H7N9 FLU VIRUS BECOMING PANDEMIC?

China is investigating the possibility of human-to-human transmission of a new strain of bird flu that has killed 17 people and is examining "family clusters" of people infected with the virus, a top health official was quoted as saying.

Authorities have slaughtered thousands of birds and closed some live poultry markets to slow the rate of human infection. But many aspects of this new variety of bird flu remain a mystery, particularly whether the H7N9 strain is being transmitted between people.

China has warned that the number of infections, 82 so far, could rise. Most of the cases and 11 of the deaths have been in the commercial capital Shanghai.

Feng Zijian, the director of the health emergency center at the Chinese Center for Disease Control and Prevention, told reporters on Wednesday that "we are paying close attention to these cases of family clusters.

"(We) are still analyzing in-depth to see which has the greatest possibility -- did it occur first from avian-to-human transmission, and then a human-to-human infection, whether they had a common history of exposure, were exposed to infected objects or whether it was caused by the environment," Feng said.

His comments were reported in a statement posted on the website of the National Health and Family Planning Commission.

One of the families that China is studying is made up of two brothers and their father who died of the virus, Feng said.

"This family cluster case still doesn't change our understanding of the characteristics of the disease in general -- that it is transmitted from birds to people and there's no evidence of human-to-human transmission," Feng said.

CONTACT WITH POULTRY

Efforts to determine the nature of the H7N9 virus are also hampered by a lack of accurate information from the victims on whether they have had contact with poultry, Feng said.

The World Health Organization said on Wednesday that a number of people who have tested positive for the new strain appear to have had no contact with poultry.

The WHO had previously reported two suspected "family clusters", but the first turned out to be a false alarm and the second was inconclusive.

Zeng Guang, chief scientist in charge of epidemiology at the China Disease Prevention and Control Centre (CDPCC), said about 40 percent of human victims had no clear history of poultry exposure, the Beijing News reported.

Feng said that not all patients "can recall the history of exposure. Just like with the H5N1 avian influenza, 50 percent of the patients knew exactly their history of exposure, the other 50 percent can't recall it at all."

He was referring to a an especially virulent strain of bird flu that had raised the threat of a global pandemic in 2003.

Feng said that as most patients were in critical condition, the government was encountering delays in obtaining information about their exposure to poultry.

The WHO said a team of experts going to China soon would examine whether the virus can be spread between people, although there was "no evidence of sustained human-to-human transmission".

The state-run China Daily newspaper, citing an unnamed source, said the team's talks with Chinese representatives would be held on Thursday. The experts would then visit affected areas.

LIVER TRANSPLANTATION FOR LOW GRADE NEUROENDOCRINE TUMORS

Liver transplantation is effective when liver metastases from neuroendocrine tumors are unresectable, according to a European Liver Transplant Registry study.

But transplant should be reserved for selected cases, when all other options have been exhausted, Dr. Yves Patrice Le Treut from Hopital de la Conception, Marseille, France told Reuters Health in an email.

Those cases include patients with "unresectable liver metastases, well differentiated neuroendocrine tumor (NET) and no need of extra hepatic resection at the time of (transplant)," he said.

Using data from the European Liver Transplant Registry, Dr. Le Treut and colleagues reviewed the short- and long-term outcomes of 213 patients who underwent liver transplantation for neuroendocrine tumors. They published their findings online March 25th in Annals of Surgery.

Mortality in the three months after transplantation was 10%, driven mostly by surgery-related complications. The median postoperative hospital stay was 25 days and the median ICU stay was 10 days. Twenty-four patients required retransplantation, including 16 within the first three months.

The mean follow-up overall was 56 months (range, 0-283 months). Among the 192 patients who survived at least three months after transplant, 103 died later. Eighty-six of these later deaths were due to recurrent disease; the remainder were due either to late postoperative complications (six patients), late retransplant complications (four patients), infectious complications (three patients), or other causes (four patients).

At the end of follow-up, 63 patients were alive without recurrence, and 26 were alive with recurrence. The median survival for patients who died without recurrent disease was eight months.

Median overall survival after liver transplantation was 67 months. Overall survival rates were 81% at one year, 65% at three years, and 52% at five years.

Five-year overall survival did not differ between patients whose primary tumor was undetected at the time of liver transplantation, those whose primary tumor was discovered and removed during or after liver transplantation, and those whose primary tumor was never identified.

Median disease-free survival was 24 months. Disease-free survival rates were 65% at one year, 40% at three years, and 30% at five years.

Independent predictors of poor prognosis included major resection in addition to liver transplantation, poor tumor differentiation, and hepatomegaly. Age over 45 years also independently predicted poor prognosis among patients treated since 2000.

"The most striking finding is that (the) overall survival rate in the whole series was more than 50% at five years, thus validating the use of liver transplantation for patients with cancer," the researchers note. "Despite this validation, the actual benefit of liver transplantation needs to be proven."

The timing of transplant in asymptomatic patients is very controversial, Dr. Le Treut noted. "This retrospective work cannot give any answer to this question," he said. "But my personal point of view is that liver transplantation must be indicated when asymptomatic patients present (with) a progressive tumor load (after a period of stable disease) that became refractory to all other treatments."

Dr. Mark Bloomston from The Ohio State University's Division of Surgical Oncology, Columbus, Ohio agreed. He told Reuters Health, "Given the scarcity of available livers, transplantation should still be reserved for patients proving to have indolent disease affecting only the liver. In other words, enough time must pass to prove the disease is not very aggressive but should not wait so long that the patient is in dire straits."

Dr. Bloomston added, "Evaluation for liver-directed therapies (including resection, transplantation, or chemoembolization) should take place early in disease course for metastatic NET, preferably when the disease is at its best (e.g., low volume, slow growth, or even stable disease). Liver-directed therapy should not be undertaken in desperation as it is doomed to failure and could be dangerous."

Dr. Gabriel Chan from the University of Montreal in Canada offered a somewhat different view. "I believe until there is further prospective evidence, liver transplantation should be reserved for patients who are symptomatic, with hepatic only, low grade NET," he said. "There is currently no proof that there is a survival benefit over the current treatments including arterial therapy, hormone therapy, and even no treatment in such patients."

Good prospective trials "are absolutely essential," Dr. Chan told Reuters Health, "and as a result of the rare situation where it is indicated, national and international cooperation is essential to provide the essential numbers and statistically significant evidence of benefit, either symptomatic or survival."

"The future may feature better situations where recurrence is diminished if the everolimus experience in metastatic NET expands over the next few years, and if the therapeutic ranges of the oncological and immunosuppressive modalities cross over," Dr. Chan concluded.

RF FOR RENAL CANCER

Elderly patients with renal cancer and patients with comorbidities who are poor candidates for surgery do well after treatment with percutaneous radiofrequency ablation and have few complications and recurrences, according to a new study.

"Nearly half of all renal cancers are now diagnosed incidentally because of the increasing use of imaging. For these patients, a conservative surgery has been developed to preserve renal function," lead investigator Pierre Balageas, MD, from Saint-André Hospital in Bordeaux, France, told Medscape Medical News.

However, Dr. Balageas, who presented the results here at the European Congress of Radiology (ECR) 2013, pointed out that "there still are patients with small renal cancers who are poor candidates for surgery because of advanced age or comorbidities. For these patients, percutaneous radiofrequency ablation works well."

To evaluate the effectiveness of the approach, Dr. Balageas and his team retrospectively reviewed all T1a renal cancers treated with percutaneous radiofrequency ablation at a single centre from 2002 to 2009. A total of 93 patients (median age, 73.5 years) underwent the procedure.

The technique used depended on tumor size, morphology, and location. "Most patients were treated with computerized-tomography-guided ablation," but 2 were treated with ultrasound guidance, Dr. Balageas noted.

The survival analysis involved 62 patients (mean age, 69.5 years) with 71 tumors (mean size, 23.9 mm). Mean follow-up was 38.8 months.

After initial treatment of the tumors, the technical success rate was more than 95%. After the retreatment of recurrences, the secondary success rate was more than 98%.

There was no change in real function 2 and 6 months after the procedure. Rates of both tumor progression (~3%) and metastatic evolution (~10%) were relatively low, and median survival was 68 months, Dr. Balageas reported.

One year after radiofrequency ablation, more than 98% of patients were alive and free of disease; 3 years after, 92% were; and 5 years after, approximately 61% were.

"In our study, tumor site was the only independent factor predicting risk for residual tumor or in situ recurrence," Dr. Balageas said, "and all tumors less than 40 mm were completed ablated after 1 procedure."

Major complications occurred at a rate of 5.9% per session. Central location of the tumor was the only factor associated with an increased risk for complications.

"Our experience using radiofrequency for renal tumors is increasingly being helped, not only by our good results, but also by the treatment strategy established with members of our surgical team, who have become convinced of the benefits of this technique," Dr. Balageas observed.

Session chair Jurgen Fütterer, MD, from the Radboud University Nijmegen Medical Centre in the Netherlands, who was asked by Medscape Medical News to comment on this study, noted that both radiofrequency ablation and cryoablation can be used to treat small renal tumors with curative intent.

"Not every patient with renal cancer is a candidate for radiofrequency ablation, but patients with localized disease who have a high mortality risk with general anesthesia are," he said.

Dr. Fütterer noted that the literature suggests that radiofrequency ablation has a success rate of ~80%, so the success rate achieved by Dr. Balageas and colleagues is very good.

Factors Affecting Success

In another study presented during the same session, Vanessa Acosta-Ruiz, a medical student at Uppsala University in Sweden, reported that her team also found very high success rates in 44 patients treated with percutaneous radiofrequency ablation over a period of 4.5 years.

"After the first ablation, 75% of the tumors were completed ablated, 8 tumors were incompletely ablated, and 7 were retreated, so we ended up with a total success rate of 85%," Acosta-Ruiz said.

Correct positioning of the electrode over the tumor favorably affected results, as might be expected, she added.

However, a tumor smaller than 30 mm and a distance from the tumor to the collecting system of at least 10 cm were more likely to be associated with complete ablation, she added.

DIGOXIN USE IN AF INCREASE MORTALITY

SAN FRANCISCO, California — Patients with atrial fibrillation (AF) starting digoxin for the first time showed an independently significant jump in mortality over an average of one year compared with nondigoxin users in an observational study reported here today at the American College of Cardiology 2013 Scientific Sessions. Stratified analysis showed the effect to be consistent in men and women and by age.

Digoxin was given for rate control; patients with heart failure had been excluded from the study.

Although mortality doubled with digoxin use, hospitalizations appeared unaffected, suggesting that the people died at home, according to lead author Dr James V Freeman (Stanford University School of Medicine, CA). And though there were no data on cause of death, he toldheartwire that ventricular arrhythmias are a hazard from digoxin toxicity, "so our hypothesis is that maybe [digoxin users] had an increase in arrhythmic death and sudden cardiac death. But there's no way to know that for certain."

Digoxin in one form or another is one of the oldest still-used drugs in medicine and was never tested in substantial clinical trials for efficacy or safety in AF. Still, Freeman observed, the drug "is much more commonly used than people think, and it's not just that people who were using it 20 years ago are still using it."

The current findings support a recent propensity-adjusted secondary analysis of the AFFIRM trial,which found a 41% jump in all-cause mortality in AF patients taking vs not taking digoxin. As previously reported by heartwire , the increased hazard was seen in both men and women and in patients with and without underlying heart failure.

The group looked at 23 272 digoxin-naive patients newly diagnosed with AF from 2006 to 2009 within Kaiser Permanente Northern and Southern California. Of that group, 12.9% were started on digoxin for rate control.

The adjusted hazard ratio (HR) for all-cause mortality over a median of 0.8 years was 2.06 (95% CI 1.73–2.45) and for hospitalization was 1.05 (95% CI 0.98–1.13). The mortality finding remained significant in subgroup analysis by sex and three age groups.

Adjusted HR (95% CI), digoxin vs no digoxin use, for death from any cause in adults with incident AF (2006–2009)

Subgroup	HR (95% CI)*
Sex
Male	2.03 (1.58–2.60)
Female	2.13 (1.67–2.71)
Age (y)
21–74	2.31 (1.68–3.17)
75–84	1.66 (1.23–2.23)
>85	2.50 (1.85–3.38)

*Adjusted for age, race, income, laboratory parameters, prior CV disease and procedures, hypertension, dyslipidemia, cancer, lung disease, and cardiovascular medications

"This is about as strong an observational cohort study as you can get. I say that for a number of reasons," Freeman noted. It's large and from a "closed" healthcare system that is responsible for all patients' medications and lab results, and it would be known whether a patient might be noncompliant with meds, for example.

And there is potential from residual confounding due to differences in comorbidities and medications, which could--though they were adjusted for--suggest the study's results are conservative rather than overstated, he observed. Interestingly, nondigoxin users were sicker and showed a significantly greater baseline history of MI, stroke, and coronary revascularization, as well as more dyslipidemia and hypertension. Understandably, they were also on more CV medications.

The strong observational data for a hazard and thin evidence base supporting it, according to Freeman, is enough to recommend a reassessment of digoxin for AF rate control and maybe to give more consideration to certain patients--such as those who are highly symptomatic--for catheter ablation.

INCREASED STROMAL CELLS WORSENS SURVIVAL IN COLORECTAL CANCER

Medscapers ahoy. I am David Kerr, Professor of Cancer Medicine at University of Oxford and past President of the European Society for Medical Oncology. Today I want to talk about another prognostic index for colon cancer. This is related to a recent publication^[1] in Annals of Oncology by Dr. Huijbers and colleagues from the University of Leiden, The Netherlands, and the excellent medical center there, and also with colleagues, including me, from the University of Oxford.

These investigators looked at the contribution of stromal cells to prognosis in colon cancer. It was a nicely conducted, large study of 710 patients who had participated in one of our adjuvant colon cancer trials, hence our involvement. We [at University of Oxford] supplied the biological materials to our colleagues in Leiden, who did all of the analysis. They looked at the percentage of stromal cells and, using simple morphologic criteria that were validated with a reading by 2 pathologists, showed that patients who have a high fraction of stromal cells [have a worse prognosis]: If more than 50% of the cells are stromal compared with [the percentage of] epithelial cancer cells, [the patient will have] a bad prognosis, with a hazard ratio of 2.0 and a P value of .0001. For patients who have high stromal components in their cancers, the 5-year survival rate is around 69% compared with an 83% survival rate for those with a low stromal involvement.

This was a validation study of 710 patients, which followed from initial observations in a couple hundred patients. Therefore, in terms of looking at American Society of Clinical Oncology criteria and how we should report biomarker evidence, the numbers are good, the biostatistics are strong, and multivariate analysis was done. Because this was a validation study, it is a retrospective-prospective trial of a novel prognostic biomarker that is morphologically simple to characterize, pathologically straightforward, and reveals very interesting data.

It does not surprise me, in a way. I must admit that I am becoming much more interested in the interaction between epithelial cancer cells and stromal cells. The stroma, of course, is composed of fibroblasts, infiltrating microphages, lymphocytes, and so on, and the interaction among these in terms of production of cytokines and growth factors clearly can have an enormous impact on the biology of the epithelial cancer cells.

Although I have spent almost a lifetime working with colleagues like Ian Tomlinson, wanting to understand the somatic tumor mutations and changes that drive the behavior of colon cancer, we must not forget environment, context, and the stroma. Next time you see a patient with colon cancer, perhaps ask the pathologist to check whether the patient has high or low levels of stroma within the tumor, and then consider how those with a high stromal component may have a significantly worse prognosis.