A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer.

Purpose SM-88 (D,L-alpha-metyrosine; racemetyrosine) is a novel anti-cancer agent, used with melanin, phenytoin, and sirolimus (SMK Therapy). This pilot first-in-human study characterized the safety, tolerability, and efficacy of SMK Therapy in subjects with advanced metastatic cancer. Methods All subjects (n = 30) received SMK Therapy for an initial 6 week Cycle (5 days on, 2 off per week) and continued if well tolerated. Safety signals, clinical response, overall survival, progression free survival (PFS), and quality of life changes were assessed. Results The most common drug related adverse events were hyperpigmentation and rash. All drug related adverse events were mild to moderate in intensity. Following treatment with SMK Therapy, 4 subjects achieved complete response, 6 partial response, and 17 stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (total clinical benefit 90%). Responses were observed within 6 weeks, and continued to improve, with 3 complete and 3 partial responders achieving best response after at least 3.2 months. Durable stable disease was observed, lasting a median duration of 11 months (range 1-31 months). Median overall survival for all subjects was 29.8 months, and median PFS was 13 months. Following 6 weeks of treatment, most (83.3%) subjects showed an improvement in Eastern Cooperative Oncology Group (ECOG) score and an improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ 30) global health status (baseline 61.2 ± 25.0; end of Cycle 1 80.7 ± 14.7; n = 29; p < 0.001). Conclusions The results of this study support continued development of SM-88.

Phase 1 Study of Hypofractionated Proton Beam Radiation Therapy in Adjuvant Pancreatic Cancer (PROTON-PANC).

PURPOSE: Despite improvement in systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) frequently experience local recurrence. We sought to determine the safety of hypofractionated proton beam radiation therapy (PBT) during adjuvant chemotherapy. METHODS AND MATERIALS: Nine patients were enrolled in a single-institution phase 1 trial (NCT03885284) between 2019 and 2022. Patients had PDAC of the pancreatic head and underwent R0 or R1 resection and adjuvant modified FOLFIRINOX (mFFX) chemotherapy. The primary endpoint was to determine the dosing schedule of adjuvant PBT (5 Gy × 5 fractions) using limited treatment volumes given between cycles 6 and 7 of mFFX. Patients received PBT on days 15 to 19 in a 28-day cycle before starting cycle 7 (dose level 1, DL1) or on days 8 to 12 in a 21-day cycle before starting cycle 7 (DL2). RESULTS: The median patient age was 66 years (range, 52-78), and the follow-up time from mFFX initiation was 12.5 months (range, 6.2-37.4 months). No patients received preoperative therapy. Four had R1 resections and 5 had node-positive disease. Three patients were enrolled on DL1 and 6 patients on DL2. One dose-limiting toxicity (DLT) occurred at DL2 (prolonged grade 3 neutropenia resulting in discontinuation of mFFX after cycle 7). No other DLTs were observed. Four patients completed 12 cycles of mFFX (range, 7-12; median, 11). No patients have had local recurrence. Five of 9 patients had recurrence: 3 in the liver, 1 in the peritoneum, and 1 in the bone. Six patients are still alive, 4 of whom are recurrence-free. The median time to recurrence was 12 months (95% CI, 4 to not reached [NR]), and median overall survival was NR (95% CI, 6 to NR; 2-year survival rate, 57%). CONCLUSIONS: PBT integrated within adjuvant mFFX was well tolerated, and no local recurrence was observed. These findings warrant further exploration in a phase 2 trial.

Patterns of Failure Following Preoperative Chemotherapy and Stereotactic Body Radiation Therapy and Resection for Patients with Borderline Resectable or Locally Advanced Pancreatic Cancer.

BACKGROUND: The role of neoadjuvant stereotactic body radiation therapy (SBRT) in the treatment of pancreatic adenocarcinoma (PDAC) is controversial and the optimal target volumes and dose-fractionation are unclear. The aim of this study is to report on treatment outcomes and patterns of failure of patients with borderline resectable (BL) or locally advanced (LA) pancreatic cancer following preoperative chemotherapy and SBRT. METHODS: We conducted a single-institution, retrospective study of patients with BL or LA PDAC. Patients received neoadjuvant chemotherapy and SBRT was prescribed to 30 Gy over 5 fractions to the pancreas planning tumor volume (PTV). A subset of patients received a simultaneous integrated boost to the high risk vascular PTV and/or elective nodal irradiation (ENI). Following neoadjuvant chemoradiation, all patients underwent subsequent resection. Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMPFS), and locoregional control (LRC) estimates were obtained using Kaplan-Meier analysis. RESULTS: Twenty-two patients with BL (18) or LA (4) PDAC were treated with neoadjuvant chemotherapy and SBRT followed by resection from 2011-2022. Following neoadjuvant treatment, 5 patients (23%) achieved a pathologic complete response (pCR) and 16 patients (73%) had R0 resection. At 24 months, there were no isolated locoregional recurrences (LRRs), 9 isolated distant recurrences (DRs), and 5 combined LRRs and DRs. Two LRRs were in-field, 2 LRRs were marginal, and 1 LRR was both in-field and marginal. 2-year median LRC, LRRFS, DMPFS, PFS, and OS were 77.3%, 45.5%, 31.8%, 31.8%, and 59.1%, respectively. For BL and LA cancers, 2-year LRC, DMPFS, and OS were 83% vs. 75%, (p = 0.423), 39% vs. 0% (p = 0.006), and 61% vs. 50% (p = 0.202), respectively. ENI was associated with improved LRC (p = 0.032) and LRRFS (p = 0.033). Borderline resectability (p = 0.018) and lower tumor grade (p = 0.027) were associated with improved DMPFS. CONCLUSIONS: Following preoperative chemotherapy and SBRT, locoregional failure outside of the target volume occurred in 3 of 5 recurrences; ENI was associated with improved LRC and LRRFS. Further studies are necessary to define the optimal techniques for preoperative radiation therapy.

Perioperative therapy landscape for locally advanced, resectable esophageal cancer: an updated literature review.

Background and Objective: The poor oncologic outcomes associated with esophageal cancer (EC) are primarily due to its presentation at an advanced stage and patient comorbidities. While multimodal therapy improves overall outcomes, there is a lack of uniform practice in terms of perioperative management, partly because this is a rapidly evolving field in a heterogeneous patient population. With numerous recent studies incorporating precision medicine with radiographic, pathologic, and genomic biomarkers and with emerging trials using targeted therapies, it is necessary for providers who care for these patients to be familiar with the current and evolving treatment standards to optimize patient outcomes. The objective of this paper is to perform an updated review of the main historical and recently emerging studies that impact the perioperative management of patients with locally advanced, upfront-resectable EC. Methods: We mined and reviewed PubMed and American Society of Clinical Oncology databases for pivotal works shaping the current perioperative treatment landscape in locally advanced EC. Key Content and Findings: EC are a vastly heterogeneous disease, and treatment options vary based on tumor anatomic location, histology, and patient comorbidities. Perioperative chemotherapy (CTX), chemoradiation (CRT), and, recently, immunotherapy have improved survival in patients with locally advanced disease. However, optimizing sequencing, de-escalating therapy, and incorporating novel targeted therapies in the perioperative setting are promising strategies that are under ongoing investigation to improve patient outcomes further. Conclusions: There is an ongoing need to identify predictive biomarkers and novel treatment strategies to personalize perioperative approaches and optimize outcomes of patients with EC.

Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFß Signaling Pathways and COP1 in Metastasis.

Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFß signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (BCAR1, COL1A1, IGSF3, RRAD, and TFPI2). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (COP1) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.

Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial.

Background: Compared with normal cells, tumour cells contain elevated levels of reactive oxygen species (ROS). Increased levels of the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) correlate negatively with the survival of patients with pancreatic cancer. Napabucasin is an investigational, orally administered ROS generator bioactivated by NQO1. Methods: In the open-label, phase 3 CanStem111P study (NCT02993731), adults with previously untreated metastatic pancreatic adenocarcinoma (mPDAC) were randomised (1:1) to napabucasin plus nab-paclitaxel with gemcitabine or nab-paclitaxel with gemcitabine alone. The primary endpoint was overall survival (OS). In exploratory analyses, OS was evaluated in the subgroup of patients with tumours positive for pSTAT3 (biomarker-positive). Findings: Between 30 January 2017 and 20 February 2019, a total of 1779 patients were screened across 165 study sites in Austria, Australia, Belgium, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Netherlands, Poland, Portugal, Russia, Singapore, Spain, Taiwan, Ukraine, and the US. Of the 565 and 569 patients randomised to the napabucasin and control treatment arms, respectively, 206 and 176 were biomarker-positive. Median (95% confidence interval [CI]) OS in the napabucasin and control treatment arms was 11.4 (10.5-12.2) and 11.7 (10.7-12.7) months, respectively (hazard ratio, 1.07; 95% CI, 0.93-1.23). Due to the lack of OS improvement in the napabucasin arm, CanStem111P was terminated due to futility. In the biomarker-positive subgroup, no difference between treatment arms was found for OS. Grade ≥3 adverse events were reported in 85.4% and 83.9% of napabucasin-treated and control-treated patients, respectively. The incidence of gastrointestinal-related grade ≥3 events was higher with napabucasin (diarrhoea: 11.6% vs 4.9%; abdominal pain: 10.0% vs 4.8%). Interpretation: Our findings suggested that although the addition of napabucasin to nab-paclitaxel with gemcitabine did not improve efficacy in patients with previously untreated mPDAC, the safety profile of napabucasin was consistent with previous reports. CanStem111P represents the largest cohort of patients with mPDAC administered nab-paclitaxel with gemcitabine in the clinical trial setting. Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC. Funding: The Sumitomo Pharma Oncology, Inc.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial.

PURPOSE: This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS: We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS: Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION: The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

The Next Frontier in Pancreatic Cancer: Targeting the Tumor Immune Milieu and Molecular Pathways.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with abysmal prognosis. It is currently the third most common cause of cancer-related mortality, despite being the 11th most common cancer. Chemotherapy is standard of care in all stages of pancreatic cancer, yet survival, particularly in the advanced stages, often remains under one year. We are turning to immunotherapies and targeted therapies in PDAC in order to directly attack the core features that make PDAC notoriously resistant to chemotherapy. While the initial studies of these agents in PDAC have generally been disappointing, we find optimism in recent preclinical and early clinical research. We find that despite the immunosuppressive effects of the PDAC tumor microenvironment, new strategies, such as combining immune checkpoint inhibitors with vaccine therapy or chemokine receptor antagonists, help elicit strong immune responses. We also expand on principles of DNA homologous recombination repair and highlight opportunities to use agents, such as PARP inhibitors, that exploit deficiencies in DNA repair pathways. Lastly, we describe advances in direct targeting of driver mutations and metabolic pathways and highlight some technological achievements such as novel KRAS inhibitors.

The Role of Immunotherapy in Pancreatic Cancer.

Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients.

Gastric carcinoma's primary presentation as multiple cutaneous nodules throughout the body.

Cutaneous metastasis resulting from internal primary tumors remains a rare phenomenon. The prompt recognition of these metastases is important, as they are an indicator of advanced disease and poor prognosis. We report the case of a 44-year-old Caucasian man presenting with a four-month history of multiple cutaneous nodules on the face, trunk, and upper extremities. Results from skin biopsy revealed strands and cords of atypical cells concerning for poorly differentiated metastatic carcinoma. An esophagogastroduodenoscopy was performed and a poorly differentiated signet-ring type invasive adenocarcinoma at the lesser curvature of the stomach was found. As the cancer had already metastasized to the skin and bones, the patient was started on chemotherapy with an oxaliplatin-based regimen and denosumab for the bone metastases, with resultant objective response and diagnostic control for greater than one year to the present date.

The current state of molecular profiling in gastrointestinal malignancies.

This is a review of the current state of molecular profiling in gastrointestinal (GI) cancers and what to expect from this evolving field in the future. Individualized medicine is moving from broad panel testing of numerous genes or gene products in tumor biopsy samples, identifying biomarkers of prognosis and treatment response, to relatively noninvasive liquid biopsy assays, building on what we have learned in our tumor analysis and growing into its own evolving predictive and prognostic subspecialty. Hence, the field of GI precision oncology is exploding, and this review endeavors to summarize where we are now in preparation for the journey ahead.

A randomized phase II study of SM-88 plus methoxsalen, phenytoin, and sirolimus in patients with metastatic pancreatic cancer treated in the second line and beyond.

BACKGROUND: This trial explores SM-88 used with methoxsalen, phenytoin, and sirolimus (MPS) in pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC) METHODS: Forty-nine patients were randomized to daily 460 or 920 mg oral SM-88 with MPS (SM-88 Regimen). The primary endpoint was objective response rate (RECIST 1.1). RESULTS: Thirty-seven patients completed ≥ one cycle of SM-88 Regimen (response evaluable population). Disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) did not differ significantly between dose levels. Stable disease was achieved in 9/37 patients (DCR, 24.3%); there were no complete or partial responses. Quality-of-life (QOL) was maintained and trended in favor of 920 mg. SM-88 Regimen was well tolerated; a single patient (1/49) had related grade 3 and 4 adverse events, which later resolved. In the intention-to-treat population of 49 patients, the median overall survival (mOS) was 3.4 months (95% CI: 2.7-4.9 months). Those treated in the second line had an mOS of 8.1 months and a median PFS of 3.8 months. Survival was higher for patients with stable versus progressive disease (any line; mOS: 10.6 months vs. 3.9 months; p = 0.01). CONCLUSIONS: SM-88 Regimen has a favorable safety profile with encouraging QOL effects, disease control, and survival trends. This regimen should be explored in the second-line treatment of patients with mPDAC. CLINICALTRIALS: gov Identifier: NCT03512756.

Randomized Phase II Study of PARP Inhibitor ABT-888 (Veliparib) with Modified FOLFIRI versus FOLFIRI as Second-line Treatment of Metastatic Pancreatic Cancer: SWOG S1513.

PURPOSE: PARP inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic cancers. This study evaluated the safety and efficacy of second-line treatment with veliparib and mFOLFIRI versus FOLFIRI (control) for metastatic pancreatic cancer. PATIENTS AND METHODS: This randomized phase II clinical trial led by the SWOG Cancer Research Network enrolled patients between September 1, 2016 and December 13, 2017. The median follow-up was 9 months (IQR 1-27). BRCA1/2 and homologous recombination DNA damage repair (HR-DDR) genetic defects were tested in blood and tumor biopsies. Patients received veliparib 200 mg twice daily, days 1-7 with mFOLFIRI days 3-5, or FOLFIRI in 14-day cycles. RESULTS: After 123 of planned 143 patients were accrued, an interim futility analysis indicated that the veliparib arm was unlikely to be superior to control, and the study was halted. Median overall survival (OS) was 5.4 versus 6.5 months (HR, 1.23; P = 0.28), and median progression-free survival (PFS) was 2.1 versus 2.9 months (HR, 1.39; P = 0.09) with veliparib versus control. Grade 3/4 toxicities were more common with veliparib (69% vs. 58%, P = 0.23). For cancers with HR-DDR defects versus wild-type, median PFS and OS were 7.3 versus 2.5 months (P = 0.05) and 10.1 versus 5.9 months (P = 0.17), respectively, with FOLFIRI, and 2.0 versus 2.1 months (P = 0.62) and 7.4 versus 5.1 months (P = 0.10), respectively, with veliparib plus mFOLFIRI. CONCLUSIONS: Veliparib plus mFOLFIRI did not improve survival for metastatic pancreatic cancer. FOLFIRI should be further studied in pancreatic cancers with HR-DDR defects.

MEK inhibitors in non-V600 BRAF mutations and fusions.

Mutations in BRAF at the 600th codon have proven sensitive to combination BRAF and MEK inhibition. Mutations outside this codon, however, are approximately as common but do not have approved targeted therapy approaches. Herein, we discuss targeting these non-V600 mutation and fusions in BRAF with MEK inhibitors.

Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies.

PURPOSE: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). PATIENTS AND METHODS: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. RESULTS: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. CONCLUSIONS: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.

Biologics in bowel cancer.

Colorectal cancer is the third most common cancer in the United States and second leading cause of cancer death with over 50,000 patients expected to die from their disease in 2017. For patients who present at diagnosis with advanced disease the standard treatment is systemic chemotherapy. Over the last decade a number of biologic therapies have emerged as viable treatment options for advance colorectal cancer. When these new drugs are combined with chemotherapy survival is prolonged, often without a detriment to quality of life. In this chapter we will review the most active biologic options for treatment of colorectal cancer and place them in the context of a rapidly growing field.

Comparison of outcomes between SBRT, yttrium-90 radioembolization, transarterial chemoembolization, and radiofrequency ablation as bridge to transplant for hepatocellular carcinoma.

PURPOSE: To evaluate and compare outcome of stereotactic body radiation therapy (SBRT), yttrium-90 radioembolization, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE) as bridge to liver transplant (LT) in patients with hepatocellular carcinoma. METHODS AND MATERIALS: We retrospectively reviewed patients treated at our institution with SBRT, TACE, RFA, or yttrium-90 as bridge to LT between 2006 and 2013. We analyzed radiologic and pathologic response and rate of failure after bridge therapy. Toxicities were reported using Common Terminology Criteria for Adverse Events, 4.0. Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival after LT. RESULTS: Sixty patients with a median age 57.5 years (range, 44-70) met inclusion criteria. Thirty-one patients (50.7%) had hepatitis C cirrhosis, 14 (23%) alcoholic cirrhosis, and 8 (13%) nonalcoholic steatohepatitis cirrhosis. Patients received a total of 79 bridge therapies: SBRT (n = 24), TACE (n = 37), RFA (n = 9), and Y90 (n = 9). Complete response (CR) was 25% for TACE, 8.6% for SBRT, 22% for RFA, and 33% for Y90. Grade 3 or 4 acute toxicity occurred following TACE (n = 4) and RFA (n = 2). Transplant occurred at a median of 7.4 months after bridge therapy. Pathological response among 57 patients was 100% necrosis (n = 23, 40%), >50% necrosis (n = 20, 35%), <50% necrosis (n = 9, 16%), and no necrosis (n = 5, 9%). Pathologic complete response was as follows: SBRT (28.5%), TACE (41%), RFA (60%), Y90 (75%), and multiple modalities (33%). At a median follow-up of 35 months, 7 patients had recurrence after LT. DFS was 85.8% and overall survival was 79% at 5 years. CONCLUSION: All bridge therapies demonstrated good pathological response and DFS after LT. SBRT and Y90 demonstrated significantly less grade ≥3 acute toxicity. Choice of optimal modality depends on tumor size, pretreatment bilirubin level, Child-Pugh status, and patient preference. Such a decision is best made at a multidisciplinary tumor board as is done at our institution.

New and emerging treatment options for biliary tract cancer.

Biliary tract cancer (BTC) is a group of relatively rare tumors with a poor prognosis. The current standard of care consists of doublet chemotherapy (platinum plus gemcitabine); however, even with cytotoxic therapy, the median overall survival is less than 1 year. The genetic basis of BTC is now more clearly understood, allowing for the investigation of targeted therapy. Combinations of doublet chemotherapy with antiepidermal growth factor receptor agents have provided modest results in Phase II and Phase III setting, and responses with small molecule inhibitors are limited. Moving forward as we continue to characterize the genetic hallmarks of BTC, a stepwise, strategic, and cooperative approach will allow us to make progress when developing new treatments.

Novel agents in mantle cell lymphoma.

Mantle cell lymphoma is a mature B cell neoplasm constituting 5-7% of all non-Hodgkin lymphoma. Overall prognosis with current therapeutics remains poor, thus numerous novel agents are currently under investigation. In this review we focus on early phase trials that have demonstrated promise in mantle cell. Constitutive activation of signaling components downstream of the B cell receptor play an important role in the pathobiology of mantle cell lymphoma. Targeting of this signaling pathway has become a focus with specific agents under development including inhibitors of spleen tyrosine kinase, phosphoinositide 3-kinase and Bruton's tyrosine kinase. Promising data also supports further development of BH-3 mimetics, a crucial component of anti-apoptotic signaling. Histone deacetylase inhibitors have an established role in cutaneous T-cell lymphoma and are now under investigation in mantle cell lymphoma as well. With further understanding of cellular signaling, the armamentarium of treatment options will be enhanced, with the hope of improving the prognosis of this disease.