Extraordinary clinical response to ibrutinib in low-grade ovarian cancer guided by organoid drug testing.

Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient's tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient's tumor identified several therapeutic choices, including Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient's CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient's CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments.

Case report: ex vivo tumor organoid drug testing identifies therapeutic options for stage IV ovarian carcinoma.

Patients presenting with stage 4 ovarian carcinoma, including low-grade serous disease, have a poor prognosis. Although platinum-based therapies can offer some response, these therapies are associated with many side effects, and treatment resistance often develops. Toxic side effects along with disease progression render patients unable to receive additional lines of treatment and limit their options to hospice or palliative care. In this case report, we describe a patient with an unusual case of metastatic low-grade serous ovarian cancer with some features of high-grade disease who had received four previous lines of treatment and was suffering from atelectasis, pulmonary embolism, and hydronephrosis. A CLIA-certified drug sensitivity assay of an organoid culture derived from the patient's tumor (PARIS® test) identified several therapeutic options, including the combination of fulvestrant with everolimus. On this treatment regimen, the patient experienced 7 months of stable disease and survived nearly 11 months before succumbing to her disease. This case emphasizes the clinical utility of ex vivo drug testing as a new functional precision medicine approach to identify, in real-time, personalized treatment options for patients, especially those who are not benefiting from standard of care treatments.

Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14).

Patients with multiple myeloma-bearing translocation t(11;14) have recently been shown to benefit from the apoptosis-inducing drug venetoclax; however, the drug lacks FDA approval in multiple myeloma thus far due to a potential safety signal in the overall patient population. Selinexor is an inhibitor of nuclear export that is FDA-approved for patients with multiple myeloma refractory to multiple lines of therapy. Here, we report that in four patients with multiple myeloma with t(11;14), the concomitant administration of venetoclax and selinexor was safe and associated with disease response. Moreover, the combination was synergistic in t(11;14) multiple myeloma cell lines and caused decreased levels of Cyclin D1 (which is overexpressed due to the CCND1-IGH fusion) when given in combination as compared to single agents. These data suggest that the combination of venetoclax and selinexor is effective and t(11;14) may serve as a therapeutic marker for response and target for future clinical trials.

ALCAM: A Novel Surface Marker on EpCAMlow Circulating Tumor Cells.

Background: Current strategies in circulating tumor cell (CTC) isolation in pancreatic cancer heavily rely on the EpCAM and cytokeratin cell status. EpCAM is generally not considered a good marker given its transitory change during Epithelial to Mesenchymal Transition (EMT) or reverse EMT. There is a need to identify other surface markers to capture the complete repertoire of PDAC CTCs. The primary objective of the study is to characterize alternate surface biomarkers to EpCAM on CTCs that express low or negligible levels of surface EpCAM in pancreatic cancer patients. Methods: Flow cytometry and surface mass spectrometry were used to identify proteins expressed on the surface of PDAC CTCs in culture. CTCs were grown under conditions of attachment and in co-culture with naïve neutrophils. Putative biomarkers were then validated in GEMMs and patient samples. Results: Surface proteomic profiling of CTCs identified several novel protein biomarkers. ALCAM was identified as a novel robust marker in GEMM models and in patient samples. Conclusions: We identified several novel surface biomarkers on CTCs expressed under differing conditions of culture. ALCAM was validated and identified as a novel alternate surface marker on EpCAMlow CTCs.

The relationship between adverse childhood experiences, the frequency and acuity of emergency department utilization and primary care engagement.

INTRODUCTION: A history of adverse child experiences (ACEs) is associated with increased high-risk adult behaviors, morbidity, mortality, and use of the emergency department. This study was designed to understand the relationship between ACEs and the characteristics of emergency department use and primary care engagement. METHODS: An in-person survey was conducted at an academic emergency department (ED) assessing ACE score, emergency department utilization and acuity, and primary care engagement. RESULTS: The prevalence of ACEs was 71.1% with 1+ ACE and 32.5% with 4+ ACE. ACE scores of four or more were associated with three or more ED visits in the past year compared those with an ACE score of zero (OR 3.22; p < 0.05) and when adjusted for sociodemographic factors (OR 3.22; p < 0.10). Higher ACE scores were associated with lower acuity presentations as indicated by the Emergency Severity Index before (ACE score 1 OR 3.91 p < 0.05; ACE score 2-3 OR 2.35 p < 0.05; ACE score 4+ OR 3.95 p < 0.05) and after adjustment (ACE score 1 OR 3.80 p < 0.10; ACE 2-3 OR 3.50 p < 0.10; ACE 4+ OR 4.36 p < 0.05). There was no association between ACE score and having a primary care provider (PCP), frequency of PCP visits, or PCP rating. CONCLUSION: Higher ACE scores were associated with higher emergency department utilization and lower acuity presentations but not associated with levels of primary care engagement. Additional investigations are needed to adequately characterize the discrete causal mechanisms behind these current findings.

Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high-throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments, validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K-AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from patients with OCCC. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC, is warranted.

Hot-Water Bathing Improves Symptoms in Patients with Cyclic Vomiting Syndrome and Is Modulated by Chronic Cannabis Use.

BACKGROUND: Cyclic vomiting syndrome (CVS) is a chronic functional GI disorder; a characteristic compulsive "hot-water bathing" pattern is reported to alleviate symptoms during an acute episode. There is limited data on this bathing pattern: proposed mechanisms include core temperature increase via effects on cannabinoid type 1 receptors in the brain, skin transient receptor potential vanilloid 1 receptor stimulation, and blood flow shift from viscera to skin. AIMS: We thus sought to characterize the hot-water bathing pattern in patients with CVS and identify differences between heavy cannabis users in comparison to occasional and non-users. METHODS: We conducted a cross-sectional study of 111 patients with CVS at a single tertiary referral center. Questionnaires regarding clinical characteristics, hot-water bathing, and cannabis use were administered. Patients were classified based on cannabis usage into regular cannabis users (≥ 4 times/week), and occasional + non-users (< 4 times/week and no current use). RESULTS: A total of 81 (73%) respondents reported the hot-water bathing behavior during an episode. The majority (> 80%) noted a marked improvement in nausea, vomiting, abdominal pain and symptoms associated with panic. Regular cannabis users were more likely to use "very-hot" water (50% vs. 16%, p = 0.01) and time to relief of symptoms was longer (> 10 min) in this group, compared to the rest of the cohort. CONCLUSIONS: Hot-water bathing relieves both GI and symptoms related to panic in most patients which appear to be modulated by chronic cannabis use. These findings can help inform future physiologic studies in CVS pathogenesis.

Lower Trabecular Bone Score and Spine Bone Mineral Density Are Associated With Bone Stress Injuries and Triad Risk Factors in Collegiate Athletes.

INTRODUCTION: Determinants of bone health and injury are important to identify in athletes. Bone mineral density (BMD) is commonly measured in athletes with Female Athlete Triad (Triad) risk factors; the trabecular bone score (TBS) has been proposed to predict fracture risk independent of BMD. Evaluation of TBS and spine BMD in relation bone stress injury (BSI) risk has not been studied in female collegiate athletes. OBJECTIVE: We hypothesized that spine BMD and TBS would each independently predict BSI and that the combined measures would improve injury prediction in female collegiate athletes. We also hypothesized that each measure would be correlated with Triad risk factors. DESIGN: Retrospective cohort. SETTING: Academic Institution. METHODS: Dual energy x-ray absorptiometry (DXA) of the lumbar spine was used to calculate BMD and TBS values. Chart review was used to identify BSI that occurred after the DXA measurement and to obtain Triad risk factors. We used logistic regression to examine the ability of TBS and BMD alone or in combination to predict prospective BSI. RESULTS: Within 321 athletes, 29 (9.0%) sustained a BSI after DXA. BMD and TBS were highly correlated (Pearson correlation r = 0.62, P < .0001). Spine BMD and TBS had similar ability to predict BSI; the C-statistic and 95% confidence intervals were 0.69 (0.58 to 0.81) for spine BMD versus 0.68 (0.57 to 0.79) for TBS. No improvement in discrimination was observed with combined BMD + TBS (C-statistic 0.70, 0.59 to 0.81). Both TBS and BMD predicted trabecular-rich BSI (defined as pelvis, femoral neck, and calcaneus) better than cortical-rich BSI. Both measures had similar correlations with Triad risk factors. CONCLUSION: Lower BMD and TBS values are associated with elevated risk for BSI and similar correlation to Triad risk factors. TBS does not improve prediction of BSI. Collectively, our findings suggest that BMD may be a sufficient measure of skeletal integrity from DXA in female collegiate athletes.

BET, SRC, and BCL2 family inhibitors are synergistic drug combinations with PARP inhibitors in ovarian cancer.

BACKGROUND: Homologous recombination deficiencies (HRD) are present in approximately half of epithelial ovarian cancers, for which PARP inhibitors (PARPi) are becoming a preferred treatment option. However, a considerable proportion of these carcinomas acquire resistance or harbour de novo resistance, posing a significant challenge to treatment. METHODS: To identify new combinatorial therapeutics to overcome resistance to PARPi, we employed high-throughput conditional RNAi and drug screening of patient-derived ovarian cancer cells. To prioritise clinically relevant drug combinations, we integrated empirical validation with analysis of The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets to nominate candidate targets and drugs, reaching three main findings. FINDINGS: Firstly, we found that the PARPi rucaparib enhanced the effect of BET inhibitors (CPI-203 & CPI-0610) irrespective of clinical subtype or HRD status. Additional drug combination screens identified that dasatinib, a non-receptor tyrosine kinase inhibitor, augmented the effects of rucaparib and BET inhibitors, proposing a potential broadly applicable triple-drug combination for high-grade serous and clear cell ovarian carcinomas. Secondly, rucaparib synergised with the BCL2 family inhibitor navitoclax, with preferential activity in ovarian carcinomas that harbour alterations in BRCA1/2, BARD1, or MSH2/6. Thirdly, we identified potentially antagonistic drug combinations between the PARPi rucaparib and vinca alkaloids, anthracyclines, and antimetabolites, cautioning their use in the clinic. INTERPRETATION: These findings propose therapeutic strategies to address PARP inhibitor resistance using agents that are already approved or are in clinical development, with the potential for rapid translation to benefit a broad population of ovarian cancer patients.

Wastewater input reductions reverse historic hypereutrophication of Boston Harbor, USA.

This paper documents the changes that followed large nutrient (N and P) and organic matter input reductions to a major metropolitan marine bay, Boston Harbor (USA). Before input reduction, its N and P inputs fell in the upper range of the < 1-> 300 gN m-2 year-1 and < 0.1-> 40 gP m-2 year-1 for coastal systems. Elevated nutrient and organic matter inputs are recognized causes of coastal eutrophication. Treatment upgrades and then diversion of its wastewater discharges offshore, lowered its N, P, and organic C inputs by 80-90%. The input decreases lowered its trophic status from hypereutrophic to eutrophic-mesotrophic. With the reversal of hypereutrophication, pelagic production and phytoplankton biomass decreased, and the nitrogen limitation relative to phosphorus limitation increased. Benthic metabolism and dissolved inorganic N fluxes decreased, and benthic-pelagic coupling was altered. Bottom-water dissolved oxygen, already at healthy levels, increased, and seagrass expanded. Coastal management requires that the changes, following the nutrient and organic matter input reductions implemented to address eutrophication, be understood. Boston Harbor's recovery, because its water column was vertically well mixed and marine, was more pronounced than in many other systems.

Impact of Adaptive Sports Participation on Quality of Life.

The health benefits of regular recreational physical activity are well known in reducing secondary health consequences of a sedentary lifestyle in the general population. However, individuals with physical disabilities participate less frequently in recreational activity compared with those without disabilities. Although evidence on the impact of recreational physical activity on quality of life in this population is in its infancy, regular recreational and sports activity participation has shown to have a positive association with improvements in quality of life, life satisfaction, community reintegration, mood, and employment in those with disabilities. Facilitators of participating in adaptive sports include a desire to improve social support, physical fitness, health, and fun. Unfortunately, those with disabilities face numerous barriers to participate in adaptive sports including accessibility, transportation, awareness, finances, and physical and cognitive impairments. Further studies are needed to investigate facilitators and barriers to participating in adaptive sports to capitalize on the physical and psychosocial benefits of regular recreational activity. The aim of this article is to review the available literature on the effects of adaptive sports participation on quality of life.

Preserving the Shoulder Function of an Elite Paratriathlete.

Shoulder pain in wheelchair users that participate in competitive adaptive sports can be a troublesome condition. Shoulder pain not only affects athletic performance but also affects functional activities such as wheelchair propulsion and weight bearing during transfers. Managing pain in these athletes thus presents a unique challenge because of the difficulty in achieving relative rest and the need to modify athletic shoulder-focused rehabilitation strategies. In all athletes, it is vital to establish an early, accurate diagnosis and optimize conservative treatment before considering surgical interventions to avoid excessive shoulder-related morbidity, loss of function, and, worse, loss of independence.

Instability after reverse total shoulder arthroplasty.

BACKGROUND: This study evaluated patients with and without a prosthetic dislocation after reverse total shoulder arthroplasty (RTSA) to identify risk factors for instability. METHODS: Dislocation and nondislocation cohorts were established for analysis in 119 patients who had undergone RTSA at our institution between 2011 and 2014. Preoperative history and parameters pertaining to RTSA design were evaluated for correlation with instability. A logistic regression model was used to analyze independent predictors. RESULTS: Eleven patients (9.2%) demonstrated instability in the early postoperative period. Dislocations occurred at an average of 8 weeks postoperatively (range, 3 days-5 months). The mean follow-up of all patients was 28 months (range, 6-106 months). Postoperative instability was associated with male gender, history of prior open shoulder surgery, and preoperative diagnoses of fracture sequelae, particularly proximal humeral or tuberosity nonunion. Absence of subscapularis repair was an independent predictor of instability. In addition, 5 of the 11 patients (45%) in the instability cohort sustained a second dislocation requiring another operation. CONCLUSIONS: Redislocation after revision surgery for the initial dislocation was an unexpected and alarming finding. Treatment for the initial dislocation event by placement of a thicker polyethylene insert was inadequate in 45% of patients of our cohort and required another revision with a larger glenosphere and thicker humeral inserts. Initial instability after RTSA must be carefully managed, especially in the revision and post-traumatic setting. Exchange to a thicker polyethylene insert only carries a higher risk of recurrent instability.

Functional Precision Medicine Identifies Novel Druggable Targets and Therapeutic Options in Head and Neck Cancer.

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low-passage tumor cells derived from a patient with treatment-resistant HPV-negative HNSCC.Experimental Design: A tumor cell culture was established and subjected to whole-exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with a siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two nontumorigenic keratinocyte cell cultures for validation and to assess cancer specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial.Results: Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(-) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor-specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome, and G2-M kinases WEE1 and CHK1 We also show the feasibility of ex vivo drug profiling for patients enrolled in a clinical trial.Conclusions: High-throughput phenotyping with siRNA and drug libraries using patient-derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology. Clin Cancer Res; 24(12); 2828-43. ©2018 AACR.

Tropical dead zones and mass mortalities on coral reefs.

Degradation of coastal water quality in the form of low dissolved oxygen levels (hypoxia) can harm biodiversity, ecosystem function, and human wellbeing. Extreme hypoxic conditions along the coast, leading to what are often referred to as "dead zones," are known primarily from temperate regions. However, little is known about the potential threat of hypoxia in the tropics, even though the known risk factors, including eutrophication and elevated temperatures, are common. Here we document an unprecedented hypoxic event on the Caribbean coast of Panama and assess the risk of dead zones to coral reefs worldwide. The event caused coral bleaching and massive mortality of corals and other reef-associated organisms, but observed shifts in community structure combined with laboratory experiments revealed that not all coral species are equally sensitive to hypoxia. Analyses of global databases showed that coral reefs are associated with more than half of the known tropical dead zones worldwide, with >10% of all coral reefs at elevated risk for hypoxia based on local and global risk factors. Hypoxic events in the tropics and associated mortality events have likely been underreported, perhaps by an order of magnitude, because of the lack of local scientific capacity for their detection. Monitoring and management plans for coral reef resilience should incorporate the growing threat of coastal hypoxia and include support for increased detection and research capacity.

Platelet-Rich Plasma.

Platelet-rich plasma (PRP) is a growing and robust therapeutic option in musculoskeletal medicine. PRP is a preparation of autologous plasma enriched with a platelet concentration above that normally contained in whole blood. The rationale for use and therapeutic potential of a high concentration of platelets is based on their capacity to supply supraphysiologic amounts of essential growth factors to provide a regenerative stimulus that promotes repair in tissues with low healing potential. This article reviews the latest basic science on PRP, clinical evidence for its use in musculoskeletal medicine, limitations in current knowledge, and critical areas for future research.