on the couch or driving your car. Before you start doing Kegel exercises, find out how to locate the correct muscles and understand the proper technique.

Benefits of Kegel exercises for men

Many factors can weaken your pelvic floor muscles, including a radical prostatectomy and conditions such as diabetes. Kegel exercises for men can help prevent, treat or delay some of the symptoms caused by weak pelvic floor muscles, such as urine leakage. You may benefit from doing Kegel exercises if you have:

  • Urinary or fecal incontinence
  • Dribble following urination

Limited research suggests that Kegel exercises for men may also benefit some men who have erectile dysfunction.

How to do Kegel exercises for men

It takes diligence to identify your pelvic floor muscles and understand how to contract and relax them. Here are some pointers:

  • Find the right muscles. To make sure you know how to contract your pelvic floor muscles, tightly squeeze the muscles that help prevent you from passing gas or try to stop the flow of urine while you’re using the toilet. If you look in the mirror, the base of your penis will move closer to your abdomen and your testicles will rise.
  • Perfect your technique. Once you’ve identified your pelvic floor muscles, empty your bladder and lie down. Contract your pelvic floor muscles, hold the contraction for three seconds, then relax for three seconds. Try it a few times in a row but don’t overdo it. When your muscles get stronger, try doing Kegel exercises while sitting, standing or walking.
  • Maintain your focus. For best results, focus on tightening only your pelvic floor muscles. Be careful not to flex the muscles in your abdomen, thighs or buttocks. Avoid holding your breath. Instead, breathe freely during the exercises.
  • Repeat three times a day. Aim for at least three sets of 10 repetitions a day. You might make a practice of fitting in a set every time you do a routine task, such as brushing your teeth.

Kegel exercises can also be done after you finish voiding, to get rid of the last few drops of urine or to return any feces that haven’t been voided up to the rectum. You might also contract your pelvic floor muscles just before and during any activity that puts pressure on your abdomen, such as sneezing, coughing, laughing or heavy lifting. In addition, you might tighten your pelvic floor muscles during sexual activity to maintain an erection or delay ejaculation.

When you’re having trouble

If you’re having trouble doing Kegel exercises, don’t be embarrassed to ask for help. Your doctor or other health care provider can give you important feedback so that you learn to isolate and exercise the correct muscles.

In some cases, biofeedback training may help. In a biofeedback session, your doctor or other health care provider inserts a small monitoring probe into your rectum. When you contract your pelvic floor muscles, you’ll see a measurement on a monitor that lets you know whether you’ve successfully contracted the right muscles. You’ll also be able to see how long you hold the contraction.

When to expect results

If you do your Kegel exercises regularly, you can expect to see results — such as less frequent urine leakage — within three to six weeks. Other results, such as improved erectile function, may take three months. For continued benefits, make Kegel exercises a permanent part of your daily routine.

Source:Mayo Clinic

 

Monoclonal antibody drugs for cancer treatment: How they work?

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Monoclonal antibody drugs are a relatively new innovation in cancer treatment. While several monoclonal antibody drugs are available for treating certain cancers, the best way to use these new drugs isn’t always clear.

If you and your doctor are considering using a monoclonal antibody as part of your cancer treatment, find out what to expect from this therapy. Together you and your doctor can decide whether a monoclonal antibody treatment may be right for you.

What is a monoclonal antibody?

A monoclonal antibody is a laboratory-produced molecule that’s carefully engineered to attach to specific defects in your cancer cells. Monoclonal antibodies mimic the antibodies your body naturally produces as part of your immune system’s response to germs, vaccines and other invaders.

How do monoclonal antibody drugs work?

When a monoclonal antibody attaches to a cancer cell, it can:

  • Make the cancer cell more visible to the immune system. The immune system attacks foreign invaders in your body, but it doesn’t always recognize cancer cells as enemies. A monoclonal antibody can be directed to attach to certain parts of a cancer cell. In this way, the antibody marks the cancer cell and makes it easier for the immune system to find.

The monoclonal antibody drug rituximab (Rituxan) attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack. Rituximab lowers the number of B cells, including your healthy B cells, but your body produces new healthy B cells to replace these. The cancerous B cells are less likely to recur.

  • Block growth signals. Chemicals called growth factors attach to receptors on the surface of normal cells and cancer cells, signaling the cells to grow. Certain cancer cells make extra copies of the growth factor receptor. This makes them grow faster than the normal cells. Monoclonal antibodies can block these receptors and prevent the growth signal from getting through.

Cetuximab (Erbitux), a monoclonal antibody approved to treat colon cancer and head and neck cancers, attaches to receptors on cancer cells that accept a certain growth signal (epidermal growth factor). Cancer cells and some healthy cells rely on this signal to tell them to divide and multiply. Blocking this signal from reaching its target on the cancer cells may slow or stop the cancer from growing.

  • Stop new blood vessels from forming. Cancer cells rely on blood vessels to bring them the oxygen and nutrients they need to grow. To attract blood vessels, cancer cells send out growth signals. Monoclonal antibodies that block these growth signals may help prevent a tumor from developing a blood supply, so that it remains small. Or in the case of a tumor with an already-established network of blood vessels, blocking the growth signals could cause the blood vessels to die and the tumor to shrink.

The monoclonal antibody bevacizumab (Avastin) is approved to treat a number of cancers, not including breast cancer. Bevacizumab targets a growth signal called vascular endothelial growth factor (VEGF) that cancer cells send out to attract new blood vessels. Bevacizumab intercepts a tumor’s VEGF signals and stops them from connecting with their targets.

  • Deliver radiation to cancer cells. By combining a radioactive particle with a monoclonal antibody, doctors can deliver radiation directly to the cancer cells. This way, most of the surrounding healthy cells aren’t damaged. Radiation-linked monoclonal antibodies deliver a low level of radiation over a longer period of time, which researchers believe is as effective as the more conventional high-dose external beam radiation.

Ibritumomab (Zevalin), approved for non-Hodgkin’s lymphoma, combines a monoclonal antibody with radioactive particles. The ibritumomab monoclonal antibody attaches to receptors on cancerous blood cells and delivers the radiation.

A number of monoclonal antibody drugs are available to treat various types of cancer. Clinical trials are studying monoclonal antibody drugs in treating nearly every type of cancer.

Monoclonal antibodies are administered through a vein (intravenously). How often you undergo monoclonal antibody treatment depends on your cancer and what drug you’re receiving. Some monoclonal antibody drugs may be used in combination with other treatments, such as chemotherapy and hormone therapy. Others are administered alone.

Monoclonal antibody drugs were initially used to treat advanced cancers that hadn’t responded to chemotherapy or cancers that had returned despite treatment. However, because these treatments have proved to be effective, certain monoclonal antibody treatments are being used earlier in the course of the disease. For instance, rituximab can be used as an initial treatment in some types of non-Hodgkin’s lymphoma, and trastuzumab (Herceptin) is used in the treatment of some forms of early breast cancer.

Many of the monoclonal antibody therapies are still considered experimental. For this reason, these treatments are usually reserved for advanced cancers that aren’t responding to standard, proven treatments.

FDA-approved monoclonal antibodies for cancer treatment
Name of drug Type of cancer it treats
Alemtuzumab (Campath) Chronic lymphocytic leukemia
Bevacizumab (Avastin) Brain cancer
Colon cancer
Kidney cancer
Lung cancer
Cetuximab (Erbitux) Colon cancer
Head and neck cancers
Ibritumomab (Zevalin) Non-Hodgkin’s lymphoma
Ofatumumab (Arzerra) Chronic lymphocytic leukemia
Panitumumab (Vectibix) Colon cancer
Rituximab (Rituxan) Chronic lymphocytic leukemia
Non-Hodgkin’s lymphoma
Tositumomab (Bexxar) Non-Hodgkin’s lymphoma
Trastuzumab (Herceptin) Breast cancer
Stomach cancer

Source: Food and Drug Administration (FDA), Center for Drug Evaluation and Research

What types of side effects do monoclonal antibody drugs cause?

In general, monoclonal antibody treatment carries fewer side effects than do traditional chemotherapy treatments. However, monoclonal antibody treatment for cancer may cause side effects, some of which, though rare, can be very serious. Talk to your doctor about what side effects are associated with the particular drug you’re receiving.

Common side effects
In general, the more-common side effects caused by monoclonal antibody drugs include:

  • Allergic reactions, such as hives or itching
  • Flu-like signs and symptoms, including chills, fatigue, fever, and muscle aches and pains
  • Nausea
  • Diarrhea
  • Skin rashes

Serious side effects
Serious, but rare, side effects of monoclonal antibody therapy may include:

  • Infusion reactions. Severe allergy-like reactions can occur and, in very few cases, lead to death. You may receive medicine to block an allergic reaction before you begin monoclonal antibody treatment. Infusion reactions usually occur while treatment is being administered or soon after, so your health care team will watch you closely for a reaction.
  • Dangerously low blood cell counts. Low levels of red blood cells, white blood cells and platelets may lead to serious complications.
  • Heart problems. Certain monoclonal antibodies may cause heart problems, including heart failure and a small risk of heart attack.
  • Skin problems. Sores and rashes on your skin can lead to serious infections in some cases. Serious sores can also occur on the tissue that lines your cheeks and gums (mucosa).
  • Bleeding. Some of the monoclonal antibody drugs are designed to stop cancer from forming new blood vessels. There have been reports that these medications can cause bleeding.

What should you consider when deciding on monoclonal antibody drug treatment?

Discuss your cancer treatment options with your doctor. Together you can weigh the benefits and risks of each treatment and decide whether a monoclonal antibody treatment is right for you.

Questions to ask your doctor include:

  • Has the monoclonal antibody drug shown a clear benefit? Some monoclonal antibody drugs are approved for advanced cancer, though they haven’t been shown to extend lives. Instead, some drugs are more likely to slow a cancer’s growth or stop tumor growth temporarily.
  • What are the likely side effects of monoclonal antibody treatment? With your doctor, you can determine whether the potential side effects of treatment are worth the likely benefit.
  • How much will monoclonal antibody treatment cost? Monoclonal antibody drugs can cost thousands of dollars per treatment. Insurance doesn’t always cover these costs.
  • Is monoclonal antibody treatment available in a clinical trial? Clinical trials, which are studies of new treatments and new ways to use existing treatments, may be available to you. In a clinical trial, the cost of the monoclonal antibody drug may be paid for as a part of the study. Also, you may be able to try new monoclonal antibody drugs. Talk to your doctor about what clinical trials may be open to you.

Source:Mayo Clinic

 

 

Is air travel during pregnancy safe, especially near the beginning or end of pregnancy?

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Generally, commercial air travel during pregnancy is considered safe for women who have healthy pregnancies. Still, if you’re pregnant, it’s best to check with your health care provider before you fly.

For women who have certain conditions — such as sickle cell disease, clotting disorders and placental insufficiency — air travel during pregnancy might increase the risk of complications. In addition, your health care provider might restrict travel of any type after 36 weeks of pregnancy or if you’re at risk of preterm delivery.

If your health care provider approves air travel and you have flexibility in your travel plans, the best time to fly might be in the middle of your pregnancy — about weeks 14 to 28. This is when you’re likely to feel your best, and the risks of miscarriage and premature labor are the lowest.

When you fly:

  • Check the airline’s policy about air travel during pregnancy. Guidelines for pregnant women may vary by carrier and destination.
  • Choose your seat carefully. For the most space and comfort, request an aisle seat.
  • Buckle up. During the trip, fasten the lap belt under your abdomen and across the tops of your thighs.
  • Promote circulation. If possible, take occasional walks up and down the aisle. If you must remain seated, flex and extend your ankles often.
  • Drink plenty of fluids. Low humidity in the cabin can lead to dehydration.

Decreased air pressure during flight may slightly reduce the amount of oxygen in your blood, but this isn’t likely to cause problems if you’re otherwise healthy. Likewise, the radiation exposure associated with air travel at high altitudes isn’t thought to be problematic for most business or leisure travelers. There’s a caveat for frequent fliers, however. Pilots, flight attendants and others who fly often might be exposed to more radiation than is considered safe during pregnancy. If you must fly frequently during your pregnancy, discuss it with your health care provider. He or she might limit your total flight time during pregnancy.

Source:Mayo Clinic.

 

Renal cancer and pneumothorax risk in Birt–Hogg–Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.

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Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD.

Methods:

In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families.

Results:

Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6–26%) and 29% (95% minimal confidence interval: 9–49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas.

Conclusion:

We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

Source:BJC

 

Role of histological type on surgical outcome and survival following radical primary tumour debulking of epithelial ovarian, fallopian tube and peritoneal cancers.

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To assess the clinical impact of the two histological types as designated in the proposed model for ovarian tumourigenesis in primary epithelial ovarian, fallopian tube or peritoneal cancer (EOC) patients.

Methods:

All consecutive EOC patients (n=632) after primary tumour debulking in our institution (09/2000–08/2010) were classified into one of two groups: type I tumours (n=100; 15.8%) composed of low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional carcinomas; and Type II tumours (n=532; 84.1%) composed of high-grade serous, high-grade endometrioid, undifferentiated and malignant mixed-mesodermal tumours. Kaplan–Meier and logistic/Cox-regression analyses were performed to assess the impact of histological type on surgical outcome and survival.

Results:

Type II patients had a significantly higher incidence of advanced disease (FIGO III/IV) than Type I patients (79.8% vs 38%, respectively; P<0.001). Median CA125 values (438 vs 93 U ml−1; P=0.001); operative time (258 vs 237 min; P=0.001); and incidence of incomplete tumour resection (34.4% vs 15%; P<0.001) were significantly higher in patients with Type II. During a mean follow-up time of 23 months (range: 1–106), 17% of patients with type I vs 34.8% of patients with type II tumours relapsed and/or died (P<0.001). Overall survival (P=0.021) and progression-free survival (P=0.003) were also significantly higher in patients with type I tumours. Multivariate analysis, while identifying postoperative tumour residuals, positive lymph nodes and extrapelvic dissemination as independent predictors of survival, failed to demonstrate any prognostic significance of histological type.

Conclusion:

  Type I EOC patients appear to present at earlier stages have significantly higher survival and more optimal surgical outcome compared with type II patients. However, in advanced stages, histology loses significance as an independent prognosticator.
Source:BJC

 

Severe clinical toxicities are correlated with survival in patients with advanced renal cell carcinoma treated with sunitinib and sorafenib.

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In advanced renal cell carcinoma (RCC), sunitinib and sorafenib tyrosine kinase inhibitors (TKI) are associated with several clinical side effects, with no definitive established data concerning their clinical impact.

Methods:

From June 2006 to June 2008, main clinical TKI-induced toxicities, including digestive, cardiac, dermatologic and asthenia were retrospectively collected using the NCI-CTC version 3.0 in patients treated with TKI for an RCC.

Results:

The median overall survival was significantly improved in patients with grade 3–4 clinical toxicities (36 vs 12 months, P=0.009). In multivariate analysis, the Memorial Sloan-Kettering Cancer Center risk groups (good vs intermediate or poor) and clinical toxicities (grade 3–4 vs 1–2) were identified as independent prognostic factors of better survival (P=0.002 and P=0.02, respectively). The Charlson comorbidity index score (>7 vs <7) was identified as independent predictive factor of severe clinical TKI-induced toxicities (P=0.02).

Conclusion:

In this unselected patients of RCC, clinical TKI-related severe toxicities were more frequent in patients with comorbidities and were associated with better survival.source:BJC

TFAP2E–DKK4 and Chemoresistance in Colorectal Cancer.

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Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy.

Methods

We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation.

Results

TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001). Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79). Epigenetic alterations of TFAP2E were independent of mutations in key regulatory cancer genes, microsatellite instability, and other genes that affect fluorouracil metabolism.

Conclusions

TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance.

Source:NEJM

 

 

 

Can Chocolate Really Be Good for You?

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Cartoon of a smiling dark chocolate bar and a sinister chocolate truffle.

Many of us would love to believe that chocolate is a health food. Maybe you’ve heard or read about its potential benefits. Eating chocolate may have some health pluses, but the research is far from certain. The drawbacks, on the other hand, are clear. Think twice before you reach for that tempting treat.

The idea that chocolate might be good for you stems from studies of the Kuna Indians, who live on islands off the coast of Panama. They have a low risk of cardiovascular disease or high blood pressure given their weight and salt intake. Researchers realized that genes weren’t protecting them, because those who moved away from the Kuna islands developed high blood pressure and heart disease at typical rates. Something in their island environment must have kept their blood pressure from rising.

“What was particularly striking about their environment was the amount of cocoa they consume, which was easily 10 times more than most of us would get in a typical day,” says Dr. Brent M. Egan, a researcher at the Medical University of South Carolina who studies the effect of chocolate on blood pressure.

But Kuna cocoa is a far cry from the chocolate that most Americans eat. The Kuna make a drink with dried and ground cocoa beans (the seeds of the cocoa tree) along with a little added sweetener. The chocolate we tend to eat, on the other hand, is made from cocoa beans that are roasted and processed in various other ways, and then combined with ingredients like whole milk.

Processing can extract 2 main components from cocoa beans: cocoa solids and cocoa butter. Powdered cocoa is made using the solids. Chocolate is made from a combination of cocoa solids and cocoa butter. The color of the chocolate depends partly on the amount of cocoa solids and added ingredients, such as milk. In general, though, the darker the chocolate, the more cocoa solids it contains. Researchers think the solids are where the healthy compounds are. White chocolate, in contrast, contains no cocoa solids at all.

The past decade has seen many studies into the health effects of chocolate. “We have good science on chocolate, especially about dark chocolate on blood pressure,” says Dr. Luc Djoussé of Harvard Medical School and Brigham and Women’s Hospital. His research team found an overall drop in blood pressure among people who eat more chocolate. “The results suggest that chocolate may, in fact, lower blood pressure,” Djoussé says. “This effect was even stronger among people with high blood pressure to begin with.”

Laboratory studies have uncovered several mechanisms that might explain chocolate’s heart-healthy benefits. However, it’s hard to prove whether the chocolate that most Americans eat actually has those effects in the human body. Controlling how much chocolate people eat and tracking them for long periods of time is not an easy task.

“The clinical trials that have been done in people have all been fairly short,” says Dr. Ranganath Muniyappa, an NIH staff clinician who studies diabetes and cardiovascular health. These studies, he explains, look at cardiovascular risk “markers”—factors related to heart health, such as blood pressure—not long-term outcomes like heart disease and stroke.

Studies looking into the long-term health effects of chocolate have relied on people to recall how much chocolate they ate. The researchers then compared those levels with health outcomes. While such studies can find associations, they can’t prove the effects of a particular food.

“People usually eat food in a pattern. A chocolate lover would eat chocolate with something else,” Djoussé explains. “It could be not so much the chocolate by itself, but chocolate in conjunction with, let’s say, whole grain or exercise or not smoking—the pattern of the lifestyle habit in general. It’s really hard to separate the effects of individual components.”

Chocolate contains high levels of compounds thought to help prevent cancer, too. But Dr. Joseph Su, an NIH expert in diet and cancer, says that direct evidence here is similarly hard to come by. Since cancer can take many years to develop, it’s difficult to prove whether eating chocolate can affect disease. Instead, researchers look to see if factors linked to cancer change when chocolate is consumed.

“Right now, some studies show really a remarkable modification of those markers,” Su says. But the evidence that chocolate can reduce cancer or death rates in people is still weak. “There are a few studies that show some effect,” Su says, “but the findings so far are not consistent.”

Some research also suggests that chocolate might help prevent diabetes. However, the challenges in proving this link are similar to those of heart disease and cancer.

Another thing that makes it hard to interpret these studies is that they often use different chocolates, and so their ingredients and health effects may vary.

Compounds called flavanols are thought to be responsible for many of chocolate’s beneficial effects. These compounds are also found in tea, wine, fruits and vegetables. Different chocolates can vary greatly in their flavanol content. Cocoa beans naturally differ in their flavanol levels. A large portion of the flavanols can also be removed during processing. In fact, companies often remove these compounds intentionally because of their bitter taste. The end result is that there’s no way to know whether the products you’re looking at contain high flavanol levels.

So should you eat chocolate? Chocolate can have a lot of calories, and the importance of a healthy weight is well known. “If you’re eating chocolate, make sure to watch the calorie content, the fat content and the sugar content,” Su says.

“For those who are already consuming chocolate, I would advise them to look for the darker ones,” Djoussé adds, “not the white chocolate or the milk chocolate. You won’t get any of the benefit. It’s just going to be unneeded calories.”

But there’s no need to start eating chocolate if you don’t already. “The science doesn’t allow us to make recommendations because the evidence is just not there,” Muniyappa says.

Meanwhile, NIH will continue to fund studies into the health effects of chocolate, and many other foods. Wouldn’t it be sweet if the research proved that chocolate is definitely good for us?

Source:NIH

Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.

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VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.

Methods A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.

Results The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.

Conclusions In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit.

Clinical trial number NCT00865904

Source:BMJ

A prospective clinical trial of lenalidomide with topotecan in women with advanced epithelial ovarian carcinoma.

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Lenalidomide is an anti-angiogenic IMiD® immunomodulatory drug. The objective of this study was to determine the maximum tolerated dose (MTD), overall safety profile, and activity of oral lenalidomide in combination with topotecan in women with advanced epithelial ovarian or primary peritoneal carcinoma.

Methods

In this Phase I/II open-label, dose-escalation study, patients with histologically or cytologically confirmed advanced ovarian or primary peritoneal carcinoma with disease progression or recurrence following first-line therapy with a platinum agent and paclitaxel were eligible. The Phase I trial utilized a standard dose-escalation design to define the MTD and evaluate the safety profile of lenalidomide and topotecan. The starting doses were lenalidomide 5 mg, days 1–14, and intravenous topotecan 1.25 mg/m2, days 1–5 of a 21-day cycle. Only the lenalidomide dose was escalated, in 5-mg increments up to 25 mg. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The Phase II portion was designed to evaluate the antitumor activity based on objective response rate of lenalidomide and topotecan.

Results

Five women with advanced epithelial ovarian carcinoma were enrolled, each receiving 5 mg oral lenalidomide and 1.25 mg/m2 topotecan. Four patients discontinued because of dose-limiting toxicity, most commonly grade 4 neutropenia (n = 3). One patient discontinued because of lack of therapeutic effect. The study was terminated early for reasons of toxicity.

Conclusion

The addition of lenalidomide to topotecan is not a feasible drug combination in women with advanced epithelial ovarian carcinoma because of dose-limiting toxicity.

Source: International Journal of Clinical Oncology