Improving clinical trial design for hepatocellular carcinoma treatments

Despite its place as the third leading cause of cancer deaths worldwide, there are currently no approved chemotherapeutic agents, devices or techniques to treat hepatocellular carcinoma. Importantly, there have been no phase III studies demonstrating survival benefit, nor any randomized studies of treatment except for transarterial chemoembolization and most recently sorafenib. The importance of well-designed clinical trials of agents to treat HCC has never been greater. However, general clinical study design issues, combined with HCC-specific issues pose significant challenges in structuring such studies. HCC-related challenges include the heterogeneity of this cancer and the fact that it is frequently accompanied by significant comorbidities at diagnosis, such as active hepatitis B or C virus replication, substantial past or on-going alcohol use, and cirrhosis, itself often a fatal disease. The recently published comparison of a newer treatment, nolatrexed to doxorubicin, and comments about this study’s initial HCC diagnostic criteria, staging system, comparator therapy and choice of endpoints have provided a platform to discuss the challenges unique to the design of HCC clinical trials. The difficulty in accurately framing study results obtained from the constantly changing HCC clinical landscape and approaches to meet these challenges will be reviewed.     

Impact of Induction Chemotherapy and Preoperative Chemoradiotherapy on Operative Morbidity and Mortality in Patients with Locoregional Adenocarcinoma of the Stomach or Gastroesophageal Junction

Background Significant tumor downstaging has been achieved in patients with localized gastric or gastroesophageal adenocarcinoma by induction chemotherapy and preoperative chemoradiotherapy (CTX–CTXRT). However, the influence of CTX–CTXRT on operative morbidity and mortality has not yet been clarified. The aim of the present study was to document the frequency and nature of morbidity and mortality after surgery combined with CTX–CTXRT, and identify factors predictive of postoperative complications in patients with localized gastric or gastroesophageal adenocarcinoma. Methods A prospectively collected database on 71 consecutive patients who underwent CTX–CTXRT at M.D. Anderson Cancer Center between January 1997 and August 2004 was reviewed. Postoperative morbidity and mortality were investigated, and risk factors for overall complications were identified by multivariate logistic regression analysis. Results Overall morbidity and mortality rates were 38.0% (27 patients) and 2.8% (2 patients), respectively. Age greater than 60 years [relative risk 11.3 (95% confidence interval 2.50–50.6)] and body mass index (BMI) of 26 kg/m² or above [relative risk 4.08 (95% confidence interval 1.08–15.4)] were significant risk factors for overall complications. Conclusions CTX–CTXRT can be performed safely with an acceptable operative morbidity and a low operative mortality rate in patients with gastric or gastroesophageal cancer, with careful consideration of added risk associated with age and obesity.     

A new lease of life. Nursing care of elderly surgical patients.

Advances in surgical techniques have meant more elderly people can now be operated on. Older people are, however, more prone to postoperative complications and require greater preoperative preparation. Forward planning and setting high standards for nursing care are prerequisites in this area of care.     

Utility of voice therapy in the management of vocal fold polyps and cysts.

OBJECTIVE: To evaluate the efficacy of voice therapy in the management of vocal fold polyps and cysts. STUDY DESIGN AND SETTING: Retrospective review of vocal fold cysts and polyps undergoing voice therapy in a tertiary care center. Symptom resolution or persistence resulting in surgical intervention was the main outcome measure. RESULTS: Fifty-seven patients were identified, of which 49.1% achieved symptom resolution with voice therapy alone. Patients with complete glottal closure and muscle tension dysphonia did not have a better response than those with incomplete glottal closure and without muscle tension dysphonia (P = 0.1, chi(2), respectively). Patients with translucent polyps more commonly responded to voice therapy than fibrotic, hyaline, or hemorrhagic polyps, 81.8% versus 15.4% and 25.0% response rate, respectively (P = 0.002, chi(2)). CONCLUSIONS: Voice therapy is an effective treatment modality for vocal fold polyps and cysts. SIGNIFICANCE: A multidisciplinary approach including a trial of voice therapy is warranted.     

Area postrema-lesions increase operant responding to sucrose in rats

Rats with lesions of the area postrema (APX) are known to exhibit an enhanced intake of highly palatable foods such as sweetened condensed milk and cookies. These observations suggest the possibility that APX rats find these foods more rewarding and will work harder to obtain these foods. Sham and APX rats were tested on fixed ratio (FR) and progressive ratio (PR) schedules. APX rats consistently pressed more times to receive sucrose solution and attained both FR 3 and FR 5 criteria significantly faster than sham-lesioned control rats. Furthermore, rats with APX had significantly higher break points than sham-lesioned control rats on a progressive ratio schedule. These results support the hypothesis that rats with lesions of the area postrema will consistently work harder to obtain a highly palatable food reward.     

Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across large domains. Our results define direct targets of the MLL fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in cancer.     

Virus persists in beta cells of islets of Langerhans and infection is associated with chemical manifestations of diabetes. II. Morphologic observations.

Persistence of lymphocytic choriomeningitis (LCM) virus in the islets of Langerhans was associated with mild hyperglycemia and abnormal glucose tolerance test results. Early histopathologic events consisted of occasional perivascular inflammatory mononuclear cells around both islet and acinar cells. Morphometric studies showed an increase in the size of islets from virus-infected mice. By electron microscopy, LCM virions were found within infected beta cells. Cytolytic injury of beta cells was minimal and did not account for the abnormalities of glucose metabolism. In contrast to the findings in islets, ultrastructural studies of acinar cells revealed LCM virions in abundance, vacuolar degeneration, and intracytoplasmic inclusions. This study extends the previous observation that LCM virus infection may persist in beta cells of the islets of Langerhans without causing structural injury but be associated with abnormalities resembling the chemical and histopathologic features of the early stage of Type II (adult-onset) human diabetes mellitus.