Dose Finding in Late-Phase Drug Development.

A drug may fail or raise concerns that must be addressed in later-phase trials because of an unacceptable toxicity profile, even if the drug meets expectations for efficacy. The problem could be due to the late onset of unacceptable toxicities that were not observed in early-phase trials. We explore methodologies to find appropriate doses in situations where a drug meets the primary efficacy objective but concerns about toxicity remain. In this manuscript, we propose a general framework to design a good phase IV trial that is designed to optimize the treatment regimen. In the first step, we learn from the existing data about the dose-response and dose-toxicity relationships and further to explore and establish the relationship using a statistical model. Noting the limitations of the exploratory analyses, these analyses are not sufficient to allow us to make definitive conclusions. However, the prediction obtained from the model, either estimated efficacy metrics or safety parameters for some doses, can be incorporated in the design of the phase IV trial. In the second step, we further propose and compare design options, including options that could effectively incorporate information from these exploratory analyses, for clinical trials to find optimal doses, including trials to fulfill postmarketing commitments or requirements.

Unclassified mucin phenotype of gastric adenocarcinoma exhibits the highest invasiveness.

BACKGROUND AND AIM: Gastric cancers present with distinctive carcinogenesis pathways that vary with the mucin phenotypes. We attempted to elucidate the relations between the characteristics of the mucin phenotypes of gastric cancer and the tumor invasiveness. METHODS: Gastric adenocarcinomas that were resected surgically between August 2005 and April 2007 were included in the present study. The gastric cancers were subclassified into gastric and intestinal mucin phenotypes if more than 10% of cancer cells exhibited gastric (MUC5AC and/or MUC6) and intestinal (MUC2 or CD10) markers, respectively. RESULTS: The mucin phenotypes of 123 gastric cancers were gastric (n = 31), intestinal (n = 43), mixed (n = 28) and unclassified (n = 21). The mucin phenotype was related to histological type (P < 0.001), Lauren's classification (P = 0.001) and size (P = 0.014) of the gastric adenocarcinoma, but not to its location or to the presence of Helicobacter pylori infection. The unclassified mucin phenotype exhibited the largest number of lymph node metastases (P = 0.007), lymphatic invasions (P < 0.001) and neural invasions (P = 0.026), whereas the intestinal mucin phenotype exhibited the lowest invasiveness. CONCLUSION: The mucin phenotype reflects the biological behavior of gastric cancer, with the intestinal and unclassified mucin phenotypes exhibiting the lowest and highest invasiveness, respectively.

Continuing reassessment of the risks of erythropoiesis-stimulating agents in patients with cancer.

PURPOSE: Erythropoiesis-stimulating agents (ESA) are approved for the treatment of anemia in patients with nonmyeloid malignancies whose anemia is due to the effect of concomitantly administered chemotherapy. Since the 1993 approval of epoetin alfa in patients with cancer, the risk of thrombovascular events, decreased survival, and poorer tumor control have been increasingly recognized. The risks of ESAs in patients with cancer and the design of trials to assess these risks have been the topic of discussion at two Oncologic Drugs Advisory Committees in 2004 and 2007. EXPERIMENTAL DESIGN: Evaluation of randomized clinical trials comparing use of ESAs to transfusion support alone in patients with active cancer. RESULTS: Six studies (Breast Cancer Erythropoeitin Survival Trial, Evaluation of NeoRecormon on outcome in Head And Neck Cancer in Europe, Danish Head and Neck Cancer, Lymphoid Malignancy, CAN-20, and Anemia of Cancer) investigating ESAs in oncology patients showed decreased survival, decreased duration of locoregional tumor control, and/or increased risk of thrombovascular events. In these six studies, ESA dosing was targeted to achieve and maintain hemoglobin values in excess of current recommendations, and in three of the six studies, ESAs were administered to patients not receiving chemotherapy. CONCLUSIONS: ESAs increase the risk of thrombovascular events and result in decreased survival and poorer tumor control when administered to achieve hemoglobin levels of > or =12 g/dL in patients with nonmyeloid malignancies. No completed or ongoing randomized, controlled trial has addressed safety issues of ESAs in patients with chemotherapy-associated anemia using currently approved dosing regimens in an epidermal tumor type. Additional studies are needed to better characterize these risks.

Prevalence and natural history of monoclonal and polyclonal B-cell lymphocytosis in a residential adult population.

BACKGROUND: Monoclonal B-cells can be detected in the peripheral blood of some adults without B-cell malignancies, a condition recently termed monoclonal B-cell lymphocytosis (MBL). The risk of individuals with MBL progressing to a B-cell malignancy is unknown. Polyclonal B-cell lymphocytosis (PCBL) has not been systematically studied in the general population. METHODS: We obtained lymphocyte subset counts on 1,926 residential adults aged 40-76 years in a series of environmental health studies between 1991 and 1994. We then conducted two follow-ups in 1997 and 2003 on consenting participants with B-cell lymphocytosis, which included nine participants with MBL. To ascertain the clinical implications of MBL, we reviewed medical records and death certificates. RESULTS: The overall prevalence of MBL was 0.57% (11/1,926): nine cases at baseline and two additional cases identified at follow-up. Two (19%) MBL cases subsequently developed a B-cell malignancy; MBL persisted in the remaining nine cases (81%). All PCBL cases where no clone emerged regressed to normal B-cell counts over the follow-up period. MBL was significantly more frequent in residents near a hazardous waste site than in the control populations (age-adjusted OR 6.2; 95%CI 1.1-36.2). CONCLUSION: MBL confers an elevated risk for developing a B-cell malignancy, although it occurs only in a minority of cases. PCBL is most often a transient state, but a monoclonal population can emerge and persist. Prospective studies are needed to distinguish stable from progressive forms of B-cell lymphocytosis and to clarify the etiologic role of environmental exposures.

Prevalence and antimicrobial resistance of enterococcus species isolated from retail meats.

From March 2001 to June 2002, a total of 981 samples of retail raw meats (chicken, turkey, pork, and beef) were randomly obtained from 263 grocery stores in Iowa and cultured for the presence of Enterococcus spp. A total of 1,357 enterococcal isolates were recovered from the samples, with contamination rates ranging from 97% of pork samples to 100% of ground beef samples. Enterococcus faecium was the predominant species recovered (61%), followed by E. faecalis (29%), and E. hirae (5.7%). E. faecium was the predominant species recovered from ground turkey (60%), ground beef (65%), and chicken breast (79%), while E. faecalis was the predominant species recovered from pork chops (54%). The incidence of resistance to many production and therapeutic antimicrobials differed among enterococci recovered from retail meat samples. Resistance to quinupristin-dalfopristin, a human analogue of the production drug virginiamycin, was observed in 54, 27, 9, and 18% of E. faecium isolates from turkey, chicken, pork, and beef samples, respectively. No resistance to linezolid or vancomycin was observed, but high-level gentamicin resistance was observed in 4% of enterococci, the majority of which were recovered from poultry retail meats. Results indicate that Enterococcus spp. commonly contaminate retail meats and that dissimilarities in antimicrobial resistance patterns among enterococci recovered from different meat types may reflect the use of approved antimicrobial agents in each food animal production class.

Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans.

The authors estimated the prevalence of post-traumatic stress disorder (PTSD) and illness resembling chronic fatigue syndrome (CFS) in the entire population of Gulf War and non-Gulf-War veterans. They also evaluated the relation between the extent of deployment-related stress and the risk of either PTSD or CFS. In 1995-1997, the authors conducted a health survey in which these two symptom-based medical diagnoses in a population-based sample of 15,000 Gulf War veterans representing four military branches and three unit components (active, reserve, and National Guard) were compared with those of 15,000 non-Gulf veteran controls. Gulf War veterans, compared with non-Gulf veteran controls, reported significantly higher rates of PTSD (adjusted odds ratio = 3.1, 95% confidence interval: 2.7, 3.4) and CFS (adjusted odds ratio = 4.8, 95% confidence interval: 3.9, 5.9). The prevalence of PTSD increased monotonically across six levels of deployment-related stress intensity (test for trend: p < 0.01), while the prevalence of CFS rose only at the low end of the stress spectrum. While deployment-related stress could account for the higher risks of both PTSD and CFS, additional factor(s) unique to the Gulf environment may have contributed to the risk of CFS among Gulf War veterans.

Evidence for a deployment-related Gulf War syndrome by factor analysis.

To identify a syndrome unique to Gulf War veterans, the authors applied an exploratory factor analysis to the 47-symptom correlation matrix of 10,423 Gulf War and 8,960 non-Gulf War veteran respondents. A separate factor analysis was performed for Gulf War and non-Gulf War veterans, and the resulting 6 factors were compared between the 2 groups. Five of the factors were very similar in the 2 groups; however, 1 of the factors in the Gulf War group, but not the non-Gulf War group, contained a cluster of symptoms consistent with neurological impairment. Symptoms specific to this factor were blurred vision, loss of balance/dizziness, tremors/shaking, and speech difficulty. The Gulf War veterans who had all of the aforementioned symptoms (n = 277) also reported exposures to several putative risk factors at a rate 3 or more times higher than other Gulf War veterans. This finding suggests a possible syndrome related to Gulf War deployment, which requires objective supporting clinical evidence.