Ovarian Cancer in BRCA Mutation Carriers: Improved Outcome After Intraperitoneal (IP) Cisplatin

Background

Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes.

Methods

Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials.

Results

Ten patients that were confirmed to have BRCA mutations—all with high-grade and stages IIC to IV disease—survived a median of 10 years (range: 4–18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively.

Conclusions

This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.     

Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study

BACKGROUND/AIMS: The aim of this study was to evaluate long term safety and antiviral activity of different doses of emtricitabine given once daily to patients chronically infected with hepatitis B. METHODS: Eligible patients were randomized in a double-blind, parallel study to evaluate 25, 100 or 200 mg once daily doses of emtricitabine for 48 weeks. Patients were then followed for an additional 48 weeks on open-label 200 mg emtricitabine. Serum HBV DNA, ALT, and hepatitis B serology were measured at regular intervals over the 2 years. Resistance surveillance was performed after 1 and 2 years on viremic samples, i.e. > 4700 copies/mL. RESULTS: Emtricitabine was well tolerated and produced a dose proportional antiviral response. After 2 years, 53% of the patients had serum HBV DNA < or = 4700 copies/mL, 33% seroconverted to anti-HBe and 85% had normal ALT. Eighteen percent of the patients who had received 200 mg emtricitabine for 2 years developed resistance mutations. CONCLUSIONS: Emtricitabine was well tolerated and demonstrated a potent antiviral response for up to 2 years in patients with chronic hepatitis B infection. Based on these data, 200 mg emtricitabine once daily was chosen as the optimal dose for future hepatitis B studies.     

Implications of new petrographic analysis for the Olmec "mother culture" model

Petrographic analysis of Formative Mexican ceramics by J. B. Stoltman et al. (see the companion piece in this issue of PNAS) refutes a recent model of Olmec "one-way" trade. In this paper, we address the model's more fundamental problems of sampling bias, anthropological implausibility, and logical non sequiturs. No bridging argument exists to link motifs on pottery to the social, political, and religious institutions of the Olmec. In addition, the model of unreciprocated exchange is implausible, given everything that the anthropological and ethnohistoric records tell us about non-Western societies of that general sociopolitical level.     

Identification and characterization of undifferentiated mast cells in mouse bone marrow

Sequential immunomagnetic isolation with 2 monoclonal antibodies was used to purify and characterize an undifferentiated mast cell in adult mouse bone marrow that had not been previously recognized. This cell represents 0.02% of the cells in the bone marrow, is CD34(+), CD13(+), and c-kit(+), and does not express FcepsilonRI. However, by polymerase chain reaction (PCR) the cell contains message for the alpha and beta subunits of FcepsilonRI, mast cell-specific proteases, and carboxypeptidase A. Morphologically, this cell has a large nucleus, little cytoplasm, few cytoplasmic organelles, and no cytoplasmic granules. In vitro, in the presence of interleukin-3 (IL-3) and stem cell factor (SCF) these cells differentiate only into a granulated mast cell that now expresses CD13, c-kit, mast cell-specific gangliosides, FcepsilonRI, and binds immunoglobulin E (IgE). When injected into lethally irradiated mice, these cells are able to reconstitute the mast cell population in the spleen.     

Comparison of cardiovascular aquaporin-1 changes during water restriction between 25- and 50-day-old rats

Purpose

Aquaporin-1 (AQP1) is the predominant water channel in the heart, linked to cardiovascular homeostasis. Our aim was to study cardiovascular AQP1 distribution and protein levels during osmotic stress and subsequent hydration during postnatal growth.

Methods

Rats aged 25 and 50 days were divided in: 3d-WR: water restriction 3 days; 3d-WAL: water ad libitum 3 days; 6d-WR+ORS: water restriction 3 days + oral rehydration solution (ORS) 3 days; and 6d-WAL: water ad libitum 6 days. AQP1 was evaluated by immunohistochemistry and western blot in left ventricle, right atrium and thoracic aorta.

Results

Water restriction induced a hypohydration state in both age groups (40 and 25 % loss of body weight in 25- and 50-day-old rats, respectively), reversible with ORS therapy. Cardiac AQP1 was localized in the endocardium and endothelium in both age groups, being evident in cardiomyocytes membrane only in 50-day-old 3d-WR group, which presented increased protein levels of AQP1; no changes were observed in the ventricle of pups. In vascular tissue, AQP1 was present in the smooth muscle of pups; in the oldest group, it was found in the endothelium, increasing after rehydration in smooth muscle. No differences were observed between control groups 3d-WAL and 6d-WAL of both ages.

Conclusion

Our findings suggest that cardiovascular AQP1 can be differentially regulated in response to hydration status in vivo, being this response dependent on postnatal growth. The lack of adaptive mechanisms of mature animals in young pups may indicate an important role of this water channel in maintaining fluid balance during hypovolemic state.     

Fecal calprotectin, MMP-9, and human beta-defensin-2 levels in pediatric inflammatory bowel disease

Purpose

Fecal MMP-9 and human beta-defensin-2 (HBD-2) levels, potential markers of intestinal inflammation, are insufficiently explored in pediatric inflammatory bowel disease (IBD). The aim was to study fecal MMP-9 and HBD-2 in pediatric IBD to compare their performance to calprotectin and to study whether they would provide additional value in categorizing patients according to their disease subtype.

Methods

Fecal calprotectin, MMP-9, and HBD-2 levels were measured with ELISA in 110 pediatric patients with IBD (Crohn’s disease, n?=?68; ulcerative colitis (UC), n?=?27; unclassified, n?=?15; median age, 14). To compare the performance of the fecal markers, the area under the receiver operating characteristics curve (±95 % CI) was used. In addition, the best cut-off values of each measure to differentiate IBD patients and controls (n?=?27 presenting with diarrhea, abdominal pain, and/or anemia) were derived by maximizing sensitivity and specificity.

Results

Of the fecal markers studied, calprotectin performed best for separation of IBD and non-IBD patients with the area under curve (AUC) of 0.944 (95 % CI, 0.907 to 0.981). For MMP-9, AUC was 0.837 (95 % CI, 0.766 to 0.909), the levels being significantly higher in active IBD and in UC compared with Crohn’s disease (p?=?0.0013), but categorization of these patient groups did not take place. HBD-2 did not categorize any of the studied groups.

Conclusions

Calprotectin was the best fecal marker in pediatric IBD, but MMP-9 showed almost comparable performance in UC, suggesting applicability as a surrogate marker of inflammation. Fecal HBD-2 did not bring information to the disease characteristics of pediatric IBD patients.     

Self-reported fertility in long-term survivors of acute myeloid leukemia

Acute myeloid leukemia (AML) survival rates in younger patients have improved considerably since the 1970s. In order to evaluate the impact of AML and its treatment on fertility and family situation in adult long-term survivors, we used the Swedish population-based registries to identify 161 adult patients diagnosed with AML within the Leukemia Group of Middle Sweden (LGMS) 1973–2003, who survived for more than 5 years and were alive in 2010. Ninety-eight patients (61 %) completed a questionnaire including items on reproductive concerns, family situation, and infertility-related distress. After excluding women >45 years and/or postmenopausal women and men >55 years, 22 women and 38 men were included in the final analysis. Nine of the women (41 %) tried to conceive after treatment, but only three succeeded. Five (83 %) of the unwillingly childless women reported “a moderate” or “a lot” of distress caused by this. Among men in the same age group, all six who wanted children after treatment succeeded. None of the men 46–55 years old cryopreserved their sperm or tried to father a child. Among patients who wanted children after AML treatment, 46 % of the women and 40 % of the younger men reported that they were not, or not fully, informed about fertility-related issues. In contrast, among men 46–55 years, none reported they would have wanted more information. Infertility among young female AML survivors thus remains an important clinical issue, and there is a need for improved clinical counseling and education in this area.