Citations

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.

AbstractThis review examines calcium and phosphate transport in the kidney through the lens of the rare X‐linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC‐5, a Cl−/H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC‐5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC‐5 KO models suggests that ClC‐5 mediates parathormone endocytosis from tubular fluid. In addition, ClC‐5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.

ObjectiveTo determine the 5‐year outcome of treatment for meniscal tear in osteoarthritis.MethodsWe examined 5‐year follow‐up data from the Meniscal Tear in Osteoarthritis Research trial (METEOR) of physical therapy versus arthroscopic partial meniscectomy. We performed primary intent‐to‐treat (ITT) and secondary as‐treated analyses. The primary outcome measure was the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain scale; total knee replacement (TKR) was a secondary outcome measure. We used piecewise linear mixed models to describe change in KOOS pain. We calculated 5‐year cumulative TKR incidence and used a Cox model to estimate hazard ratios (HRs) for TKR, with 95% confidence intervals (95% CIs).ResultsThree hundred fifty‐one participants were randomized. In the ITT analysis, the KOOS pain scores were ~46 (scale of 0 [no pain] to 100 [most pain]) at baseline in both groups. Pain scores improved substantially in both groups over the first 3 months, continued to improve through the next 24 months (to ~18 in each group), and were stable at 24–60 months. Results of the as‐treated analyses of the KOOS pain score were similar. Twenty‐five participants (7.1% [95% CI 4.4–9.8%]) underwent TKR over 5 years. In the ITT model, the HR for TKR was 2.0 (95% CI 0.8–4.9) for subjects randomized to the arthroscopic partial meniscectomy group, compared to those randomized to the physical therapy group. In the as‐treated analysis, the HR for TKR was 4.9 (95% CI 1.1–20.9) for subjects ultimately treated with arthroscopic partial meniscectomy, compared to those treated nonoperatively.ConclusionPain improved considerably in both groups over 60 months. While ITT analysis revealed no statistically significant differences following TKR, greater frequency of TKR in those undergoing arthroscopic partial meniscectomy merits further study.

Abstract PURPOSE: RTOG 0933 demonstrated benefits to memory following HA-WBRT, supporting the hypothesis of hippocampal radiosensitivity and associated memory specificity. However, some patients demonstrated cognitive decline, suggesting mechanisms outside hippocampal radiosensitivity playing a role. WMI has been implicated in RT-induced cognitive decline. This secondary analysis explored the relationship between pre-treatment WMI and memory following HA-WBRT. METHODS AND MATERIALS: 113 patients received HA-WBRT. Standardized cognitive assessments were performed at baseline, 2, 4, and 6 months. The primary endpoint was Hopkins Verbal Learning Test Delayed Recall (HVLT-DR) at 4 mos. Secondary endpoints included HVLT Total Recall (HVLT-TR) and Recognition (HVLT-Recog). Of 113 patients, 34 underwent pre-treatment and 4-month post-treatment HVLT testing and pre-treatment post-contrast volumetric T1 and axial T2/FLAIR MRI. Volumetric analysis of metastatic disease burden and disease-unrelated WMI was conducted on the pre-treatment MRI. Correlational analyses were performed examining the relationship between pre-treatment WMI and HVLT outcomes following HA-WBRT. RESULTS: Correlation was found between larger volumes of pre-treatment WMI and decline in HVLT-Recog (r=.54, p< .05) and a correlational trend was observed between larger volume of pre-treatment WMI and decline in HVLT-DR (r=.31, p=.08). Patients with higher pre-treatment disease burden experienced a greater magnitude of stability or positive shift in HVLT-recall and –delayed recall following HA-WBRT. (r=-.36 and r=-.36, p’s < .05), compared to the magnitude of stability/positive shift in those with lesser disease burden. CONCLUSION: In patients receiving HA-WBRT, pre-treatment-WMI predicts memory decline, suggesting white matter integrity pre-treatment contributes to the pathogenesis of post-WBRT cognitive toxicity independent of hippocampal stem cell radiosensitivity. Less decline or improvement in HVLT following HA-WBRT for patients with higher pre-treatment intracranial metastatic burden supports the importance of WBRT-induced intracranial control on cognition. These imaging biomarkers for cognitive toxicity will be further explored on NRG CC001 and CC003, phase III trials of WBRT with or without HA.

Abstract BACKGROUND: NRG CC001, a phase III trial of WBRT+memantine (WBRT+M) with or without Hippocampal Avoidance (HA), sought to assess the neuro-protective effects of lowering the radiation dose received by the hippocampus. METHODS: Patients (pts) with brain metastases were stratified by RPA class and prior radiosurgery/surgery and randomized to either WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized neurocognitive function (NCF) tests were performed at baseline, 2, 4, 6, and 12 months (mos.). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory with Brain Tumor module and analyzed using mixed effects models and t-tests. RESULTS: From 7/2016 to 3/2018, 518 patients were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted HR=0.74, p=0.02) due to lower risk of deterioration in executive function at 4 mos. (p=0.01); and encoding (p=0.049) and consolidation (p=0.02) at 6 mos. Age≤61 predicted for lower NCF failure risk (HR=0.60, p=0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p=0.036); difficulty speaking (p=0.049); and problems remembering things (p=0.013) at 6 mos. favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p=0.011) and symptom interference (p=0.008) at 6 mos. Treatment arms did not significantly differ in toxicity; intracranial progression or overall survival. CONCLUSIONS: While achieving similar intracranial control and survival; Hippocampal Avoidance during WBRT+M for brain metastases better preserves NCF and patient-reported symptoms. Supported by UG1CA189867 (NCORP) and DCP from the NCI.

Abstract Background: Immunoprevention via targeting antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a less invasive prevention strategy than endoscopic surveillance. Specificity of the immune response and long-term memory provide the potential for prolonged protection. Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a double-blind randomized trial in individuals with a diagnosis of advanced colorectal adenomas within the previous year. We are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC as an adjuvant, for its immunogenicity, ability to elicit immune memory and prevent recurrence of colorectal adenomas. Aims: We previously reported on the vaccine immunogenicity at week 12 (vaccine administered at 0, 2, and 10 weeks) compared to placebo. Here we report the ability of the vaccine to elicit long-term memory by measuring increase in anti-MUC1 antibody levels following a booster administered at one year. Methods: Subjects with endoscopically resected advanced adenoma (defined as ≥1cm, tubululovillous or villous histology, or with high grade dysplasia) were randomized. The primary endpoint was the response to the vaccine at week 12 assessed by monitoring anti-MUC1 IgG antibody titer ratio defined as t12/t0, where t0 was the titer pre-vaccination, and t12 was the titer at week 12. The key secondary endpoint was to assess anti-MUC1 IgG response at week 55 to a booster at week 52 in the vaccine arm compared to placebo. Results: 102 eligible subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. The mean age was 59.4±7.0 (range 40-70), 60.8% male, 88.2% white, and 18.6% Hispanic or Latino ethnicity. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of individuals receiving vaccine (ratio range -0.5-17.3), vs. 0/50 in placebo group (2-sided p=.0001), and was ≥1.5 in 19/52 (36.5%) individuals receiving vaccine compared to 1/50 (2%) in placebo group (P<.0001). To evaluate immune memory, 1-year booster data available for 95 patients (51-MUC1, 44-placebo) were analyzed. 10/13 (76.9%) of the week 12 vs. week 0 vaccine responders showed a response at week 52 vs. baseline and 11/13 (84.6%) at week 55 vs. week 52. Using an IgG ratio of 2 (per-protocol), the response rate was 33% for MUC1 vs. 5% for placebo (1-sided p=0.0003). Using a ratio of 1.5 yielded similar results (37% MUC1 vs. 9% Placebo (1-sided p=0.0008). The MUC1 arm had significantly higher IgG at week 52 (1-sided p=0.0294), week 55 (1-sided p=0.0048), and significantly higher week 55 to week 52 IgG ratio values (1-sided p=0.0293). Conclusions: Subjects with a recent history of advanced adenoma receiving a MUC1 vaccine compared with a placebo were significantly more likely to develop an immune response at week 12, confirming the vaccine’s immunogenicity, and to respond again at week 55 to a booster injection on week 52, confirming the vaccine’s ability to elicit immune memory. Follow-up colonoscopy to evaluate the vaccine’s potential to lower adenomatous polyp recurrence rates are in progress. Citation Format: Olivera J. Finn, Lisa Boardman, Marcia Cruz-Correa, Ajay Bansal, David Kastenberg, Chin Hurr, Sharon Kaufman, Colleen Akerley, Lynda Dzubinski, April Felt, Karrie Fursa, L.M. Rodriguez, Ellen Richmond, Asad Umar, Eva Szabo, John McKolanis, Ryan McMurray, Nathan Foster, Andres Salazar, Paul Limburg, Robert Schoen. Randomized, double-blind, placebo-controlled trial of preventative MUC1 vaccine in patients with newly diagnosed advanced adenomas: Results from one-year booster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT236.

Abstract Background: Smoking is the most common etiology for lung cancer. Smoking cessation, even when successful, does not eliminate risk of lung cancer. With inconsistent results of lung chemoprevention trials, an emerging area of interest is immunoprevention, in particular vaccines. MUC1 is a transmembrane glycoprotein aberrantly overexpressed in adenocarcinomas, including lung cancer. Abnormal MUC1 expression is also characteristic of premalignant lesions, including bronchial dysplasia and atypical adenomatous hyperplasia. This suggests that immunization with a MUC1 vaccine in the premalignant or high-risk setting, before the tumor and cytotoxic therapy could suppress the immune system, might be effective in inducing strong immunity and reducing cancer risk. Trial design: Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a two-center pilot trial to evaluate co-primary endpoints: immunogenicity of the MUC1 peptide plus polyICLC adjuvant vaccine (assessed at 12 weeks) and safety (assessed at up to 24 weeks) in current and former smokers who are at high risk for lung cancer. 50 participants will be screened in order to have 40 evaluable participants for baseline and 12-week immunogenicity assessments. Eligibility: Smoking history of ≥30 pack-years and either current smoker (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria are standard. Immunogenicity and safety: MUC1 peptide plus polyICLC adjuvant vaccine will be administered at week 0, 2 and 10. The primary endpoint is anti-MUC1 IgG titer that is ≥2 fold higher at week 12 compared to baseline. Based on previous studies of this vaccine, we expect that 40 evaluable participants will provide 96% power to detect immunogenicity response rate of 15% versus 40% using a 2-sided test of proportions with type I error rate of 0.05. AEs and toxicities will be monitored for up to 24 weeks from the first vaccine. Secondary Objectives: We will explore differences, if any, in vaccine immunogenicity in current vs. former smokers. Smoking induces chronic inflammation (hallmark of cancer) associated with immunosuppression. We will evaluate pre-vaccination levels of circulating myeloid derived suppressor cells (MDSC) and correlate with the response to the vaccine. We will explore the impact, if any, of this vaccine on the markers of inflammation (hsCRP, IL-6) and the effect of baseline levels of these markers on the ability to successfully vaccinate. We will also assess the relationship between COPD status and immune response in current versus former smokers. The trial is open to accrual. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Lisa Bengtson, John McKolanis, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Nathan Foster, Andres Salazar, Malgorzata Wojtowicz, Eva Szabo, Paul Limburg, David Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT222.

Abstract Background: Standard treatment for stage III melanoma is surgery followed by consideration of adjuvant therapy. This strategy is inadequate for high-risk stage III patients who have a substantial risk of subsequent relapse and distant metastasis. The goals of this trial are to improve oncologic outcomes, assess treatment response and spare patients with poorly responsive, rapidly metastatic disease from a futile operation. This protocol based on the hypothesis that treatment before surgery will immunize patients against his or her own unique tumor. While new drugs are now FDA-approved for adjuvant treatment of stage III melanoma, outcomes are still suboptimal in high-risk patients. The neoadjuvant approach is largely untested and preclinical data suggest neoadjuvant therapy is more effective than adjuvant immunotherapy. While targeted therapies can be rapidly effective, immunotherapy responses, when they occur, tend to be much more durable, prompting this study. Our specific strategy is based on the fact that BRAFm melanoma patients benefit both from BRAF/MEK inhibition (vemurafenib/cobimetinib) and PD-1 axis inhibition (atezolizumab) while patients with BRAFwt melanoma benefit from PD-1 axis inhibition (atezolizumab) and intermittent MEKi (cobimetinib) may increase effector function in tumor-infiltrating T cells. A second component of the study is robust evaluation of biomarkers of response, toxicity and outcome. Specific correlatives include assessment of the predictive value of Bim levels in tumor-related T cells, correlation of sPD-L1 with efficacy and toxicity, correlation of PD-L1 expression with efficacy, and determination of key relationships between tumor and immune cells via mIHC spatial analysis, gene expression profiles and microbiome associations with clinical response. Methods: The NeoACTIVATE trial enrolls melanoma patients with resectable clinically detectable nodal metastases (by physical examination or imaging), dual nodal basin disease or nodal recurrence of melanoma. Neoadjuvant systemic therapy is based on BRAF mutation status; participants receive either vemurafenib, cobimetinib and atezolizumab (vem/cobi/atezo), or cobimetinib and atezolizumab (cobi/atezo) before surgery. Following surgery, all patients receive atezo immunotherapy. The primary aim of the study is RFS estimates for each cohort. Secondary aims are safety/toxicity, pathologic complete response rate and prospective evaluation of biomarkers of treatment response and toxicity. This study is significant in that it is the first to test 1) combined of targeted and immunotherapy in the neoadjuvant setting for patients with resectable Stage III melanoma and 2) the novel combination of MEK-inhibition with immunotherapy in the neoadjuvant setting for resectable Stage III melanoma. As of January 1, 2019, 10% of planned patients have been enrolled and enrollment continues. Citation Format: Tina J. Hieken, Vera J. Suman, Shernan G. Holtan, Thomas J. Flotte, Lisa A. Kottschade, Matthew S. Block. Neoadjuvant combination targeted and immunotherapy for high-risk resectable stage III melanoma (NeoACTIVATE), NCT03554083 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT121.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.