FDA Approval Summary: Nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib.

On March 10, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to nivolumab in combination with ipilimumab for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. The recommended approved dosage was nivolumab 1 mg/kg i.v. plus ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles, followed by nivolumab 240 mg i.v. every 2 weeks. The approval was based on data from cohort 4 of CheckMate 040, which randomized patients with advanced unresectable or metastatic HCC previously treated with or who were intolerant to sorafenib to receive one of three different dosing regimens of nivolumab in combination with ipilimumab. Investigator-assessed overall response rate (ORR) was the primary endpoint, and ORR assessed by blinded independent central review (BICR) was an exploratory endpoint. BICR-assessed ORR and duration of response (DoR) form the primary basis of the FDA's regulatory decision, and BICR-assessed ORR was comparable in all three arms at 31%-32% with 95% confidence interval [CI] 18%-47%. The DoR ranged from 17.5 to 22.2 months across the three arms, with overlapping 95% CIs. Adverse events (AEs) were generally consistent with the known AE profiles of nivolumab and ipilimumab, and no new safety events were identified. This article summarizes the FDA review of the data supporting the approval of nivolumab and ipilimumab for the treatment of HCC. IMPLICATIONS FOR PRACTICE: Nivolumab and ipilimumab combination therapy is another option for patients with advanced hepatocellular carcinoma who experience radiographic progression during or after sorafenib or sorafenib intolerance. No new toxicities were identified, but, as expected, increased toxicity was observed with the addition of ipilimumab to nivolumab as compared with nivolumab alone, which is also approved for the same indication. Whether to administer nivolumab as a single agent or in combination with ipilimumab is expected to be a joint decision between the oncologist and patient, taking into consideration the potential for a higher likelihood of response and the potentially higher rate of toxicity with the combination.

FDA Approval Summary: Durvalumab and Pembrolizumab, Immune Checkpoint Inhibitors for the Treatment of Biliary Tract Cancer.

On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials that randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial, the median OS of patients receiving durvalumab was 12.8 months [95% confidence interval (CI), 11.1-14.0] and 11.5 months (95% CI, 10.1-12.5) in patients receiving placebo [hazard ratio (HR), 0.80 (95% CI, 0.66-0.97)]. In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI, 11.5-13.6) and 10.9 months (95% CI, 9.9-11.6) in patients receiving placebo [HR, 0.83 (95% CI, 0.72-0.95)]. The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals, and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic options for these patients.

Age-related differences in the reproductive and metabolic implications of polycystic ovarian syndrome: findings in an obese, United States population.

The objective of this study was to explore age-related differences in the reproductive and metabolic manifestations of polycystic ovarian syndrome (PCOS). Using a prospective cross-sectional design, we compared metabolic and reproductive findings in women attending a multidisciplinary clinic for PCOS, stratified across the following age groups: 18-25 (n = 71), 26-35 (n = 129), and 36-45 (n = 29). The study included primarily overweight and obese women, with a mean BMI of 31.1 in the entire study group. Older women had a decreased prevalence of biochemical hyperandrogenemia (p-trend: 0.0005). Of women meeting diagnostic criteria for PCOS, older women (n = 15) had larger median waist circumference and higher median diastolic blood pressure, total cholesterol, LDL cholesterol and fasting glucose compared to younger women (p-trend: 0.03, 0.01, 0.01, 0.01 and 0.06, respectively). The odds of metabolic syndrome for women ages 36-45 are increased four-fold relative to the younger groups (OR: 4.01; 95% CI: 1.04-15.4; p = 0.04). We conclude that there are significant age-related differences in both the clinical presentation and metabolic manifestations of PCOS.

U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia.

PURPOSE: To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS). RESULTS: The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL. CONCLUSIONS: On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.

Occurrence and overlooked sources of the biocide carbendazim in wastewater and surface water.

Carbendazim is a fungicide commonly used as active substance in plant protection products and biocidal products, for instance to protect facades of buildings against fungi. However, the subsequent occurrence of this fungicide and potential endocrine disruptor in the aqueous environment is a major concern. In this study, high resolution mass spectrometry shows that carbendazim can be detected with an increasing abundance from the source to the mouth of the River Rhine. Unexpectedly, the abundance of carbendazim correlates poorly with that of other fungicides used as active ingredients in plant protection products (r2 of 0.32 for cyproconazole and r2 of 0.57 for propiconazole) but it correlates linearly with that of pharmaceuticals (r2 of 0.86 for carbamazepine and r2 of 0.89 for lamotrigine). These results suggest that the occurrence of carbendazim in surface water comes mainly from the discharge of treated domestic wastewater. This hypothesis is further confirmed by the detection of carbendazim in wastewater effluents (n = 22). In fact, bench-scale leaching tests of textiles and papers revealed that these materials commonly found in households could be a source of carbendazim in domestic wastewater. Moreover, additional river samples collected nearby two paper industries indicate that the discharge of their treated process effluents is also a source of carbendazim in the environment. While characterizing paper and textile as overlooked sources of carbendazim, this study also shows the biocide as a possible ubiquitous wastewater contaminant that would require further systematic and worldwide monitoring due to its toxicological properties.

Angiotensin II/Angiotensin (1-7) ratio and 24-h blood pressure throughout the menstrual cycle and in women using oral contraceptives.

BACKGROUND: Women using oral contraceptives have higher ambulatory blood pressures (BPs) than other women. We sought to learn whether this was associated with an alteration in the balance of angiotensin II (Ang)/Ang (1-7) and whether this ratio and BP remained constant throughout the menstrual cycle. METHOD: In total, 30 (15 ovulatory, 15 taking oral contraceptives) healthy, normotensive women aged 18-30 years were studied. The ovulatory group was assessed within days 1-5 (follicular phase) and 19-23 (luteal phase) and the oral contraceptive group within days 19-23. Peripheral, central and 24-h BP, vascular wall stiffness, and body composition were measured along with plasma estradiol, progesterone, renin, aldosterone, Ang II, and Ang (1-7) concentrations. RESULTS: In ovulatory women plasma renin activity (P < 0.001), renin concentration (P < 0.01) and aldosterone (P < 0.05) were higher in the luteal than follicular phase, whereas BP, Ang II and the Ang II/Ang (1-7) ratio remained constant. In women taking oral contraceptives, plasma renin activity (P < 0.001) and concentration (P < 0.01) were higher than in follicular phase ovulatory women whereas 24-h BP, Ang II, Ang (1-7), and the Ang II/Ang (1-7) ratio (P < 0.01) were higher than in both phases of the ovulatory group. However, there was no significant correlation between BP and the Ang II/Ang (1-7) ratio. CONCLUSION: This study confirms that BP is constant throughout the normal menstrual cycle along with a constant balance between the vasoconstrictor (Ang II) and vasodilator [Ang (1-7)] arms of the renin-Ang-aldosterone system. Women taking oral contraceptives have a higher Ang II/Ang (1-7) ratio associated with their BP elevation although no causal relationship has been found.

Leucine supplementation at the onset of high-fat feeding does not prevent weight gain or improve glycemic regulation in male Sprague-Dawley rats.

Obesity is a major public health concern and it is essential to identify effective treatments and preventative strategies to stop continued increases in obesity rates. The potential functional roles of the branched chain amino acid leucine make this amino acid an attractive candidate for the treatment and/or prevention of obesity. The objective of this study was to determine if long-term leucine supplementation could prevent the development of obesity and reduce the risk factors for chronic disease in rats fed a high-fat (60 % fat) diet. Male Sprague-Dawley rats (n = 30 per dietary treatment) were meal-fed (3 meals/day) either a control, low-fat diet (LF), control + leucine (LFL), high-fat (HF), or high-fat + leucine (HFL) for 42 days. On day 42, rats were sacrificed at 0, 30, or 90 min postprandial. Animals fed the HF and HFL diets had higher (P < 0.05) final body weights and weight gain compared to animals fed the LF and LFL diets. Leucine supplementation increased epididymal fat mass (P < 0.05) and decreased muscle mass (P < 0.05). There was no effect of leucine supplementation on postprandial glucose or insulin response. However, there was a significant effect (P < 0.05) of diet and time on free fatty acid concentrations. There was no effect of leucine on muscle markers of protein synthesis (4E-BP1, p70S6K) or energy metabolism (Akt, AMPK). Leucine supplementation decreased (P < 0.05) PGC1α expression and increased (P < 0.05) PPARγ expression in skeletal muscle. In conclusion, long-term leucine supplementation does not prevent weight gain, improve body composition, or improve glycemic control in rats fed a high-fat diet.

FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib.

On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28-49] and 44% (95% CI, 36-53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI, 46-74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit-risk profile for the treatment of the indicated population. Clin Cancer Res; 22(21); 5171-6. ©2016 AACR.

A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome of the first year.

BACKGROUND: Despite the use of mood stabilizers, a significant proportion of patients with bipolar affective disorder experience frequent relapses. A pilot study of cognitive therapy (CT) specifically designed to prevent relapses for bipolar affective disorder showed encouraging results when used in conjunction with mood stabilizers. This article reports the outcome of a randomized controlled study of CT to help prevent relapses and promote social functioning. METHODS: We randomized 103 patients with bipolar 1 disorder according to the DSM-IV, who experienced frequent relapses despite the prescription of commonly used mood stabilizers, into a CT group or control group. Both the control and CT groups received mood stabilizers and regular psychiatric follow-up. In addition, the CT group received an average of 14 sessions of CT during the first 6 months and 2 booster sessions in the second 6 months. RESULTS: During the 12-month period, the CT group had significantly fewer bipolar episodes, days in a bipolar episode, and number of admissions for this type of episode. The CT group also had significantly higher social functioning. During these 12 months, the CT group showed less mood symptoms on the monthly mood questionnaires. Furthermore, there was significantly less fluctuation in manic symptoms in the CT group. The CT group also coped better with manic prodromes at 12 months. CONCLUSION: Our findings support the conclusion that CT specifically designed for relapse prevention in bipolar affective disorder is a useful tool in conjunction with mood stabilizers.

Monocarboxylate transporter expression at the onset of skeletal muscle regeneration.

The onset of skeletal muscle regeneration is characterized by proliferating myoblasts. Proliferating myoblasts have an increased energy demand and lactate exchange across the sarcolemma can be used to address this increased demand. Monocarboxylate transporters (MCTs) are involved in lactate transport across the sarcolemma and are known to be affected by various physiological stimuli. However, MCT expression at the onset of skeletal muscle regeneration has not been determined. The purpose of this study was to determine if skeletal muscle regeneration altered MCT expression in regenerating tibialis anterior (TA) muscle. Male C57/BL6 mice were randomly assigned to either a control (uninjured) or bupivacaine (injured) group. Three days post injection, the TA was extracted for determination of protein and gene expression. A 21% decrease in muscle mass to tibia length (2.4 ± 0.1 mg/mm vs. 1.9 ± 0.2 mg/mm, P < 0.02) was observed. IGF-1 and MyoD gene expression increased 5.0-fold (P < 0.05) and 3.5-fold (P < 0.05), respectively, 3 days post bupivacaine injection. MCT-1 protein was decreased 32% (P < 0.03); however, MCT-1 gene expression was not altered. There was no difference in MCT4 protein or gene expression. Lactate dehydrogenase (LDH)-A protein expression increased 71% (P < 0.0004). Protein levels of LDH-B and mitochondrial enzyme cytochrome C oxidase subunit decreased 3 days post bupivacaine injection. CD147 and PKC-θ protein increased 64% (P < 0.03) and 79% (P < 0.02), respectively. MCT1 but not MCT4 expression is altered at the onset of skeletal muscle regeneration possibly in an attempt to regulate lactate uptake and use by skeletal muscle cells.

Quantitation of tetrabromobisphenol-A from dust sampled on consumer electronics by dispersed liquid-liquid microextraction.

Tetrabromobisphenol-A (TBBPA) is a brominated flame retardant used worldwide. Despite its widespread use, there are few data concerning environmental concentrations of TBBPA. Thus, the objective of this work was to optimize an ultrasound-assisted dispersed liquid-liquid microextraction (DLLME) method to analyze swabbed surfaces of consumer electronics to determine TBBPA concentrations. Upon sample preparation with DLLME, TBBPA was derivatized with acetic anhydride and then analyzed by gas chromatography-mass spectrometry (GC/MS). Using a (13)C12-TBBPA internal standard to improve precision and quantitation, a recovery study was performed. At concentrations of 250-1000 ng/mL, recoveries were 104-106%. Sample preparation with solid phase extraction had comparable recoveries, although overall, improved analyte recovery and precision were achieved with DLLME. In a small survey study, TBBPA concentrations in dust collected from 100 cm(2) areas on electronic surfaces (monitor, microwave, refrigerator, and TV) were determined to range from less than the LOQ to 523 ng/mL.

Elevated gene expression in chalcone synthase enzyme suggests an increased production of flavonoids in skin and synchronized red cell cultures of North American native grape berries.

Anthocyanins are antioxidants and are among the natural products synthesized via the flavonoid biosynthesis pathway. Anthocyanins have been recommended for dietary intake in the prevention of cardiovascular diseases, cancer, and age-related conditions such as Alzheimer's disease or dementia. With an increasingly aging population in many parts of the world, strategies for the commercial production of in vitro synchronized red cell cultures as natural antioxidants will be a significant contribution to human medicine. Red pigmented fruits such as grapes (Vitis sp.) are a major source of bioavailable anthocyanins and other polyphenols. Since the level of antioxidants varies among cultivars, this study is the first one that phytochemically and genetically characterizes native grape cultivars of North America to determine the optimal cultivar and berry cells for the production of anthocyanins as antioxidants. Using real-time PCR and bioinformatics approaches, we tested for the transcript expression of the chalcone synthase (CHS) gene, an enzyme involved in the flavonoid and anthocyanin biosynthesis pathway, in different parts of physiologically mature grape berries and in vitro synchronized red cells. A low level of expression was recorded in berry flesh, compared with an elevated expression in berry skins and in vitro synchronized red cells, suggesting increased production of flavonoids in skin and cell cultures. This preliminary study demonstrates the potential of functional genomics in natural products research as well as in systematic studies of North American native grapes, specifically in muscadine (Vitis rotundifolia).

Patient willingness to participate in a clinical trial with preimplantation genetic diagnosis.

OBJECTIVE: To investigate patients' interest in preimplantation genetic diagnosis (PGD) as a method for aneuploidy screening and their willingness to participate in a clinical trial using PGD. DESIGN: Anonymous questionnaire. SETTING: University infertility clinic. PATIENT(S): Women seeking treatment for infertility at the study clinic. INTERVENTION(S): Subjects completed a two-part structured questionnaire. The questionnaire included demographic and fertility history questions, followed by opinion questions on testing for genetic diseases. The second portion of the questionnaire included opinion questions about willingness to use PGD and to participate in a clinical trial using PGD after reading a document explaining PGD. MAIN OUTCOME MEASURE(S): Patients' interest in using PGD and willingness to participate in a clinical trial involving PGD. RESULT(S): Before reading a description of PGD, 84% of participants indicated that they were interested in having their embryos tested. The majority (86%) remained interested in testing their embryos with PGD after reading the informational paragraph. Most (91%) of the women who remained interested in PGD also indicated a willingness to participate in a clinical trial involving PGD. Of the patients who initially were not interested in testing their embryos, nearly half of them (47%) indicated an interest in PGD after reading the informational paragraph, and nearly all of those who changed their mind were willing to be in a trial. CONCLUSION(S): Many women undergoing IVF are interested in the possibility of utilizing PGD for aneuploidy screening. Better evidence is needed regarding outcomes using PGD for this indication before it can be routinely incorporated into practice. A clinical trial using PGD in this setting appears possible because a majority of the patients, in this survey, would be willing to participate.

Leucine supplementation at the onset of high-fat feeding does not prevent weight gain or improve glycemic regulation in male Sprague-Dawley rats

Obesity is a major public health concern and it is essential to identify effective treatments and preventative strategies to stop continued increases in obesity rates. The potential functional roles of the branched chain amino acid leucine make this amino acid an attractive candidate for the treatment and/or prevention of obesity. The objective of this study was to determine if long-term leucine supplementation could prevent the development of obesity and reduce the risk factors for chronic disease in rats fed a high-fat (60 % fat) diet. Male Sprague-Dawley rats (n = 30 per dietary treatment) were meal-fed (3 meals/day) either a control, low-fat diet (LF), control + leucine (LFL), high-fat (HF), or high-fat + leucine (HFL) for 42 days. On day 42, rats were sacrificed at 0, 30, or 90 min postprandial. Animals fed the HF and HFL diets had higher (P < 0.05) final body weights and weight gain compared to animals fed the LF and LFL diets. Leucine supplementation increased epididymal fat mass (P < 0.05) and decreased muscle mass (P < 0.05). There was no effect of leucine supplementation on postprandial glucose or insulin response. However, there was a significant effect (P < 0.05) of diet and time on free fatty acid concentrations. There was no effect of leucine on muscle markers of protein synthesis (4E-BP1, p70S6K) or energy metabolism (Akt, AMPK). Leucine supplementation decreased (P < 0.05) PGC1α expression and increased (P < 0.05) PPARγ expression in skeletal muscle. In conclusion, long-term leucine supplementation does not prevent weight gain, improve body composition, or improve glycemic control in rats fed a high-fat diet (AU)

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