Genetic studies of human disease have traditionally focused on the detection of disease-causing mutations in afflicted individuals. Here we describe a complementary approach that seeks to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders. A comprehensive screen of 874 genes in 589,306 genomes led to the identification of 13 adults harboring mutations for 8 severe Mendelian conditions, with no reported clinical manifestation of the indicated disease. Our findings demonstrate the promise of broadening genetic studies to systematically search for well individuals who are buffering the effects of rare, highly penetrant, deleterious mutations. They also indicate that incomplete penetrance for Mendelian diseases is likely more common than previously believed. The identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies.

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This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan).
Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2.
Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment.
The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.

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Extensive-disease small-cell lung cancer (ED-SCLC) is characterized by rapid progression and relapse, despite high initial response rates to chemotherapy. The primary objective of this trial was to demonstrate the non-inferiority of amrubicin and cisplatin (AP) combination therapy compared with the standard first-line regimen of etoposide and cisplatin (EP) for previously untreated ED-SCLC in a Chinese population. When non-inferiority was verified, the objective was switched from non-inferiority to superiority.
From June 2008 to July 2010, 300 patients were enrolled and randomly assigned at a 1:1 ratio to AP and EP groups. AP-treated patients received cisplatin (60 mg/m(2), day 1) and amrubicin (40 mg/m(2), days 1-3) once every 21 days. EP-treated patients received cisplatin (80 mg/m(2), day 1) and etoposide (100 mg/m(2), days 1-3) once every 21 days. Treatment was continued for four to six cycles, except in cases of progressive disease or toxicity, and patient refusal.
Median overall survival (OS) for AP vs. EP treatment was 11.8 vs. 10.3 months (p = 0.08), respectively, demonstrating non-inferiority of AP to EP (AP group: 95 % confidence interval for hazard ratio 0.63-1.03 months). Median progression-free survival and overall response rates for AP vs. EP groups were 6.8 vs. 5.7 months (p = 0.35) and 69.8 % vs. 57.3 %, respectively. Drug-related adverse events in both groups were similar, with neutropenia being the most frequent (AP 54.4 %; EP 44.0 %). Leukopenia, pyrexia, and fatigue were more prevalent in the AP group, but all were clinically reversible and manageable.
AP therapy demonstrated non-inferiority to EP therapy, prolonging OS for 1.5 months, but this difference was not statistically significant; thus we propose AP as a promising treatment option for ED-SCLC in China.
This trial was registered on 10 April 2008 (ClinicalTrials.gov NCT00660504 ).

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On April 13, 2016 Cancer Research UK reported that rising levels of obesity among UK women have helped fuel a 54 per cent increase in womb cancer rates over the last two decades, according to Cancer Research UK’s latest statistics published today (Press release, Cancer Research UK, APR 12, 2016, View Source [SID:1234510752]).

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"Obesity is linked to 10 different types of cancer, including womb cancer, and is the single biggest preventable cause of the disease after smoking." – Dr Julie Sharp, Cancer Research UK
In the early 1990s, around 19 women in every 100,000 developed the disease. That figure has now climbed to 29 women in every 100,000 – with obesity being the most likely culprit.*

Around 9,000 women are diagnosed with womb (uterine) cancer every year in the UK, and around 2,000 women die from the disease. Twenty years ago, there were around 4,800 new cases of womb cancer each year with around 1,500 deaths.**

Professor Jonathan Ledermann, director of the Cancer Research UK and UCL Cancer Trials Centre, said: "It’s worrying that womb cancer cases are going up so sharply. We don’t know all the reasons why. But we do know that about a third of cases are linked to being overweight so it’s no surprise to see the increases in womb cancer cases echo rising obesity levels.

"The good news is that thanks to research and improved treatments survival has improved. In the 1970s, almost six in 10 women diagnosed with the disease survived for at least 10 years. Now almost eight in 10 women survive. But we need more research to understand the biology of the disease better and to know more about how it is caused so that we can improve the treatment of these women as well as preventing more cases."

The science behind how extra weight can cause cancer is not completely clear. But there is evidence that extra fat in the body can raise cancer risk by producing hormones and growth factors that encourage cells to divide.***

A lack of exercise and taking HRT (hormone replacement therapy) are also risk factors – but are linked to fewer cases of womb cancer than obesity****. A woman’s age and genetic make-up can also affect her risk.

Symptoms of womb cancer include abnormal vaginal bleeding – particularly in post-menopausal women – blood in your pee and abdominal pain. The disease is usually diagnosed early, and most women can be cured by surgery.

Kath Bebbington, aged 56 from Stoneclough, Greater Manchester, was diagnosed with womb cancer at the end of 2013 after going to the doctor because she was bleeding between periods. She had a hysterectomy in March 2014.

Kath kick-started her healthy lifestyle after she finished treatment – since then she’s lost three stone. She said: "My cancer diagnosis was a wake-up call for me. It was a shock because I don’t smoke, I don’t drink and I walk a lot. And we don’t know what caused the cancer but I had to admit to myself that I needed to make some life-style changes to lose some extra pounds I had been carrying and stack the odds in my favour for a healthy future.

"So I began eating more healthy food and exercising to feel better and to be a role model for my daughters. I also trained to take part in Race for Life events which I’ve done with my daughters by my side."

Dr Julie Sharp, head of health information at Cancer Research UK, said: "It’s concerning that more women are developing womb cancer, but it’s important that they are informed about ways to reduce their risk of the disease. Obesity is linked to 10 different types of cancer, including womb cancer, and is the single biggest preventable cause of the disease after smoking. While there are no guarantees against cancer, keeping a healthy weight can help you stack the odds in your favour and has lots of other benefits too."

Clostridium difficile infection (CDI) represents a significant economic healthcare burden, especially the cost of recurrent disease. Fidaxomicin produced significantly lower recurrence rates and higher sustained cure rates in clinical trials. We evaluated the cost-effectiveness and budget impact of fidaxomicin compared with vancomycin in Germany in the first-line treatment of patient subgroups with CDI at increased risk of recurrence.
A semi-Markov model was used to compare the cost-effectiveness and budget impact of fidaxomicin vs. vancomycin from a payer perspective in Germany. The model cycle length was 10 days. The time horizon was 1 year. Model inputs were probability of clinical cure, 30-day probability of recurrence, and 30-day attributable mortality based on evidence from two randomized controlled trials comparing fidaxomicin and vancomycin in patients with CDI. Cost-effectiveness outcomes were cost per quality-adjusted life year gained, cost per bed-day saved, and cost per recurrence avoided.
Despite higher drug acquisition costs, fidaxomicin was dominant in the cancer subgroup (less costly and more effective) and cost-effective in the other subgroups, with incremental cost-effectiveness ratios vs. vancomycin ranging from €26,900 to €44,500. Hospitalization costs of the first-line treatment of CDI with fidaxomicin vs. vancomycin were lower in every patient subgroup, resulting in budget impacts ranging from -€1325 (in patients ≥65 years) to -€2438 (in cancer patients). Reductions in the cost of treating recurrence with fidaxomicin ranged from -€574.32 per patient in those receiving concomitant antibiotics to -€1500.68 per patient in renally impaired patients.
In patient subgroups with CDI at increased recurrence risk, fidaxomicin was cost-effective vs. vancomycin, and less costly and more effective in patients with cancer.

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