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Introduction: Cholangiocarcinomas (CCA) are rare, aggressive tumors often diagnosed in advanced stages with limited evidence guiding therapy on progression. Case Report: We report a case of advanced CCA with rapid and aberrant progression, refractory to multiple lines of therapy, that resulted in severe hepatic dysfunction secondary to tumor burden with a BRAF V600E mutation and high tumor proportion score (TPS) of 99%. To our knowledge, this is the first reported use of BRAF/MEK inhibition to target BRAF V600E in a patient with severe hepatic dysfunction leading to rapid normalization of the patient’s liver dysfunction within days. No adverse events were recorded during either initial titration or maintenance periods. Programmed death-1 (PD-1) inhibitor was added to BRAF/MEK inhibition, and the patient continues to have clinical therapeutic response. Conclusion: This case highlights the use of BRAF/MEK inhibition in CCA with BRAF V600E mutations in hepatic dysfunction due to tumor burden and the role of combining immune checkpoint inhibitors.

MEK inhibition (MEKi) is proposed to enhance antitumor immunity but has demonstrated mixed results as an immunomodulatory strategy in human clinical trials. MEKi exerts direct immunomodulatory effects on tumor cells and tumor-infiltrating lymphocytes (TIL), but these effects have not been independently investigated. Here we modeled tumor-specific MEKi through CRISPR/Cas-mediated genome editing of tumor cells [MEK1 knockout (KO)] and pharmacologic MEKi with cobimetinib in a RAS-driven model of colorectal cancer. This approach allowed us to distinguish tumor-mediated and tumor-independent mechanisms of MEKi immunomodulation. MEK1 KO tumors demonstrated upregulation of JAK/STAT signaling, enhanced MHCI expression, CD8+ T-cell infiltration and T-cell activation, and impaired tumor growth that is immune dependent. Pharmacologic MEKi recapitulated tumor-intrinsic effects but simultaneously impaired T-cell activation in the tumor microenvironment. We confirmed a reduction in human peripheral-lymphocyte activation from a clinical trial of anti–PD-L1 (atezolizumab) with or without cobimetinib in biliary tract cancers. Impaired activation of TILs treated with pharmacologic MEKi was reversible and was rescued with the addition of a 4-1BB agonist. Collectively, these data underscore the ability of MEKi to induce context-dependent immunomodulatory effects and suggest that T cell–agonist therapy maximizes the beneficial effects of MEKi on the antitumor immune response.

Supplementary Figures 1-5 and Supplementary Table 1

Supplementary Figures S1, S2. Supplementary Figure 1 shows pharmacodynamic biomarkers for two of the pancreatic cancer subcutaneous patient-derived xenografts. Supplementary Figure 2 shows necropsy, indicating significantly decreased metastases in animals treated with the combination of dinaciclib + MK-2206

Supplementary Figure Legends

Pharmacokinetic parameters of guadecitabine and decitabine after guadecitabine injection

LINE1 changes in tumor CpG 1-3 on cycle 1 day 8 from baseline. LINE1 changes in tumor DNA in individual patient biopsy samples.

LINE1 changes in circulating DNA CpG 1-3 as compared to baseline.

Purpose:Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in patients with mCRC previously treated with irinotecan.Patients and Methods:In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m2; DL −1: guadecitabine 30 mg/m2; DL −1G: guadecitabine 30 mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m2 with GFS].Results:Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and −1G), biliary drain infection (DL −1), colonic obstruction (DL −1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment.Conclusions:We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m2 and irinotecan 125 mg/m2 with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.

Background: INT230-6 is a novel formulation of cisplatin and vinblastine with an amphiphilic cell penetration enhancer that has been shown to enhance dispersion of the drug throughout tumors and allow diffusion into cells when given intratumorally. INT230-6 is being evaluated in monotherapy and in combination with immune checkpoint inhibitors (ICIs) in subjects with various advanced solid tumors, including advanced breast cancer. Methods: This phase 1/2 study evaluated INT230-6 in superficial and deep tumors with INT230-6 Q2W intratumoral injections for 5 doses alone or in combination with 200mg pembrolizumab IV Q3W for 2 years. Total INT230-6 injected in a subject ranged from 0.89 to 649 mL over 5 INT230-6 dosing sessions in each subject, except one subject who had only 2 dosing sessions. Subjects who had completed treatment in dose escalation cohorts were eligible for retreatment; and one subject was retreated with INT230-6 in multiple arms of the study. Advanced breast cancer subjects with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or below who have failed one or more approved therapies, or have no alternate approved therapy, were enrolled. Subjects must have adequate organ function and measurable disease by RECIST 1.1 criteria including one target tumor for injection. Tumor response using RECIST 1.1 was evaluated at 12 weeks from the first INT230-6 dose and then every 8 weeks. Tumor biopsies were taken prior to INT230-6 dosing on day 0 and on day 28 post dose. Results: 7 advanced triple negative breast cancer subjects (4 monotherapy, 3 pembrolizumab combination) were evaluable as of June 1, 2021. The median age was 56 (range 46-82) years old, with a median of 8 (2, 17) prior systemic therapies for metastatic disease. The intratumoral INT230-6 dose was up to 164 mL (82 mg of CIS, 16.4mg VIN) to tumors in a single dosing session. With INT230-6, 133-200% more volume is injected into the tumor and pharmacokinetics (PK) analysis shows that 95% of INT230-6 active agents remain in the tumor. Accordingly, assessment of tumor response using RECIST principles may be challenging, and even stable disease may represent a large decrease in viable tumor cells as indicated by biopsy evaluations. The most common (>20%) related treatment related adverse events (AE) were localized tumor related pain (71%), nausea (57%), anemia (29%), fatigue (29%), neck pain (29%), and vomiting (29%). AEs were mostly low grade and only one subject experienced grade 3 anemia (13%). There were no related grade 4 or 5 AEs or serious AEs. Disease control rate (DCR), defined as the percent of patients with a complete response, partial response, or stable disease at the first radiologic assessment, was 57%. Median overall survival was 12 months. Pre- and post- biopsy at 28 days after two INT230-6 doses (n= 3 evaluable, monotherapy, and combination with pembrolizumab) showed a 55% decrease in Ki67 and 69% reduction in viable cancer cells. In addition, multiplex immunofluorescence (n= 3 evaluable, combination with pembrolizumab) showed an influx of activated CD4 and CD8 T cells and in some cases a reduction in FoxP3 T-reg cells.. Conclusion: INT230-6 is a potential first-in-class intratumoral therapy for advanced breast cancer being developed in monotherapy and in combination with ICIs. There is a favorable safety profile in this population, similar to the broader metastatic solid tumor population presented elsewhere. There are early signs of cancer cell death in injected tumors and immune activation in heavily pre-treated patients. A Phase 2 expansion cohort of INT230-6 in combination with ICIs is ongoing. In addition, INT230-6 in being studied in a separate randomized Phase 2 neoadjuvant breast cancer study. Citation Format: Philippe Bedard, Lillian L Siu, Jacob Thomas, Diana Hanna, Anthony J Olszanski, Nilofer Azad, Giles Whalen, Matthew Ingham, Syed Mahmood, Lewis H Bender, Ian B Walters, Anthony El-Khoueiry. Safety and efficacy of INT230-6, a potential first-in-class intratumoral therapy, in monotherapy and in combination with pembrolizumab: Results from the IT-01 study [KEYNOTE-A10] in subjects with locally advanced, unresectable and metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-13.

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a “watch-and-wait” nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.

Background: Isocitrate dehydrogenase 1/2 (IDH1/2) is mutated in a subset of cholangiocarcinoma (CCA), gliomas, and other solid tumors. LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 study of oral LY3410738 in patients (pts) with IDH1/2m CCA, and IDH1m glioma or other solid tumors. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced IDHm CCA and other solid tumors (NCT04521686). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 80 pts including 42 with CCA (33 IDH1m, 9 IDH2m), 27 with glioma (IDH1m), and 11 other tumor types (IDH1m) received LY3410738 dosed at 25-600 mg QD or 300 mg BID. Pts were median 52 years of age (range, 23-80) with a median of 2 prior therapies (range, 1-7). 19% of CCA pts had received prior IDH1 inhibitor. Median time on treatment was 3.7 months (range, 0.1-19). No DLTs or treatment related deaths were observed; the MTD was not reached. Treatment emergent adverse events (TEAEs) ≥15% included nausea (35%), vomiting (21%), and decreased appetite (19%) and were mostly grade 1-2. Most frequent grade ≥3 TEAEs >2% were anemia (4%), cholangitis (3%), headache (3%), decreased lymphocyte count (3%), and hyponatremia (3%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels, including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Among the 42 pts with R/R CCA, the best response included 1 PR and 22 SD. Of the 22 glioma pts with contrast enhancing tumors, best response included 3 PR and 9 SD. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1/2m advanced solid tumors. Consistent with the expectations for IDH inhibitor monotherapy in this setting, CCA and glioma pts exhibited prolonged stable disease. RP2D evaluation is ongoing. Updated data on LY3410738 monotherapy will be presented at the meeting. Citation Format: Jordi Rodon, Lipika Goyal, Teresa Macarulla Mercade, Masafumi Ikeda, Shunsuke Kondo, Do-Youn Oh, Li-Yuan Bai, Makoto Ueno, Antoine Italiano, Kyriakos Papadopoulos, David Spigel, Sani H. Kizilbash, Rasha Cosman, Joon Oh Park, Li-Tzong Chen, Tomoya Yokota, Anita A. Turk, Chih-Yi Liao, Rachna Shroff, Anthony El-Khoueiry, Taroh Satoh, Antoine Hollebecque, Mitesh J. Borad, Nilofer Azad, Kurt A. Jaeckle, Herbert H. Loong, Jorge Adeva, Wei Peng Yong, Junjie Zhao, Hui Liu, Anna M. Szpurka, Ivelina Gueorguieva, Kamnesh R. Pradhan, Xiaojian Xu, James J. Harding. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT098.

Purpose: Mistletoe extract is widely used in cancer patients to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration. Patients and Methods: This phase I trial of intravenous Mistletoe (Helixor M) aimed to determine the recommended phase 2 dosing and to evaluate safety. Solid tumor patients progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL. Results: Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The maximum tolerated dose was 600mg. Treatment-related adverse events (AEs) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in three patients (14.8%). Stable disease was observed in five patients who had 1-6 prior therapies. Reductions in baseline target lesions were observed in three patients who had 2-6 prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by FACT-G increased from 79.7 at week 1 to 93 at week 4. Conclusions: Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted. Citation Format: Channing J. Paller, Lin Wang, Wei Fu, Rajedra Kumar, Jennifer Durham, Nilofer Azad, Daniel Laheru, Ilene Browner, Sushant Kachhap, Kavya Boyapati, Thomas Odeny, Deborah Armstrong, Christian Meyer, Stephanie Gaillard, Julie Brahmer, Ivelisse Page, Hao Wang, Luis A. Diaz. Phase I trial of intravenous mistletoe extract in advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1600.

PURPOSE An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors. CLINICAL CONTEXT An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection. PROVISIONAL CLINICAL OPINION Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel–based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase ( NTRK) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker–linked options relative to other approved or investigational treatments. Additional information is available at www.asco.org/assays-and-predictive-markers-guidelines .

Background Colon cancer (CC) is treatable if detected in its early stages. Improved CC detection assays that are highly sensitive, specific, and available at point of care are needed. In this study, we systematically selected and tested methylated markers that demonstrate high sensitivity and specificity for detection of CC in tissue and circulating cell-free DNA. Methods Hierarchical analysis of 22 candidate CpG loci was conducted using The Cancer Genome Atlas (TCGA) COAD 450K HumanMethylation database. Methylation of 13 loci was analyzed using quantitative multiplex methylation-specific PCR (QM-MSP) in a training set of fresh frozen colon tissues (N = 53). Hypermethylated markers were identified that were highest in cancer and lowest in normal colon tissue using the 75th percentile in Mann–Whitney analyses and the receiver operating characteristic (ROC) statistic. The cumulative methylation status of the marker panel was assayed in an independent test set of fresh frozen colon tissues (N = 52) using conditions defined and locked in the training set. A minimal marker panel of 6 genes was defined based on ROC area under the curve (AUC). Plasma samples (N = 20 colorectal cancers, stage IV and N = 20 normal) were tested by cMethDNA assay to evaluate marker performance in liquid biopsy. Results In the test set of samples, compared to normal tissue, a 6-gene panel showed 100% sensitivity and 90% specificity for detection of CC, and an AUC of 1.00 (95% CI 1.00, 1.00). In stage IV colorectal cancer plasma versus normal, an 8-gene panel showed 95% sensitivity, 100% specificity, and an AUC of 0.996 (95% CI 0.986, 1.00) while a 5-gene subset showed 100% sensitivity, 100% specificity, and an AUC of 1.00 (95% CI 1.00, 1.00), highly concordant with our observations in tissue. Conclusions We identified high performance methylated DNA marker panels for detection of CC. This knowledge has set the stage for development and implementation of novel, automated, self-contained CC detection assays in tissue and blood which can expeditiously and accurately detect colon cancer in both developed and underdeveloped regions of the world, enabling optimal use of limited resources in low- and middle-income countries.

Management of primary and secondary hepatic malignancy is a complex problem. Achieving optimal care for this challenging population often requires the involvement of multiple medical and surgical disciplines. Because of the wide variety of potential therapies, treatment protocols for various malignancies continue to evolve. Consequently, development of appropriate therapeutic algorithms necessitates consideration of medical options, such as systemic chemotherapy; surgical options, such as resection or transplantation; and loco-regional therapies, such as thermal ablation and transarterial embolization techniques. This article provides a review of treatment strategies for the three most common subtypes of hepatic malignancy treated with loco-regional therapies: hepatocellular carcinoma, neuroendocrine metastases, and colorectal metastases. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature and voted on five variants to establish appropriate recommended treatment of borderline and unresectable pancreatic cancer. The guidelines reviewed the use of radiation, chemotherapy, and surgery. Radiation technique, dose, and targets were evaluated, as was the recommended chemotherapy, administered either alone or concurrently with radiation. This report will aid clinicians in determining guidelines for the optimal treatment of borderline and unresectable pancreatic cancer.

For resectable gastric cancer, perioperative chemotherapy or adjuvant chemoradiation with chemotherapy are standards of care. The decision making for adjuvant therapeutic management can depend on the stage of the cancer, lymph node positivity, and extent of surgical resection. After gastric cancer resection, postoperative chemotherapy combined with chemoradiation should be incorporated in cases of D0 lymph node dissection, positive regional lymph nodes, poor clinical response to induction chemotherapy, or positive margins. In the setting of a D2 lymph node dissection, especially those with negative regional lymph nodes, adjuvant chemotherapy alone could be considered. The American College of Radiology (ACR) Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Introduction: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 occur in a spectrum of solid and hematologic malignancies. Mutant IDH1/2 in cancer cells results in the neomorphic production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which impairs cellular differentiation via an epigenetic mechanism. AG-120 is a first-in-class, oral, potent, reversible and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, phase 1, open-label, single-arm study of AG-120 (NCT02073994). Aims: Key objectives are to evaluate the safety, tolerability, and maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity. Key exploratory objectives include an analysis of tumor tissue samples in non-glioma subjects and magnetic resonance imagining/spectroscopy (MRI/MRS) in glioma subjects, pre and on AG-120 treatment. Methods: Patients with advanced, IDH1-mutant solid tumors, including glioma, who have recurred or progressed following standard therapy, or who have not responded to standard therapy, are eligible to receive continuous, single-agent, oral AG-120 dosed daily in 28-day cycles. Informed consent is obtained prior to entry. Sequential dose cohorts are being enrolled, with expansion cohorts planned. Blood and tumor biopsies are collected for PK/PD assessment. Objective responses are investigator assessed using either RECIST or RANO criteria for subjects with solid tumors and gliomas, respectively. Results: As of 1 July 2015, 55 patients (glioma: 20, non-glioma: 35) were treated with AG-120. Median age was 54 years (range, 23-88) and median number of prior systemic regimens 3 (range, 1-6). Doses administered were 100 mg BID (n = 4), 300 mg QD (n = 9), 400 mg QD (n = 5), 500 mg QD (n = 17), 600 mg QD (n = 5), 800 mg QD (n = 6), 900 mg QD (n = 4), and 1200 mg QD (n = 5). Median treatment duration was 1.9 months (range, 0.1-12.5). The MTD was not reached. PK analyses showed high plasma exposure and drug accumulation following oral administration and a mean half-life of 73.1 ± 66.6 hr. Overall, treatment was well tolerated: 49 patients experienced treatment-emergent adverse events (AEs), regardless of causality. Most frequently occurring AEs (%) were nausea (21.8), diarrhea (16.4), vomiting (14.5), anemia (12.7), and abdominal pain (10.9). There were no treatment-related serious AEs. Summary/Conclusion: AG-120 is a first-in-class, oral, potent, selective inhibitor of mutant IDH1 in development for solid and liquid tumors. Updated safety and clinical activity, as well as exploratory PD analyses will be presented. Future development plans for AG-120 in solid tumors will also be highlighted. Citation Format: Howard Burris, Ingo Mellinghoff, Elizabeth Maher, Patrick Wen, Murali Beeram, Mehdi Touat, Jason Faris, Nilofer Azad, Timothy Cloughesy, Lia Gore, Jonathan Trent, Daniel Von Hoff, Meredith Goldwasser, Bin Fan, Sam Agresta. The first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a Phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL04-05.

The management of rectal cancer in patients with metastatic disease at presentation is highly variable. There are no phase III trials addressing therapeutic approaches, and the optimal sequencing of chemotherapy, radiation therapy, and surgery remains unresolved. Although chemoradiation is standard for patients with stage II/III rectal cancer, its role in the metastatic setting is controversial. Omitting chemoradiation may not be appropriate in all stage IV patients, particularly those with symptomatic primary tumors. Moreover, outcomes in this setting are vastly different, as some treatments carry the potential for cure in selected patients, while others are purely palliative. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (Modified Delphi) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment.

To investigate whether pre-existing diabetes modifies racial disparities in colorectal cancer (CRC) survival.We analyzed prospective data from 16 977 patients (age ≥ 67 years) with CRC from the Surveillance Epidemiology and End Results (SEER)-Medicare database. SEER registries included data on demographics, tumor characteristics, and treatment. Medicare claims were used to define pre-existing diabetes and comorbid conditions. Mortality was confirmed in both sources.At baseline, 1332 (8%) were African Americans and 26% had diabetes (39% in blacks; 25% in whites). From 2000 to 2005, more than half of the participants died (n = 8782, 52%). This included 820 (62%) deaths (23.8 per 100 person-years) among blacks, and 7962 (51%) deaths (16.6 per 100 person-years) among whites. Among older adults with diabetes, blacks had significantly higher risk of all-cause and CRC mortality after adjustments for demographic characteristics (hazard ratio [HR], 95% confidence interval [CI]: 1.21 [1.08-1.37] and 1.21 [1.03-1.42]), respectively, but these associations attenuated to null after additional adjustments for cancer stage and grade. Among adults without diabetes, the risk of all-cause mortality (HR [95% CI]: 1.14 [1.04-1.25]) and CRC mortality (HR [95% CI]: 1.21 [1.08-1.36]) remained higher in blacks than whites in fully adjusted models that included demographic variables, cancer stage, grade, treatments, and comorbidities.Among older adults with CRC, diabetes is an effect modifier on the relationship between race and mortality. Racial disparities in survival were explained by demographics, cancer stage, and grade in patients with diabetes.

In mammals, males and females differ both genetically and hormonally, making it difficult to assess the relative contributions of genetic constitution and fetal environment in the process of sexual differentiation. Many reptiles lack sex chromosomes, relying instead on the temperature of incubation to determine sex. In the leopard gecko (Eublepharis macularius), an incubation temperature of 26 degrees C produces all females, whereas 32.5 degrees C results in mostly males. Incubation temperature is the primary determinant of differences both within and between the sexes in growth, physiology, and sociosexual behavior, as well as the volume and metabolic capacity of specific brain nuclei. To determine if incubation temperature organizes the brain directly rather than via gonadal sex hormones, the gonads of male and female leopard geckos from the two incubation temperatures were removed and, in some instances, animals were given exogenous testosterone. In vertebrates with sex chromosomes, the size of sexually dimorphic nuclei are sensitive to hormone levels in adulthood, but in all species studied to date, these changes are restricted to the male. Therefore, after behavior tests, morphometrics of certain limbic and nonlimbic brain areas were determined. Because nervous system tissue depends on oxidative metabolism for energy production and the level of cytochrome oxidase activity is coupled to the functional level of neuronal activity, cytochrome oxidase histochemistry also was performed on the same brains. Hormonal manipulation had little effect on the volume of the preoptic area or ventromedial hypothalamus in geckos from the all-female incubation temperature, but significantly influenced the volumes of these brain areas in males and females from the male-biased incubation temperature. A similar relationship was found for cytochrome oxidase activity of the anterior hypothalamus, amygdala, dorsal ventricular ridge, and septum. The only sex difference observed was found in the ventromedial hypothalamus; males showed no significant changes in cytochrome oxidase activity with hormonal manipulation, but females from both incubation temperatures were affected similarly. The results indicate that incubation temperature organizes the brain directly rather than via hormones arising from its sex-determining function. This is the first demonstration in a vertebrate that factors other than steroid hormones can modify the organization and functional activity of sexually differentiated brain areas.