Clinical outcomes of first line FOLFIRINOX vs. gemcitabine plus nab-paclitaxel in metastatic pancreatic cancer at the Yale Smilow Hospital System.

BACKGROUND: FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GN) are established first line therapies for metastatic pancreatic cancer (MPC). There are, however, no randomized controlled trials comparing FFX and GN in the first line setting and real-world data on their comparative effectiveness is limited. We aimed to evaluate the outcomes of patients with MPC who were treated with first line FFX and GN and to further characterize dose modifications, discontinuation rates due to treatment toxicity, and rates of hospitalizations while on treatment. METHODS: We manually abstracted data from the electronic medical records (EMR) system at Yale Smilow Hospital and Smilow Cancer Hospital Care Centers for patients with MPC treated with at least one cycle of first line FFX or GN from January 2011 to April 2019. Patients who received prior neoadjuvant or adjuvant FFX or GN and adjuvant gemcitabine less than 6 months prior to metastatic recurrence were excluded. The median time to treatment discontinuation (TTD) and overall survival (OS) were determined using Kaplan-Meier method. RESULTS: We identified 363 patients for analysis; 269 (74%) patients were treated with FFX and 94 (26%) with GN. Median TTD was 4.8 (IQR, 2.3-8.0) months in the FFX group compared to 3.4 (IQR, 1.3-5.7) months in the GN group (P=0.0037). Median OS was 11.3 (95% CI: 10.7-12.9) months in the FFX group and 7.0 (95% CI: 6.0-8.7) months in the GN group (P<0.001). Initial dose modifications occurred in 264 (98%) and 86 (91%) of FFX and GN treated patients, respectively (P=0.001). While on treatment, 56 (60%) of GN-treated patients had at least one hospitalization vs. 110 (41%) in the FFX-group (P=0.002). Treatment was discontinued due to chemotherapy toxicity in 26 (10%) and 14 (15%) among the FFX and GN cohorts, respectively (P=0.275). CONCLUSIONS: Patients treated with first line FFX had increased survival and TTD compared to patients treated with GN despite increased dose modifications and similar rates of treatment discontinuation due to treatment-related toxicity. GN-treated patients were older and more likely to be hospitalized while on treatment. Further study evaluating comparative effectiveness between these two regimens is warranted.

Semiautomated Measure of Abdominal Adiposity Using Computed Tomography Scan Analysis.

BACKGROUND: The obesity epidemic has prompted the need to better understand the impact of adipose tissue on human pathophysiology. However, accurate, efficient, and replicable models of quantifying adiposity have yet to be developed and clinically implemented. We propose a novel semiautomated radiologic method of measuring the visceral fat area (VFA) using computed tomography scan analysis. MATERIALS AND METHODS: We obtained a cohort of 100 patients with rectal adenocarcinoma, with a median age of 60.9 y (age range: 35-87 y) and an average body mass index of 28.8 kg/m2 ± 6.56 kg/m2. The semiautomated quantification method of adiposity was developed using a commercial imaging suite. The method was compared to two manual delineations performed using two different picture archiving communication systems. We quantified VFA, subcutaneous fat area (SFA), total fat area (TFA), and visceral-to-subcutaneous fat ratio (V/S ratio) on computed tomography axial slices that were at the L4-L5 intervertebral level. RESULTS: The semiautomated method was comparable to manual measurements for TFA, VFA, and SFA with intraclass correlation (ICC) of 0.99, 0.97, and 0.96, respectively. However, the ICC for the V/S ratio was only 0.44, which led to the identification of technical outliers that were identified using robust regression. After removal of these outliers, the ICC improved to 0.99 for TFA, VFA, and SFA and 0.97 for the V/S ratio. Measurements from the manual methodology highly correlated between the two picture archiving communication system platforms, with ICC of 0.98 for TFA, 0.98 for VFA, 0.96 for SFA, and 0.95 for the V/S ratio. CONCLUSIONS: This semiautomated method is able to generate precise and reproducible results. In the future, this method may be applied on a larger scale to facilitate risk stratification of patients using measures of abdominal adiposity.

Quantitative Assessment of Visceral Obesity and Postoperative Colon Cancer Outcomes.

BACKGROUND: Quantitative computed tomography (CT) assessment of visceral adiposity may be superior to body mass index (BMI) as a predictor of surgical morbidity. We sought to examine the association of CT measures of obesity and BMI with short-term postoperative outcomes in colon cancer patients. METHODS: In this retrospective study, 110 patients treated with colectomy for stage I-III colon cancer were classified as obese or non-obese by preoperative CT-based measures of adiposity or BMI [obese: BMI ≥ 30 kg/m2, visceral fat area (VFA) to subcutaneous fat area ratio (V/S) ≥0.4, and VFA > 100 cm2]. Postoperative morbidity and mortality rates were compared. RESULTS: Obese patients, by V/S and VFA but not BMI, were more likely to be male and have preexisting hypertension and diabetes. The overall complication rate was 25.5%, and there were no mortalities. Obese patients by VFA (with a trend for V/S but not BMI) were more likely to develop postoperative complications as compared to patients classified as non-obese: VFA (30.5 vs.10.7%, p = 0.03), V/S (29.2 vs. 9.5%, p = 0.05), and BMI (32.4 vs. 21.9%, p = 0.23). CONCLUSIONS: Elevated visceral obesity quantified by CT is associated with the presence of key metabolic comorbidities and increased postoperative morbidity and may be superior to BMI for risk stratification.

Aspergillus Terreus Brain Abscess Complicated by Tension Pneumocephalus in a Patient with Angiosarcoma.

BACKGROUND Aspergillus terreus is an evolving opportunistic pathogen, and patients with A. terreus often have poor outcomes due to its intrinsic resistance to several systemic antifungal agents. Here we present a unique case of intracranial abscesses of A. terreus in a patient with recurrent angiosarcoma, complicated by development of tension pneumocephalus. CASE REPORT A 67-year old gentleman with history of scalp angiosarcoma with wide excision two years prior presented to the hospital for left arm clumsiness, altered mental status, and low-grade fever. Staphylococcus aureus and Proteus mirabilis bacteremia was detected, and Computed Tomography (CT) of the head showed right frontal lobe abscesses. He was started on steroids, intravenous vancomycin and cefepime, and was eventually discharged. He presented to the hospital again due to persistent and worsening symptoms. MRI showed progression of the brain lesions, and surgical biopsy and culture of lesions revealed A. terreus and gram-positive cocci. He was started on trimethroprim/sulfamethoxazole and voriconazole and symptoms improved. On post-op day four, he acutely decompensated with total loss of left arm strength; MRI demonstrated tension pneumocephalus. Conservative management was undertaken with continuous supplemental oxygen. Serial x-ray imaging over the next week demonstrated resolution of the pneumocephalus, and the patient was able to regain all proximal lower and upper extremity strength. CONCLUSIONS Never before has a case of A. terreus been associated with angiosarcoma or tension pneumocephalus in the literature. Proper identification and prompt diagnosis of species is crucial in the immunocompromised patient. Tension pneumocephalus should be included in the differential diagnosis of nontraumatic hemiparesis for emergent evaluation and management.

Potential Use of Flavopiridol in Treatment of Chronic Diseases.

This chapter describes the potential use of flavopiridol, a CDK inhibitor with anti-inflammatory and anti-proliferative activities, in the treatment of various chronic diseases. Flavopiridol arrests cell cycle progression in the G1 or G2 phase by inhibiting the kinase activities of CDK1, CDK2, CDK4/6, and CDK7. Additionally, it binds tightly to CDK9, a component of the P-TEFb complex (CDK9/cyclin T), and interferes with RNA polymerase II activation and associated transcription. This in turn inhibits expression of several pro-survival and anti-apoptotic genes, and enhances cytotoxicity in transformed cells or differentiation in growth-arrested cells. Recent studies indicate that flavopiridol elicits anti-inflammatory activity via CDK9 and NFκB-dependent signaling. Overall, these effects of flavopiridol potentiate its ability to overcome aberrant cell cycle activation and/or inflammatory stimuli, which are mediators of various chronic diseases.

Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers.

BACKGROUND: The incidence and outcomes of patients with colorectal cancer (CRC) varies by age. Younger patients tend to have sporadic cancers that are not detected by screening and worse survival. To understand whether genetic differences exist between age cohorts, the authors sought to characterize unique genetic alterations in patients with CRC. METHODS: In total, 283 patients who were diagnosed with sporadic CRC between 1998 and 2010 were identified and divided by age into 2 cohorts-ages ≤45 years (the younger cohort) and ≥65 years (the older cohort)-and targeted exome sequencing was performed. The Fisher exact test was used to detect differences in mutation frequencies between the 2 groups. Whole exome sequencing was performed on 21 additional younger patient samples for validation. Findings were confirmed in The Cancer Genome Atlas CRC data set. RESULTS: In total, 246 samples were included for final analysis (195 from the older cohort and 51 from the younger cohort). Mutations in the FBXW7 gene were more common in the younger cohort (27.5% vs 9.7%; P = .0022) as were mutations in the proofreading domain of polymerase ε catalytic subunit (POLE) (9.8% vs 1%; P = .0048). There were similar mutation rates between cohorts with regard to TP53 (64.7% vs 61.5%), KRAS (43.1% vs 46.2%), and APC (60.8% vs 73.8%). BRAF mutations were numerically more common in the older cohort, although the difference did not reach statistical significance (2% vs 9.7%; P = .082). CONCLUSIONS: In this retrospective study, a unique genetic profile was identified for younger patients who have CRC compared with patients who are diagnosed at an older age. These findings should be validated in a larger study and could have an impact on future screening and treatment modalities for younger patients with CRC. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2828-2835. © 2016 American Cancer Society.

Portal Hypertension Over the Last 25 Years: Where Did It Go?

BACKGROUND: Portal hypertension has seemingly vanished from surgery; this study was undertaken to determine where it has gone. STUDY DESIGN: Data from the Agency for Health Care Administration for 33,166,201 hospital inpatients in Florida for the periods 1988 to 1992, 1998 to 2002, and 2008 to 2012 were analyzed. RESULTS: Admissions with a diagnosis of portal hypertension dramatically increased: 5,473 patients from 1988 to 1992, 7,366 patients from 1998 to 2002, and 36,554 patients from 2008 to 2012. Endoscopic treatment of esophageal varices also dramatically increased. The number of decompressive shunts placed nominally increased, but application of endoscopic therapy increased significantly faster than the application of decompressive shunts (p < 0.0001). The percentage of patients who underwent shunting dramatically and significantly decreased (p < 0.0001), and surgeons undertook proportionally fewer shunts (42% in 1992 to 4% in 2012; p < 0.0001). For patients with a diagnosis of portal hypertension, in-hospital mortality progressively decreased, from 9% in 1988 to 1992 to 3% in 2008 to 2012 (p < 0.0001). CONCLUSIONS: In the state of Florida, over 25 years, there has been a 7-fold increase in the number of patients admitted with a diagnosis of portal hypertension, with a 65% reduction of in-hospital mortality. Application of endoscopic treatment of varices has increased dramatically. Decompressive shunts are applied to an ever-decreasing percentage of patients, and when applied, are now routinely undertaken by nonsurgeons. Therefore, portal hypertension has disappeared from the purview of surgery and has migrated toward the world of medical and endoscopic therapy, probably never to return.