A phase II study evaluating axitinib in patients with unresectable, recurrent or metastatic head and neck cancer.

BACKGROUND: Axitinib is an oral, potent, small molecule tyrosine kinase inhibitor with selective inhibition of VEGFR 1,2, 3, as well as inhibition of potential downstream effectors of the EGFR pathway. Given the upregulation of EGFR and VEGFR in head and neck squamous cell carcinoma, treatment with axitinib holds promise as a rational targeted therapy. PATIENTS AND METHODS: Patients with unresectable, recurrent or metastatic head and neck squamous cell carcinoma were included in this open label, single arm, phase II trial. Primary endpoint was 6 month progression free survival. All patients received single agent axitinib with planned dose escalation based on tolerability. A planned interim efficacy analysis was performed after enrollment of 30 patients. RESULTS: Forty-two patients were registered, 30 were evaluable. While treatment was well-tolerated with no severe bleeding events, only 19 patients were able to achieve full planned dose. The best overall response rate was 6.7% (two partial responses) with a disease control rate of 76.7%. Median progression free survival was 3.7 months (95% Confidence Interval (CI): 3.5-5.7) and overall survival was 10.9 months (95% CI: 6.4-17.8). Exploratory analysis demonstrated that patients with a smaller sum of diameter of target lesions experienced improved response rates, and better progression-free and overall survival. CONCLUSION: Treatment with single agent axitinib should be considered due to acceptable toxicity profile and favorable median overall survival compared to standard therapies.

SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.

End stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.

Longitudinal Dynamic in Weight Loss Impacts Clinical Outcomes for Veterans Undergoing Curative Surgery for Colorectal Cancer.

Background: Definitions of malnutrition imperfectly reflect nutritional status or predict perioperative consequences. We sought to identify predictive nutritional trends by examining the effect of preoperative weight on postoperative outcomes in patients with colorectal cancer (CRC). Methods: This retrospective review examined 148 patients with CRC treated with curative-intent surgery at the Veterans Affairs Ann Arbor Healthcare System in Michigan from January 1, 2015 to December 31, 2019. We evaluated weight dynamics of patients, starting 1 year before cancer diagnosis until 1 year after surgery. We evaluated the association of these weight dynamics with surgical outcomes. Primary outcomes observed were hospital readmission and length of stay (LOS), chemotherapy completion, and delayed recovery defined as abnormal clinical developments. Results: There were 115 patients in the colon cancer (CC) cohort and 33 in the rectal cancer (RC) cohort. Low preoperative albumin (< 3.5 g/dL) was present in 25 patients with CC (22%) and 11 patients with RC (33%). Six-month preoperative weight loss of at least 3% occurred in 32 patients with CC (36%). Delayed recovery was observed in 35 patients with CC (30%) and 21 patients with RC (64%). Nutrition consultation rates for the CC and RC groups were 15% and 36%, respectively, before the operation; 95% and 100%, respectively, for postoperative inpatients; and 12% and 73%, respectively, for postoperative outpatients. Six-month preoperative weight loss of ≥ 3% was significantly associated with delayed recovery (P < .001) and 60-day readmissions (P = .015) but not increased LOS or chemotherapy noncompletion. Conclusions: A ≥ 3% weight loss 6 months preceding curative surgery for CRC was associated with adverse outcomes. An intensive nutrition prehabilitation program initiated at the time of cancer diagnosis is needed and may reduce associated complications.

Unique characteristics of the tumor immune microenvironment in young patients with metastatic colorectal cancer.

Introduction: Metastatic colorectal cancer (mCRC) remains a common and highly morbid disease, with a recent increase in incidence in patients younger than 50 years. There is an acute need to better understand differences in tumor biology, molecular characteristics, and other age-related differences in the tumor microenvironment (TME). Methods: 111 patients undergoing curative-intent resection of colorectal liver metastases were stratified by age into those <50 years or >65 years old, and tumors were subjected to multiplex fluorescent immunohistochemistry (mfIHC) to characterize immune infiltration and cellular engagement. Results: There was no difference in infiltration or proportion of immune cells based upon age, but the younger cohort had a higher proportion of programmed death-ligand 1 (PD-L1)+ expressing antigen presenting cells (APCs) and demonstrated decreased intercellular distance and increased cellular engagement between tumor cells (TCs) and cytotoxic T lymphocytes (CTLs), and between TCs and APCs. These trends were independent of microsatellite instability in tumors. Discussion: Age-related differences in PD-L1 expression and cellular engagement in the tumor microenvironment of patients with mCRC, findings which were unrelated to microsatellite status, suggest a more active immune microenvironment in younger patients that may offer an opportunity for therapeutic intervention with immune based therapy.

Total Neoadjuvant Therapy (TNT) with Full Dose Concurrent Chemotherapy in Locally Advanced Rectal Adenocarcinoma Including Signet Ring and Mucinous Cancers.

PURPOSE: Total neoadjuvant therapy (TNT) with pre-operative chemotherapy and chemoradiotherapy results in improved survival and is becoming the new standard of care in locally advanced rectal cancer (LARC). We describe our experience with TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin. METHODS: Adults with biopsy-proven, newly diagnosed LARC with high-risk characteristics on pelvic MRI (T4a or T4b, extramural vascular invasion, N2, mesorectal fascia involvement, enlargement/tumor deposits on lateral lymph nodes) were included. The TNT protocol comprised of six biweekly courses of modified FOLFOX6 followed by pelvic RT with four concurrent cycles of biweekly 5-FU 2600 mg/m2 + LV 200 mg/m2 without oxaliplatin to complete 20 uninterrupted weeks of full dose 5FU. Surgery was planned 11-13 weeks after completing chemoradiotherapy. RESULTS: Eighty-four LARC patients, including 26% with signet-ring cell carcinoma, with high-risk MRI characteristics were treated with the TNT protocol with a 96% completion rate. Significant (> grade 3) toxicities included neutropenia (23.8%), diarrhea (14.2%) anemia (10.7%), and two deaths. The median DFS at 2 years was 22.5 months with better survival noted for those who underwent surgery or had cCR (with NOM) compared to those who did not undergo surgery (due to progression, inadequate regression, or patient preference despite residual disease) -mDFS 27.7 months versus 11.4 months, p = < 0.0001 and mOS 29.2 months versus 15 months p = < 0.0001. CONCLUSION: The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment-related deaths. Ability to undergo surgery after TNT predicted for improved DFS and OS.

A Case of Chronic Eosinophilic Leukemia in a Patient With Recurrent Cough, Dyspnea, and Eosinophilia.

We report the case of a 40-year-old man with no significant past medical history who had been hospitalized multiple times over the course of one year with recurring cough, dyspnea, pruritic rash, and variable degrees of eosinophilia. He was variably diagnosed with asthma and pneumonia. After his last hospitalization with severe symptoms, the patient was referred for pulmonary evaluation where hypereosinophilia (HE) led to a hematologic workup. Fluorescence in situ hybridization revealed the FIP1L1-PDGFRA gene fusion and bone marrow analysis confirmed a diagnosis of chronic eosinophilic leukemia. The patient was treated with daily imatinib and prednisone and he was symptom-free at a four-week follow-up examination.

Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer.

The safety of oncolytic adenovirus-mediated suicide and interleukin-12 (IL 12) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/mutTKSR39 rep-hIL-12) expressing yCD/mutTKSR39 (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 (IL 12) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 1011, 3 × 1011, or 1 × 1012 viral particles). Subjects received 5-fluorocytosine (5-FC) therapy for 7 days followed by chemotherapy (FOLFIRINOX or gemcitabine/albumin-bound paclitaxel) starting 21 days after adenovirus injection. The study endpoint was toxicity through day 21. Experimental endpoints included measurements of serum IL 12, interferon gamma (IFNG), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells and proliferation markers were analyzed by flow cytometry. Twelve patients received Ad5-yCD/mutTKSR39 rep-hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/mutTKSR39 rep-hIL-12 DNA was detected in the blood of two patients. Elevated serum IL 12, IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTKSR39 rep-hIL-12 administration. The median survival of patients in the third cohort is 18.1 (range, 3.5-20.0) months. The study maximum tolerated dose (MTD) was not reached.

Neoadjuvant Phase II Trial of Chemoradiotherapy in Patients With Resectable and Borderline Resectable Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma is a largely incurable cancer. Surgical resection remains the only potential option for cure. Even in surgically resectable patients, only about 10% to 20% are long-term survivors. Emerging data suggest a role for neoadjuvant therapy to target occult micrometastatic disease. AIM: To report our institutional experience with a novel neoadjuvant chemoradiation (CRT) regimen in resectable and borderline resectable pancreatic cancer. MATERIALS AND METHODS: Patients were treated with 2 cycles of induction chemotherapy with FOLFOX and then received CRT with gemcitabine and intensity-modulated radiotherapy (IMRT). RESULTS: From April 2014 to June 2017, 24 patients were enrolled. Eighteen patients were borderline resectable and 6 patients were resectable. All patients received induction chemotherapy with FOLFOX. Thirteen patients underwent pancreatectomy after CRT with a resection rate of 62%. R0 resection achieved in 11 patients (84.6%) and 2 patients had R1 resection (15.4%). For patients who underwent resection, the median progression-free survival (PFS) was 31 months, 1-year PFS rate was 69.2% (95% confidence interval [CI], 0.48-0.99), and 2-year PFS rate was 51.9% (95% CI, 0.3-0.89). Median overall survival (OS) was 34.8 months (95% CI, 1.045 to infinity), 1-year OS rate was 91.7% (95% CI, 0.77-1.0), and 2-year OS rate was 75% (95% CI, 0.54-1.0). Median CA 19-9 at screening for patients who underwent surgery was 659 (range, 18 to 2154), which decreased to 146.9 (range, 18 to 462) after CRT before resection. CONCLUSION: Neoadjuvant therapy for borderline resectable and resectable pancreatic ductal adenocarcinoma with CRT facilitated R0 resection in 84% patients who underwent surgery.

The SREBP pathway in Drosophila: regulation by palmitate, not sterols.

In mammals, synthesis of cholesterol and unsaturated fatty acids is controlled by SREBPs, a family of membrane-bound transcription factors. Here, we show that the Drosophila genome encodes all components of the SREBP pathway, including a single SREBP (dSREBP), SREBP cleavage-activating protein (dSCAP), and the two proteases that process SREBP at sites 1 and 2 to release the nuclear fragment. In cultured Drosophila S2 cells, dSREBP is processed at sites 1 and 2, and the liberated fragment increases mRNAs encoding enzymes of fatty acid biosynthesis, but not sterol or isoprenoid biosynthesis. Processing requires dSCAP, but is not inhibited by sterols as in mammals. Instead, dSREBP processing is blocked by palmitic acid. These findings suggest that the ancestral SREBP pathway functions to maintain membrane integrity rather than to control cholesterol homeostasis.

Weekly chemotherapy with radiation versus high-dose cisplatin with radiation as organ preservation for patients with HPV-positive and HPV-negative locally advanced squamous cell carcinoma of the oropharynx.

BACKGROUND: Optimal treatment for locally advanced squamous cell carcinoma of the oropharynx (SCCOP) is not well defined. Here we retrospectively compare survival and toxicities from 2 different organ preservation protocols. METHODS: The matched dataset consisted of 35 patients from each trial matched for age, stage, smoking, and tumor human papillomavirus (HPV) status. Patients in the University of Michigan Cancer Center (UMCC) trial 9921 were treated with induction chemotherapy (IC) followed by high-dose cisplatin and radiation in responders or surgery in nonresponders. Patients in the UMCC trial 0221 were treated with weekly carboplatin and paclitaxel and radiation. RESULTS: Survival was comparable for both studies and did not differ significantly across each trial after stratifying by HPV status. Grade 3 and 4 toxicities were more frequent in UMCC 9921. At 6 months posttreatment, gastrostomy tube (G-tube) dependence was not statistically different. CONCLUSION: These data suggest that survival outcomes in patients with locally advanced SCCOP are not compromised with weekly chemotherapy and radiation therapy, and such treatment is generally more tolerable.

Mebendazole monotherapy and long-term disease control in metastatic adrenocortical carcinoma.

OBJECTIVE: To describe successful long-term tumor control in metastatic adrenocortical carcinoma, a relatively rare tumor with limited treatment options outside of surgery. METHODS: We present the clinical, radiologic, and pathologic findings in a patient with failure of or intolerance to conventional treatments for metastatic adrenocortical carcinoma. RESULTS: A 48-year-old man with adrenocortical carcinoma had disease progression with systemic therapies including mitotane, 5-fluorouracil, streptozotocin, bevacizumab, and external beam radiation therapy. Treatment with all chemotherapeutic drugs was ceased, and he was prescribed mebendazole, 100 mg twice daily, as a single agent. His metastases initially regressed and subsequently remained stable. While receiving mebendazole as a sole treatment for 19 months, his disease remained stable. He did not experience any clinically significant adverse effects, and his quality of life was satisfactory. His disease subsequently progressed after 24 months of mebendazole monotherapy. CONCLUSION: Mebendazole may achieve long-term disease control of metastatic adrenocortical carcinoma. It is well tolerated and the associated adverse effects are minor.

Reconstitution of sterol-regulated endoplasmic reticulum-to-Golgi transport of SREBP-2 in insect cells by co-expression of mammalian SCAP and Insigs.

In mammalian cells, membrane-bound sterol regulatory element-binding proteins (SREBPs) are transported from ER to Golgi where they are processed proteolytically to generate soluble transcription factors that activate lipid synthesis. ER-to-Golgi transport requires SCAP, a sterol-regulated escort protein. In sterol-treated cells, the SCAP/SREBP complex binds to Insig-1 or Insig-2, which retains the complex in the ER, blocking SREBP processing and decreasing lipid synthesis. In Drosophila cells, the endogenous SCAP/SREBP complex is transported to Golgi, but transport is blocked by phosphatidylethanolamine instead of sterols. Here, we show that mammalian SREBP-2 is not transported to Golgi when expressed in Drosophila cells. Transport requires co-expression of mammalian SCAP. Sterols block transport of the mammalian SCAP/SREBP-2 complex, but only when mammalian Insig-1 or -2 is co-expressed. These reconstitution studies define SCAP and Insig as the minimal requirements for sterol-regulated transport of SREBPs from ER to Golgi. They indicate that insect cells can respond to sterols when proper regulatory proteins are expressed.