Phase Ib/II study of ceritinib in combination with ribociclib in patients with ALK-rearranged non-small cell lung cancer.

BACKGROUND: Preclinical data show that the combination of an ALK inhibitor (ALKi) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) may act synergistically to overcome drug resistance mechanisms. Here, we assessed the safety, tolerability, and preliminary clinical activity of ceritinib, an ALKi in combination with ribociclib, a CDK4/6i, in patients with ALK-rearranged non-small cell lung cancer (NSCLC). METHODS: This was a multicenter, open-label, phase Ib/II dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for ceritinib plus ribociclib therapy. RESULTS: Twenty-seven adult patients with ALK-rearranged advanced NSCLC with an ECOG PS ≤ 2 were enrolled into five cohorts to receive various dose combinations of ceritinib (range, 300-450 mg/day) and ribociclib (range, 100-300 mg/day). Median age of patients was 57 years. MTDs were not reached in this study. Enrollment into phase Ib was terminated early and phase II was not opened due to changes in the ALK-rearranged NSCLC treatment landscape. Ceritinib 300 mg/day and ribociclib 200 mg/day (3-weeks-on/1-week-off schedule) was identified as the RP2D. Among the 27 evaluable patients, the overall response rate (ORR) was 37.0% (95% CI, 19.4-57.6) and median progression-free survival (mPFS) was 21.5 months (95% CI, 5.5-25.0). At RP2D, the ORR was 50.0%, disease control rate was 75%, and mPFS was 24.8 months (95% CI, 5.5-25.1). Safety profile of the combination therapy was consistent with single-agent safety data. CONCLUSION: Combination of ceritinib and ribociclib showed clinical activity with a manageable safety profile in patients with advanced ALK-rearranged NSCLC.

The Effectiveness of Superficial Drain to Reduce Surgical Site Infection in Colorectal Surgery.

Background The incidence of surgical site infection (SSI) in colorectal surgery is high, which can complicate and delay postoperative recovery. This study mainly aims to evaluate the efficacy of subcutaneous drains in decreasing superficial surgical site infection in colorectal surgery patients.  Study design This is a retrospective cohort study that included patients over 16 years old who underwent colorectal surgery from the 1st of January 2015 till the 31st of December 2020. Patients were divided into two groups, with and without a subcutaneous drain. The incidence of superficial SSI was measured as the primary objective, and the incidence of other complications like seromas, hematomas, and wound dehiscence was measured as the secondary objectives or outcomes. Chi-square and Fisher's exact were used to analyze the data, and a p-value less than 0.05 was accepted for significance. Results A total of 208 patients who underwent colorectal surgery in our hospital were included. Of these, 29 had a subcutaneous drain, and 179 did not have a subcutaneous drain. Although the incidence of dehiscence was higher in the drain group, the overall incidence of superficial SSI (20.7%) and seroma/hematoma (3.4%) in patients with subcutaneous drains was lower than without subcutaneous drains (25.7% and 7.8%, respectively). However, no statistical significance was found between drain presence and complications. Conclusion In conclusion, this study demonstrated a lower incidence of superficial SSI and seroma/hematoma in patients with a subcutaneous drain than those who did not have a drain.

Phase Ib Study of Ribociclib plus Fulvestrant and Ribociclib plus Fulvestrant plus PI3K Inhibitor (Alpelisib or Buparlisib) for HR+ Advanced Breast Cancer.

PURPOSE: Resistance to treatment with endocrine therapy in patients with HR+, HER2- advanced breast cancer (ABC) is common and dual inhibition of CDK4/6 and PI3K pathways may delay the development of resistance. This phase Ib trial evaluates the safety and tolerability of triple and double regimens containing the CDK4/6 inhibitor ribociclib. PATIENTS AND METHODS: In this open-label, multicenter, phase Ib study, 70 postmenopausal women with HR+, HER2- ABC were enrolled into one of four treatment combinations: ribociclib (once daily, 3 weeks on, 1 week off) plus fulvestrant; ribociclib (continuous dosing) plus fulvestrant; ribociclib plus alpelisib plus fulvestrant; or ribociclib plus buparlisib plus fulvestrant. RESULTS: The recommended phase II dose (RP2D) of ribociclib was confirmed to be 600 mg (3 weeks on, 1 week off) and 400 mg (continuous dosing) plus fulvestrant 500 mg. For the triple combination with buparlisib, the RP2D was ribociclib 400 mg plus buparlisib 30 mg plus fulvestrant 500 mg. Enrollment for the triple combinations was stopped due to unexpected toxicity. No RP2D was determined for the alpelisib combination. The safety profiles of the ribociclib plus fulvestrant combinations were consistent with those in previous studies. There was no marked difference in ribociclib exposure in the presence of triple-combination partners. The highest overall response rate was seen in the buparlisib triple combination (25.0%; 95% confidence interval, 9.8-46.7). CONCLUSIONS: Ribociclib plus fulvestrant demonstrated safety in the treatment of patients with HR+, HER2- ABC. Triple combinations with alpelisib or buparlisib plus fulvestrant are not recommended for phase II investigation.See related commentary by Clark et al., p. 371.

Intraoral Dual Wavelength Laser Diode Therapy for Chronic Maxillary Sinusitis.

BACKGROUND: Chronic sinusitis is one of the most common chronic diseases involving different age groups. The different etiological factors and difficult diagnostic procedures contribute to misdiagnosis and chronicity of sinusitis. There is no standard treatment for sinusitis. Long term use of corticosteroids and antibiotics may lead to numerous adverse side effects. Laser therapy has been suggested as a non-invasive treatment for sinusitis. It has anti-inflammatory and antibacterial effects. When considering maxillary sinusitis, discharge tends to collect in the sinus base due to its anatomy and altered physiology. To improve penetration of laser into the maxillary sinus, intraoral laser at the vestibule depth of the maxilla may be more effective. MATERIAL AND SUBJECT: Thirty-four patients with chronic maxillary sinusitis were assigned into two groups. All were assessed before and after treatment. Group A received laser radiation plus standard medical treatment and group B received medical treatment only. The treatment plan was performed in 12 sessions using a Diode laser with a wavelength of 810 nm and 980nm. The SNOT-22 questionnaire and Computed Tomography were used to evaluate patients. A p-value < 0.05 was considered statistically significant. RESULTS: Both groups showed a significant improvement in symptoms following treatment (p < .001), however, the laser therapy group demonstrated greater improvements for all variables in response to treatment as compared to the traditional treatment group (p < .001). CONCLUSIONS: Using high intensity intra-oral laser therapy with medical treatment is more effective than using medical treatment only for treatment of chronic maxillary sinusitis.

Evaluation of Absolute Oral Bioavailability and Bioequivalence of Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, in Healthy Subjects.

Ribociclib, a selective and potent cyclin-dependent kinase 4/6 inhibitor, has demonstrated safety and efficacy in combination with endocrine therapy in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer. In 2 open-label crossover studies in healthy participants, the absolute bioavailability of a single oral dose of a ribociclib 600-mg tablet (n = 16) was compared with a single intravenous ribociclib infusion of 150 mg (n = 16), and the bioequivalence of a ribociclib 600-mg tablet (n = 31) and a ribociclib 600-mg capsule (n = 31) was evaluated. The pharmacokinetics of ribociclib and its major metabolite, LEQ803, were assessed in both studies. The oral bioavailability of the 600-mg ribociclib tablet was 65.8% (90% confidence interval [CI], 59.1-73.2%). The geometric mean systemic clearance of ribociclib was moderate (40.2 L/h; 27.4% intersubject variability [CV%]) compared with hepatic blood flow, and the geometric mean volume of distribution was high (979 L; 25.2 CV%). LEQ803-to-ribociclib metabolic ratios were 0.198 for the oral administration and 0.125 for intravenous infusion. Bioequivalence of the tablet and capsule formulations was demonstrated for ribociclib. The geometric mean ratios of maximum concentration and area under the curve from time 0 to last quantifiable concentration and to infinity were 1.01, 1.00, and 0.937, respectively, within the predefined bioequivalence range of 0.80 to 1.25. The median time to reach maximum concentration was 3 hours with both formulations. No serious adverse events were observed in either study.

Primary angiosarcoma of the breast: Case report of a rare vascular tumor.

This is a case report of a woman in her sixth decade of life diagnosed with primary angiosarcoma of the breast using mammography and ultrasound, confirmed with imaging-guided biopsy, and finally treated with surgery and radiation. Imaging studies obtained and discussed include mammography, ultrasonography, and MRI. Further discussion on the presenting symptoms, useful imaging modalities, and treatment options takes place. It is important to consider primary angiosarcoma of the breast, though rare, in any woman presenting with a palpable breast mass and, if feasible, an MRI will be most helpful in the diagnosis of this rare tumor.

Association of Patterns of Mild Traumatic Brain Injury with Neurologic Deterioration: Experience at a Level I Trauma Center.

INTRODUCTION: There are about 2.5 million emergency room visits for traumatic brain injury (TBI) every year and 75%-95% of all TBI patients have mild TBI. Previous studies have suggested that a large proportion of mild TBI patients can be treated in a non-aggressive manner, but they have not differentiated mild TBI as per radiological patterns to help in the selection of these patients. Our study aimed to identify different patterns of mild TBI to determine if certain injuries make patients more prone to neurologic worsening than others, and thus require more intensive monitoring. We also studied the factors associated with neurologic deterioration. METHODS: We conducted a retrospective study using an institutional trauma database to identify TBI patients between the years of 2015 and 2016 with admission Glasgow Coma Score (GCS) of 13 to 15, through chart review by the investigators. Radiological and neurological worsening was determined through computed tomography (CT) scan results, GCS scores, and the requirement for neurosurgical intervention. We identified the prevalence of demographic characteristics, radiological patterns, and risk factors. We studied neurologic deterioration (decline in GCS to less than 13 at 48 hours or earlier after admission) and surgical intervention among patients with different radiological patterns of TBI. We further studied the cohort of isolated subdural hematoma (SDH) patients requiring surgery to evaluate the associated risk factors. RESULTS: Out of 374 patients with mild TBI (mean age was 63 years), 59% were male, 77% were Caucasian, the median GCS was 15, majority of patients had isolated SDH (45%), and mixed pattern of hemorrhage (39%); the use of antiplatelet (33%) was the most commonly identified risk factors. Overall 7% of patients were found to have neurologic deterioration (GCS to less than 13) and 9% required surgical intervention at 48 hours or earlier after admission. The most common pattern of TBI requiring surgical intervention was isolated SDH (85%). Among the cohort of patients with isolated SDH, 17% required surgical intervention and 69% of those isolated SDH patients requiring surgery had neurologic deterioration. The most common risk factor in isolated SDH patients requiring surgery was antiplatelet use (34%), anticoagulant use (20%), alcohol abuse (17%), severe renal failure (17%), and thrombocytopenia (7%). Mean size of SDH in patients requiring surgery was 1.6 cm with 0.8 cm of midline shift. CONCLUSION: This study identified the pattern of mild TBI associated with neurological worsening at our Level I Trauma Center. Among patients with mild TBI, SDH patients seem to be at highest risk for deterioration and requirement for surgery. If these results can be externally validated through a multi-center study, these patients could be selectively identified for aggressive monitoring in the intensive care unit (ICU) and repeat CT scans.

Losartan may inhibit the progression of liver fibrosis in chronic HCV patients.

BACKGROUND: Abundant experimental evidence indicates overproduction of angiotensin II in the injured liver, and a role in stimulation of hepatic stellate cell (HSC) activation and fibrogenesis thereby, representing an attractive antifibrotic target. The aim of this study was to examine the antifibrotic effect of losartan on histopathologic level in chronic HCV patients. METHODS: A prospective study on fifty patients with chronic HCV and liver fibrosis proved by liver biopsy was conducted. They included patients who did not respond (n=36) or comply (n=2) or receive therapy due to established cirrhosis (n=10), or refused to receive (n=2) combined interferon and ribavirin therapy. They were divided randomly into 2 groups. The 1(st) group (n=25) was given losartan 50 mg OD for 1 year and the 2(nd) group (25 patients) was given silymarin, 140 mg t.i.d., (silymarin group). Liver biopsy was done at baseline and 1 year from the onset of treatment (end of study). RESULTS: In the second liver biopsy after 1 year, the decrease in fibrosis stage was significantly different between losartan group and silymarin group (a decrease of 1.88±0.96 (50.9%) vs. 0.45±0.93 (11.7%), respectively; P<0.01). In patients treated with losartan, regression in fibrosis stage was observed in 14/16 patients vs. 2/11 in silymarin group (P<0.01). No differences were observed in inflammation grades in both groups. A significant increase in albumin and prothrombin levels and a decrease in systolic blood pressure were found in losartan but not in silymarin group (P=0.009, 0.001 & 0.018 respectively and P=0.158, 0.603 & 0.288, respectively). CONCLUSIONS: Histopathological scores showed that losartan had an inhibitory effect on progression and even led to regression of fibrosis stage but had no effect on the grade of inflammation.

Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers.

BACKGROUND: Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. OBJECTIVE: The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. METHODS: EFV was administered to healthy volunteers (n = 57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. RESULTS: EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ∆∆QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 95% CI [-1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 µg/mL significantly inhibited outward hERG tail currents (P < 0.05). CONCLUSIONS: This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG.

Gene expression analysis of parthenogenetic embryonic development of the pea aphid, Acyrthosiphon pisum, suggests that aphid parthenogenesis evolved from meiotic oogenesis.

Aphids exhibit a form of phenotypic plasticity, called polyphenism, in which genetically identical females reproduce sexually during one part of the life cycle and asexually (via parthenogenesis) during the remainder of the life cycle. The molecular basis for aphid parthenogenesis is unknown. Cytological observations of aphid parthenogenesis suggest that asexual oogenesis evolved either through a modification of meiosis or from a mitotic process. As a test of these alternatives, we assessed the expression levels and expression patterns of canonical meiotic recombination and germline genes in the sexual and asexual ovaries of the pea aphid, Acyrthosiphon pisum. We observed expression of all meiosis genes in similar patterns in asexual and sexual ovaries, with the exception that some genes encoding Argonaute-family members were not expressed in sexual ovaries. In addition, we observed that asexual aphid tissues accumulated unspliced transcripts of Spo11, whereas sexual aphid tissues accumulated primarily spliced transcripts. In situ hybridization revealed Spo11 transcript in sexual germ cells and undetectable levels of Spo11 transcript in asexual germ cells. We also found that an obligately asexual strain of pea aphid produced little spliced Spo11 transcript. Together, these results suggest that parthenogenetic oogenesis evolved from a meiosis-like, and not a mitosis-like, process and that the aphid reproductive polyphenism may involve a modification of Spo11 gene activity.