Management of breast cancer risk in BRCA1/2 mutation carriers who are unaffected with cancer.

Pathogenic mutations in BRCA1 and BRCA2 genes markedly increase the risk of breast cancer and other cancers such as ovarian/fallopian tube, pancreatic, prostate, and melanoma. Patients with BRCA1 mutations have a slightly higher lifetime risk of breast cancer than BRCA2 mutation carriers, and both BRCA1 and BRCA2 carriers tend to develop breast cancer at an earlier age than the general population. In this review, we will discuss management recommendations to reduce breast cancer risk for BRCA1/2 mutation carriers including special populations of carriers such as pregnant or lactating patients and men. Breast cancer screening, including clinical breast examination, mammogram, and breast MRI, is important for detecting breast cancer at an early and likely curable stage. In addition to screening, counseling on risk-reducing surgeries is strongly recommended for BRCA1/2 carriers. Risk-reducing mastectomy decreases the risk of breast cancer development, and risk-reducing salpingo-oophorectomy decreases ovarian cancer-specific as well as overall mortality, but controversy exists regarding its impact on breast cancer-specific mortality. Given the effectiveness of screening for breast cancer, further management should be carried out on an individual basis taking into account quality of life and psychosocial factors, and recommendations should be readdressed periodically as science progresses and patients' goals may change.

Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors.

LESSONS LEARNED: Modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury followed by fowlpox virus-BN-Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty-three percent of patients developed CD4+ and/or CD8+ T-cell responses to brachyury after vaccination. BN-Brachyury vaccine also induced T-cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines. BACKGROUND: Brachyury, a transcription factor, plays an integral role in the epithelial-mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)-Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules. METHODS: Patients with metastatic solid tumors were treated with two monthly doses of MVA-brachyury s.c., 8 × 108 infectious units (IU), followed by FPV-brachyury s.c., 1 × 109 IU, for six monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability. RESULTS: Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose-limiting toxicities were observed. The most common treatment-related adverse event was grade 1/2 injection-site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6-month progression-free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients. CONCLUSION: BN-Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.

Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors.

BACKGROUND: HuMax-IL8 (now known as BMS-986253) is a novel, fully human monoclonal antibody that inhibits interleukin-8 (IL-8), a chemokine that promotes tumor progression, immune escape, epithelial-mesenchymal transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that high serum IL-8 levels correlate with poor prognosis in many malignant tumors. Preclinical studies have shown that IL-8 blockade may reduce mesenchymal features in tumor cells, making them less resistant to treatment. METHODS: Fifteen patients with metastatic or unresectable locally advanced solid tumors were enrolled in this 3 + 3 dose-escalation trial at four dose levels (4, 8, 16, or 32 mg/kg). HuMax-IL8 was given IV every 2 weeks, and patients were followed for safety and immune monitoring at defined intervals up to 52 weeks. RESULTS: All enrolled patients (five chordoma, four colorectal, two prostate, and one each of ovarian, papillary thyroid, chondrosarcoma, and esophageal) received at least one dose of HuMax-IL8. Eight patients had received three or more prior lines of therapy and five patients had received prior immunotherapy. Treatment-related adverse events occurred in five patients (33%), mostly grade 1. Two patients receiving the 32 mg/kg dose had grade 2 fatigue, hypophosphatemia, and hypersomnia. No dose-limiting toxicities were observed, and maximum tolerated dose was not reached. Although no objective tumor responses were observed, 11 patients (73%) had stable disease with median treatment duration of 24 weeks (range, 4-54 weeks). Serum IL-8 was significantly reduced on day 3 of HuMax-IL8 treatment compared to baseline (p = 0.0004), with reductions in IL-8 seen at all dose levels. CONCLUSIONS: HuMax-IL8 is safe and well-tolerated. Ongoing studies are evaluating the combination of IL-8 blockade and other immunotherapies. TRIAL REGISTRATION: NCTN, NCT02536469. Registered 23 August 2015, https://clinicaltrials.gov/ct2/show/NCT02536469?term=NCT02536469&rank=1 .

Product review: avelumab, an anti-PD-L1 antibody.

Although immunotherapies have been employed for many decades, immune checkpoint inhibitors have only recently entered the oncologic landscape. Avelumab is a fully human monoclonal antibody that blocks the interaction between PD-L1 on tumor cells and PD-1 on T cells, thereby inhibiting immunosuppression in the tumor microenvironment and reducing tumor growth. Most early clinical trials of avelumab as monotherapy and in combination regimens were part of the international JAVELIN clinical trial program, which included more than 7000 patients in more than 30 trials with at least 15 tumor types. Avelumab has been approved by the U.S. FDA for the treatment of metastatic Merkel cell carcinoma and metastatic urothelial carcinoma that has progressed during or following treatment with a platinum-based regimen. Its acceptable safety profile and ability to induce durable responses in otherwise deadly tumors provide the rationale for its use in other tumor types and in combination with other therapies.

Combining vaccines and immune checkpoint inhibitors to prime, expand, and facilitate effective tumor immunotherapy.

INTRODUCTION: Multiple immune checkpoint inhibitors (ICIs) that modulate immune cells in the periphery and the tumor microenvironment (TME) have been approved, as have the therapeutic cancer vaccines sipuleucel-T for metastatic castration-resistant prostate cancer and talimogene laherparepvec (T-VEC) for metastatic melanoma. These developments provide rationale for combining these modalities to improve response rates and durability of responses in a variety of cancers. Preclinical data have shown that vaccines can induce immune responses that turn a tumor from 'cold' to 'hot,' but vaccines do not appear to be highly active as monotherapy. AREAS COVERED: Here, we provide a review of the current state of vaccine and ICI combination studies. EXPERT COMMENTARY: Most combination trials are in early phases, but several are now in phase III. Vaccines that target antigens expressed exclusively on tumor cells, neoantigens, have the potential to induce robust antitumor responses. Several techniques for predicting which neoepitopes to target, based on tumor mutational profiling, are in various stages of development. To be successful, combination immunotherapy approaches must seek to prime the immune system, expand the immune response, and facilitate immune function within the TME.

Cancer vaccines: Enhanced immunogenic modulation through therapeutic combinations.

Therapeutic cancer vaccines have gained significant popularity in recent years as new approaches for specific oncologic indications emerge. Three therapeutic cancer vaccines are FDA approved and one is currently approved by the EMA as monotherapy with modest treatment effects. Combining therapeutic cancer vaccines with other treatment modalities like radiotherapy (RT), hormone therapy, immunotherapy, and/or chemotherapy have been investigated as a means to enhance immune response and treatment efficacy. There is growing preclinical and clinical data that combination of checkpoint inhibitors and vaccines can induce immunogenic intensification with favorable outcomes. Additionally, novel methods for identifying targetable neoantigens hold promise for personalized vaccine development. In this article, we review the rationale for various therapeutic combinations, clinical trial experiences, and future directions. We also highlight the most promising developments that could lead to approval of novel therapeutic cancer vaccines.

Emergent renal dysfunction with colistin pharmacotherapy.

STUDY OBJECTIVE: To evaluate the association between the administration of intravenous (IV) colistin and the emergence of renal dysfunction. DESIGN: A retrospective medical record review. SETTING: A tertiary care academic medical center. PATIENTS: A total of 174 critically ill patients who received at least one dose of IV colistin between 2004 and 2007. MEASUREMENTS AND MAIN RESULTS: The primary outcome was development of renal dysfunction, defined as an increase in serum creatinine of 50% or more during therapy or the initiation of renal replacement therapy (RRT), in patients who received at least one dose of colistin and were not already on RRT. The severity of renal dysfunction was further categorized by the RIFLE criteria. Demographic and clinical characteristics were analyzed by logistic regression for association with new renal dysfunction. A total of 174 patients were evaluated for renal dysfunction. Of these patients, 84 (48%) experienced renal dysfunction on colistin. On multivariate analysis, age in years (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05) and receipt of concurrent nephrotoxin(s) (OR 3.35, 95% CI 1.34-8.36) significantly increased the risk of developing renal dysfunction. CONCLUSION: In this critically ill population, renal dysfunction occurred frequently and was associated with older age and receipt of nephrotoxins.

Noninvasive classification of hepatic fibrosis based on texture parameters from double contrast-enhanced magnetic resonance images.

PURPOSE: To demonstrate a proof of concept that quantitative texture feature analysis of double contrast-enhanced magnetic resonance imaging (MRI) can classify fibrosis noninvasively, using histology as a reference standard. MATERIALS AND METHODS: A Health Insurance Portability and Accountability Act (HIPAA)-compliant Institutional Review Board (IRB)-approved retrospective study of 68 patients with diffuse liver disease was performed at a tertiary liver center. All patients underwent double contrast-enhanced MRI, with histopathology-based staging of fibrosis obtained within 12 months of imaging. The MaZda software program was used to compute 279 texture parameters for each image. A statistical regularization technique, generalized linear model (GLM)-path, was used to develop a model based on texture features for dichotomous classification of fibrosis category (F ≤2 vs. F ≥3) of the 68 patients, with histology as the reference standard. The model's performance was assessed and cross-validated. There was no additional validation performed on an independent cohort. RESULTS: Cross-validated sensitivity, specificity, and total accuracy of the texture feature model in classifying fibrosis were 91.9%, 83.9%, and 88.2%, respectively. CONCLUSION: This study shows proof of concept that accurate, noninvasive classification of liver fibrosis is possible by applying quantitative texture analysis to double contrast-enhanced MRI. Further studies are needed in independent cohorts of subjects.

Prevalence and characteristics of patients with undiagnosed HIV infection in an urban emergency department.

The Centers for Disease Control and Prevention (CDC) recommends offering HIV testing to persons admitted to emergency departments (EDs). Whether by opt-in or opt-out, many EDs (including our own) have found a seroprevalence of 0.8-1.5% when rapid testing is offered. The true seropositivity rate is unknown. We performed a retrospective chart analysis upon all patients presenting to our ED over a 2-week period in the fall of 2007 who had serum drawn as a part of their emergency care. Demographics and clinical characteristics were linked via de-identified serum, which was sent for HIV testing. Nine hundred fifty nine patients had sera available for rapid HIV testing. One hundred twenty one (13%) samples were reactive via the OraQuick(®) test (OraSure Technologies, Bethlehem, PA), a point of care rapid antibody test. Due to concerns about the appropriateness of sera as substrate for the OraQuick(®) technology, reactive samples were retested via standard enzyme immunoassay (EIA)/Western blot. One hundred twelve analyzable samples were retested-38 were positive and 27 of these were from patients who reported a history of HIV infection. The rate of undiagnosed HIV infection was 1.2% (11/914 potentially analyzable samples). Of all patients with HIV in our ED, 29% of them were presumably unaware of their diagnosis. In conclusion, HIV seroprevalence in our urban ED is high, and a large fraction of the patients appears to be unaware of the infection.

Effects of intravenous gadolinium administration and flip angle on the assessment of liver fat signal fraction with opposed-phase and in-phase imaging.

PURPOSE: To assess the effects of intravenous gadolinium (Gd) and flip angle (FA) on liver fat quantification by opposed-phase (OP) and in-phase (IP) imaging. MATERIALS AND METHODS: Our Institutional Review Board (IRB) approved this Health Insurance Portability and Accountability Act (HIPAA)-compliant, retrospective, clinical study. We identified 79 patients in whom abdominal OP and IP gradient-echoes were obtained at 1.5T before and after Gd administration. All 79 patients were imaged at high FA (> or =70 degrees ); 57 were also imaged at low FA (< or =20 degrees ). Fat signal fraction (FSF) was calculated from pre- and post-Gd liver images for each subject and FA using the formula, FSF = (S(IP) - S(OP))/2S(IP), where S(IP) and S(OP) are the OP and IP signal intensities, respectively. The dataset pairs (pre-Gd vs. post-Gd; high-FA vs. low-FA) were compared using linear regression analysis. RESULTS: Before Gd, FSF was significantly greater at high FA than at low FA, with regression parameters (slope/intercept) of 1.27*/0.02*, where * indicates P value <0.01. After Gd, FSF was similar at high and low FA (0.99/-0.00). Gd administration caused an FA-dependent reduction in FSF, larger at high FA (0.68*/-0.03*) than at low FA (0.94, -0.01*). CONCLUSION: FSF by OP-IP imaging is highly dependent on FA before Gd, but this dependency is eliminated after administration of Gd. Gd appears to minimize the effect of T1-weighting and may improve the accuracy of liver fat quantification.