The TOTAL trial for weight management participation: A randomized controlled trial protocol.

BACKGROUND: The three types of evidence-based treatment options for adults with overweight and obesity - behavioral weight management, anti-obesity medications (AOM), and bariatric surgery - are underutilized in the Veterans Health Administration (VHA) system. Our objective in this manuscript is to describe the study protocol for an adequately powered randomized controlled trial (RCT) of a behavioral intervention: TOTAL (Teaching Obesity Treatment Options to Adult Learners) to increase patient uptake of obesity treatment. METHODS: In this multi-site, parallel, RCT, eligible Veterans with a body mass index [BMI] ≥ 27 who had not received obesity treatment within the past 12 months were randomly assigned to TOTAL or usual care. TOTAL involves watching an 18-min video that highlights obesity health risks, pros/cons of all three evidence-based obesity treatments, and expected treatment outcomes. It also includes motivational sessions delivered via televideo at 2 weeks, 6 months, and 12 months after the video (target n = 494 participants). The primary outcome is initiation of behavioral weight management treatment within 18 months of randomization. Secondary outcomes include sustained behavioral weight management treatment, initiation of AOM, bariatric surgery referral, and weight change across 18 months. CONCLUSION: TOTAL, which seeks to increase delivery of weight management treatment within the largest integrated health system in the U.S., combines patient education with motivational interviewing components. If efficacious in this trial, further evaluation of intervention effectiveness and implementation throughout the VHA and other healthcare systems would be warranted.

Impact of a Rheumatology Clinic Protocol on Tobacco Cessation Quit Line Referrals.

OBJECTIVE: Smoking increases cardiopulmonary and rheumatic disease risk, yet tobacco cessation intervention is rare in rheumatology clinics. This study aimed to implement a rheumatology staff-driven protocol, Quit Connect, to increase the rate of electronic referrals (e-referrals) to free, state-run tobacco quit lines. METHODS: We conducted a quasi-experimental cohort study of Quit Connect at 3 rheumatology clinics comparing tobacco quit line referrals from 4 baseline years to referrals during a 6-month intervention period. Nurses and medical assistants were trained to use 2 standardized electronic health record (EHR) prompts to check readiness to quit smoking within 30 days, advise cessation, and connect patients using tobacco quit line e-referral orders. Our objective was to use EHR data to examine the primary outcome of tobacco quit line referrals using pre/post design. RESULTS: Across 54,090 pre- and post-protocol rheumatology clinic visits, 4,601 were with current smokers. We compared outcomes between 4,078 eligible pre-implementation visits and 523 intervention period visits. Post-implementation, the odds of tobacco quit line referral were 26-fold higher compared to our pre-implementation rate (unadjusted odds ratio [OR] 26 [95% confidence interval (95% CI) 6-106]). Adjusted odds of checking readiness to quit in the next 30 days increased over 100-fold compared to pre-implementation (adjusted OR 132 [95% CI 99-177]). Intervention led to e-referrals for 71% of quit-ready patients in <90 seconds; 24% of referred patients reported a quit attempt. CONCLUSION: Implementing Quit Connect in rheumatology clinics was feasible and improved referrals to a state-run tobacco quit line. Given the importance of smoking cessation to reduce cardiopulmonary and rheumatic disease risk, future studies should investigate disseminating cessation protocols like Quit Connect that leverage tobacco quit lines.

Feline cutaneous lymphoma: an evaluation of disease presentation and factors affecting response to treatment.

OBJECTIVES: The primary goal of this study was to characterize the clinical presentation of feline cutaneous lymphoma. The secondary aims included determining if treatment or initial response to treatment affected the overall survival of patients, and understanding if disease characteristics such as immunophenotype, cell size or the presence of epitheliotropism influenced response to treatment. METHODS: Veterinary medical oncologists at four academic veterinary teaching hospitals submitted cases of feline patients with cutaneous lymphoma diagnosed by histopathology or cytology. Signalment, feline leukemia virus (FeLV)/feline immunodeficiency virus (FIV) status, physical examination findings, clinical signs, diagnostic tests, therapy, response and outcome, and necropsy findings, when available, were recorded. RESULTS: Forty-one patients were identified and described. The majority of patients were domestic shorthair cats (n = 29). The median age at diagnosis was 12.3 years. Males were over-represented in the population (n = 30). In the majority of patients (n = 33), the FIV/FeLV status was unknown. Twenty patients were fully staged. Thirty-four patients were treated with a variety of modalities, including surgery, radiation, single-agent or combination chemotherapy, or prednisolone only. In multiple patients, surgery or radiation was combined with a systemic therapy. Of 34 patients treated with some form of therapy, 20 responded (achieving either a partial response or complete remission). CONCLUSIONS AND RELEVANCE: Clinical signs and physical examination findings varied among patients. Response to therapy appeared to be associated with survival (P = 0.0025); however, this population was highly censored. Immunophenotype, cell size and the presence of epitheliotropism did not influence treatment response. Results were limited by small numbers of patients, heterogeneous disease manifestations and treatment protocols. Further studies are necessary to evaluate the effect of specific treatment modalities and disease subtype on prognosis.

Comparison of International Ovarian Tumor Analysis Simple Rules to Society of Radiologists in Ultrasound Guidelines for Detection of Malignancy in Adnexal Cysts.

OBJECTIVE. The purpose of this study was to evaluate the International Ovarian Tumor Analysis (IOTA) simple rules and the Society of Radiologists in Ultrasound (SRU) guidelines for detecting ovarian malignancy in a general population of women presenting to radiology departments with adnexal cystic lesions. MATERIALS AND METHODS. A retrospective multicenter study of ultrasound-detected adnexal cystic lesions with appropriate follow-up was conducted. Lesions were classified into benign, indeterminate, or malignant categories according to criteria based on the IOTA simple rules and the SRU guidelines. The prevalence of nonneoplastic cysts, neoplasms, and malignant tumors was calculated. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated, and ROC analysis for the diagnosis of malignancy was performed. RESULTS. A total of 697 women with 764 cystic lesions were included; 85.2% (651/764) of the lesions were nonneoplastic, 12.2% (93/764) were benign neoplasms, and 2.6% (20/764) were malignant neoplasms. Nearly all malignancies were classified into indeterminate and malignant categories. The prevalence of malignancy in the indeterminate category was 4.8% (7/145) (SRU) to 10.7% (7/65) (IOTA) and in the malignant category was 18.1% (13/72) (SRU) to 34.3% (12/35) (IOTA). Only one malignancy was misclassified as benign by the IOTA simple rules. The sensitivity of the IOTA simple rules for malignancy was 90.0%; specificity, 96.5%; PPV, 29.0%; NPV, 99.8%; and accuracy, 96.4%. The corresponding values for the SRU guidelines were 100%, 89.6%, 14.9%, 100%, and 89.8%. In ROC analysis, the IOTA simple rules were slightly more accurate than the SRU guidelines (AUC, 0.9805 versus 0.9713; p = 0.0003). CONCLUSION. Both imaging characterization methods were sensitive for identifying ovarian malignancies, but the PPV was low among women presenting to radiology departments, and the indeterminate classification harbored one-third of the total malignancies. Exploration of varied clinical settings and inclusion of secondary tests may help to refine these systems.

Association of Sjögren's Syndrome With Reduced Lifetime Sex Hormone Exposure: A Case-Control Study.

OBJECTIVE: To test whether cumulative estrogen exposure, as determined by age at menarche, age at menopause, female hormone use, hysterectomy, and parity, have an effect on the development of primary Sjögren's syndrome (SS). METHODS: We performed a case-control study of 2,680 women from the Sjögren's International Collaborative Clinical Alliance registry, including 1,320 registrants with primary SS and 1,360 with sicca symptoms but no key features of primary SS (sicca controls). The composite estrogen score (CES) was calculated by point assignment for early menarche (age ≤10 years), high parity (>3 pregnancies), hysterectomy, female hormone use, and late menopause (age ≥53 years). Cumulative menstrual cycling (CMC) was calculated as years menstruating minus time pregnant. RESULTS: Using a regression model that adjusted for age, recruitment site, ethnicity, education, employment status, and smoking, we observed a progressive inverse trend between primary SS and CES. The odds ratio (OR) and 95% confidence interval (95% CI) were as follows for the sicca control group: CES 1, OR 0.81 (95% CI 0.67-0.99); CES 2, OR 0.74 (95% CI 0.57-0.97); CES 3, OR 0.50 (95% CI 0.30-0.86). This trend was corroborated by analysis of CMC. At the highest level of CMC within the postmenopausal group there was a 24% reduction in cumulative sex hormone exposure among primary SS participants relative to controls. CONCLUSION: Women with primary SS have lower estrogen exposure and CMC compared to sicca controls. Increasing estrogen exposure was negatively associated with development of primary SS. Further longitudinal studies of sex hormone exposure in primary SS are needed to confirm these findings.

Neoadjuvant chemotherapy is associated with a high rate of perioperative blood transfusion at the time of interval cytoreductive surgery.

BACKGROUND: The oncologic safety of allogeneic blood transfusion in ovarian cancer patients is unknow. We sought to determine the prevalence and oncologic safety of perioperative allogeneic blood transfusion during interval cytoreduction surgery among women receiving neoadjuvant chemotherapy for ovarian cancer. METHODS: We utilized retrospective chart review to identify a cohort of patients undergoing interval cytoreduction at a large academic tertiary referral center. We compared outcomes in patients who were exposed to perioperative blood transfusion compared with patients who were not exposed. Our primary endpoint was progression free survival; our secondary endpoint was overall survival. Baseline clinical characteristics were collected for patients in each group. RESULTS: Sixty-six women were included in the final cohort of women undergoing interval cytoreductive surgery after NACT. A total of 51 women (77%) were exposed to allogeneic perioperative pRBC transfusion. Fifteen women (23%) were not exposed to transfusion. The baseline characteristics were generally well matched. Women who were not exposed to a perioperative blood transfusion were more likely to have a normalized CA125 prior to undergoing cytoreductive surgery. Preoperative hemoglobin concentration was lower in the transfusion group (10.5 g/dLvs 11.5 g/dL, p < 0.009). Perioperative transfusion was not associated with a significant difference in progression free survival (PFS = 7.6 months for transfused, 9.4 months for not transfused; log-rank test p = 0.4617). Similarly, there was no observed difference between groups for overall survival (OS = 23.6 months for transfused, 22.5 months for not transfused; log-rank test p = 0.1723). CONCLUSIONS: Women undergoing neoadjuvant chemotherapy for ovarian cancer are at high risk of exposure to blood transfusion at the time of interval cytoreductive surgery. Future studies will continue to evaluate the safety and impact of transfusion on ovarian cancer survival in this at risk population.

Peri-operative allogeneic blood transfusion is associated with poor overall survival in advanced epithelial ovarian Cancer; potential impact of patient blood management on Cancer outcomes.

BACKGROUND: Transfusion related immune modulation associated with red blood cell (RBC) transfusion is thought to result in decreased cancer survival. Results in epithelial ovarian cancer (EOC) have been mixed however most suggest worse oncologic outcomes in patients who were transfused at the time of debulking surgery. The impact of restrictive transfusion strategies on this patient population is currently not known. METHODS: We conducted a retrospective study of women with EOC. The study population was divided into two groups based on whether they were transfused RBCs during the peri-operative period or not. Clinical characteristics and prognosticators were compared between groups. Overall survival was compared between groups based on transfusion status and other known prognostic factors. Cox proportional hazard modeling was used to examine the association between the prognostic factors and the study endpoint. RESULTS: Sixty-six percent of women were transfused. Transfusion was associated with CA125, the use of neoadjuvant chemotherapy (NACT), surgical blood loss, and anemia. The mean pre-transfusion Hgb was 7.8 + 0.6 g/dL and 94% had a hemoglobin level greater than the transfusion threshold of 7 g/dL. RBC transfusion, suboptimal debulking, anemia, and NACT were associated with decreased survival. Only RBC transfusion and suboptimal debulking status remained significant in a multivariate model. CONCLUSIONS: Peri-operative RBC transfusion compromises survival in ovarian cancer supporting the need to minimize the use of transfusion at the time of debulking surgery. Adherence to evidence-based transfusion guidelines offers an opportunity to reduce transfusion rates in this population with a resulting positive influence on survival.

Neoadjuvant chemotherapy is associated with more anemia and perioperative blood transfusions than primary debulking surgery in women with advanced stage ovarian cancer.

OBJECTIVE: The purpose of this case-controlled study was to determine the prevalence of anemia and incidence of perioperative blood transfusions in patients undergoing treatment for advanced ovarian cancer with neoadjuvant chemotherapy (NACT) or primary debulking surgery (PDS). METHODS: We performed a single institution review of patients diagnosed with stage IIIB-IVB epithelial ovarian cancer between 2010 and 2013 undergoing either NACT or PDS. Anemia was defined as a hemoglobin (Hgb) concentration of ≤11.5 g/dL. Continuous variables were compared by student t-test and binary variables compared via chi square analysis. RESULTS: One hundred thirty-one women were included, 66 treated with NACT and 65 treated with PDS. Average Hgb prior to surgery was lower in women who received NACT (10.7 g/dL vs 12.8 g/dL, p < 0.0001). Women treated with NACT had a decrease in mean Hgb during chemotherapy treatment (11.8 g/dL at diagnosis to 10.7 g/dL preoperatively). Seventy-seven percent of NACT patients were anemic prior to surgery compared to 15% of patients prior to PDS (p < 0.001). Mean EBL at debulking was higher in patients selected for PDS (871 mL) than NACT (544 mL); however, the perioperative transfusion rate was higher during interval debulking surgeries (NACT 77% vs PDS 56%, p = 0.01). CONCLUSION: Women selected for NACT were more likely to be anemic at diagnosis and became progressively anemic during NACT. Despite less blood loss during debulking surgery, NACT patients receive more blood transfusions perioperatively than patients undergoing PDS. This represents a potential opportunity for therapeutic intervention during NACT to correct anemia prior to interval debulking surgery.

Indeterminate Adnexal Cysts at US: Prevalence and Characteristics of Ovarian Cancer.

Purpose To assess the prevalence of indeterminate adnexal cysts in women presenting to academic medical centers for pelvic ultrasonography (US), determine the incidence of malignancy, and identify cyst and patient characteristics that are predictive of malignancy. Materials and Methods A multicenter study of US-detected adnexal cysts with appropriate follow-up (surgical pathologic examination, imaging and/or clinical examination) was conducted from January 2008 to June 2012. Indeterminate cysts were classified as category 1 (typical benign appearing cysts >5 cm) or category 2 (cysts with avascular solid components) on the basis of a combination of definitions in the existing literature. The incidence of neoplasms and malignant tumors was calculated. Patient and cyst characteristics associated with neoplasm and malignant tumors were evaluated with the χ2 test or Fisher exact test for categorical variables and the t test for continuous variables. A backward stepwise logistic regression model was performed for two outcomes: (a) the presence of any neoplasm (benign or malignant) and (b) the presence of a malignant tumor. Results There were 1637 women with an adnexal cyst at US; 391 (mean age = 41.8 years ± 13.5.1; range = 17-91 years) had an indeterminate adnexal cyst at US. The prevalence of indeterminate adnexal cysts was 23.9% (391 of 1637; 95% confidence interval [CI]: 0.22, 0.26). Three hundred three indeterminate cysts in 280 women (mean age = 42.9 years ± 14.1; range = 17-88 years) had adequate follow-up. The incidence of ovarian neoplasms (benign and malignant) was 24.8% (75 of 303 cysts; 95% CI: 0.20, 0.30), and the incidence of malignant tumors was 3.6% (11 of 303 cysts; 95% CI: 0.02, 0.06). The proportion of ovarian neoplasms differed between category 1 and category 2 cysts (17.5% [25 of 143 cysts; 95% CI: 0.12, 0.25] vs 31.3% [50 of 160 cysts; 95% CI: 0.24, 0.39], respectively; P = .001). The proportion of malignant tumors differed between categories 1 and 2 cysts (0% [0 of 143 cysts] vs 6.9% [11 of 160 cysts; 95% CI: 0.03, 0.12]; P < .001). The presence of an avascular nodular component was a significant predictor of malignancy at stepwise logistic regression analysis (odds ratio = 2.83; P ≤ .0001; 95% CI: 1.69, 4.70). Conclusion The presence of an avascular nodular component was the most significant predictor of the presence of malignancy in indeterminate adnexal cysts. The risk of malignancy is higher with category 2 cysts than with category 1 cysts. © RSNA, 2018.

Oxidative stress via inhibition of the mitochondrial electron transport and Nrf-2-mediated anti-oxidative response regulate the cytotoxic activity of plumbagin.

Plumbagin, an anti-cancer agent, is toxic to cells of multiple species. We investigated if plumbagin targets conserved biochemical processes. Plumbagin induced DNA damage and apoptosis in cells of diverse mutational background with comparable potency. A 3-5 fold increase in intracellular oxygen radicals occurred in response to plumbagin. Neutralization of the reactive oxygen species by N-acetylcysteine blocked apoptosis, indicating a central role for oxidative stress in plumbagin-mediated cell death. Plumbagin docks in the ubiquinone binding sites (Q0 and Qi) of mitochondrial complexes I-III, the major sites for oxygen radicals. Plumbagin decreased oxygen consumption rate, ATP production and optical redox ratio (NAD(P)H/FAD) indicating interference with electron transport downstream of mitochondrial Complex II. Oxidative stress induced by plumbagin triggered an anti-oxidative response via activation of Nrf2. Plumbagin and the Nrf2 inhibitor, brusatol, synergized to inhibit cell proliferation. These data indicate that while inhibition of electron transport is the conserved mechanism responsible for plumbagin's chemotoxicity, activation of Nrf2 is the resulting anti-oxidative response that allows plumbagin to serve as a chemopreventive agent. This study provides the basis for designing potent and selective plumbagin analogs that can be coupled with suitable Nrf2 inhibitors for chemotherapy or administered as single agents to induce Nrf2-mediated chemoprevention.

Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition.

Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044-53. ©2017 AACR.

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC.

Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257-68. ©2017 AACR.

Acute Fetal Demise with First Trimester Maternal Infection Resulting from Listeria monocytogenes in a Nonhuman Primate Model.

Infection with Listeria monocytogenes during pregnancy is associated with miscarriage, preterm birth, and neonatal complications, including sepsis and meningitis. While the risk of these conditions is thought to be greatest during the third trimester of pregnancy, the determinants of fetoplacental susceptibility to infection, the contribution of gestational age, and the in vivo progression of disease at the maternal-fetal interface are poorly understood. We developed a nonhuman primate model of listeriosis to better understand antecedents of adverse pregnancy outcomes in early pregnancy. Four pregnant cynomolgus macaques (Macaca fascicularis) received a single intragastric inoculation between days 36 and 46 of gestation with 107 CFU of an L. monocytogenes strain isolated from a previous cluster of human listeriosis cases that resulted in adverse pregnancy outcomes. Fecal shedding, maternal bacteremia, and fetal demise were consistently noted within 7 to 13 days. Biopsy specimens of maternal liver, spleen, and lymph node displayed variable inflammation and relatively low bacterial burden. In comparison, we observed greater bacterial burden in the decidua and placenta and the highest burden in fetal tissues. Histopathology indicated vasculitis, fibrinoid necrosis, and thrombosis of the decidual spiral arteries, acute chorioamnionitis and villitis in the placenta, and hematogenous infection of the fetus. Vascular pathology suggests early impact of L. monocytogenes infection on spiral arteries in the decidua, which we hypothesize precipitates subsequent placentitis and fetal demise. These results demonstrate that L. monocytogenes tropism for the maternal reproductive tract results in infection of the decidua, placenta, and the fetus itself during the first trimester of pregnancy.IMPORTANCE Although listeriosis is known to cause significant fetal morbidity and mortality, it is typically recognized in the third trimester of human pregnancy. Its impact on early pregnancy is poorly defined. Here we provide evidence that exposure to L. monocytogenes in the first trimester poses a greater risk of fetal loss than currently appreciated. Similarities in human and nonhuman primate placentation, physiology, and reproductive immunology make this work highly relevant to human pregnancy. We highlight the concept that the maternal immune response that protects the mother from serious disease is unable to protect the fetus, a concept relevant to classic TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes) infections and newly illuminated by current Zika virus outbreaks. Studies with this model, using the well-understood organism L. monocytogenes, will permit precise analysis of host-pathogen interactions at the maternal-fetal interface and have broad significance to both recognized and emerging infections in the setting of pregnancy.

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma.

On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.

Defining the boundaries and expanding the utility of head and neck cancer patient derived xenografts.

BACKGROUND: Patient derived xenografts (PDXs) represent an essential tool in oncologic research, and we sought to further expand our repertoire of head and neck squamous cell carcinoma (HNSCC) while determining potential boundaries for this system. METHODS: We consented new patients for PDX development and determined if a 24-h time delay from tumor excision to xenograft implantation affected PDX establishment. We developed a tissue microarray (TMA) from formalin fixed, paraffin embedded PDXs and their subsequent passages and carried out quantitative immunohistochemistry for EGFR, pEGFR, pAkt, pERK and ERCC1. First and last passaged PDXs were compared via a paired t-test to examine for the stability of protein expression across passages. We performed a similar comparison of the mutational profile of the patient tumor and resulting xenografts using a targeted sequencing approach. RESULTS: No patient/tumor characteristics influenced PDX take rate and the 24-h time delay from tumor excision to xenograft implantation did not affect PDX establishment, growth or histology. There was no significant difference in biomarker expression between the first and last passaged PDXs for EGFR, pEGFR, pAkt, and ERCC1. For pERK there was a significant difference (p=0.002), but further analysis demonstrated this only arose in three of 15 PDXs. Targeted sequencing revealed striking stability of passenger and likely driver mutations from patient to xenograft. CONCLUSIONS: The stability of protein expression across PDX passages will hopefully allow greater investigation of predictive biomarkers in order to identify ones for further pre-clinical and clinical investigation.

Renin-angiotensin system transgenic mouse model recapitulates pathophysiology similar to human preeclampsia with renal injury that may be mediated through VEGF.

Using a transgenic cross, we evaluated features of preeclampsia, renal injury and the sFlt1/VEGF changes. Transgenic hAGT and hREN, or wild-type (WT) C57Bl/6 mice were cross-bred: female hAGT × male hREN for preeclampsia (PRE) model and female WT × male WT for pregnant controls (WTP). Samples were collected for plasma VEGF, sFlt1, and urine albumin. Blood pressures (BP) were monitored by telemetry. Vascular reactivity was investigated by wire myography. Kidneys and placenta were immunostained for sFlt1 and VEGF. Eleven PRE and 9 WTP mice were compared. PRE more frequently demonstrated albuminuria, glomerular endotheliosis (80% vs. 11%; P = 0.02), and placental necrosis (60% vs. 0%; P < 0.01). PRE group demonstrated declining BPs with advancing gestation. Plasma sFlt1 increased across pregnancy in PRE; VEGF did not vary. IHC demonstrated the presence of sFlt1 in glomeruli, lymphatics, and collecting tubules of PRE kidneys, suggesting excretion. VEGF immunostaining was increased specifically in the glomeruli of PRE kidneys. Placenta in PRE showed marked immunostaining for sFlt1. We conclude that this transgenic model of preeclampsia recapitulates human preeclamptic state with high fidelity, and that, vascular adaptation to pregnancy is suggested by declining BPs and reduced vascular response to PE and increased response to acetylcholine. Placental damage with resultant increased release of sFlt1, proteinuria, deficient spiral artery remodeling, and glomerular endotheliosis were observed in this model of PRE. Increased VEGF binding to glomerular endothelial cells in this model of PRE is similar to human PRE and leads us to hypothesize that renal injury in preeclampsia may be mediated through local VEGF.