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Background: Life-threatening immune-related adverse events (irAEs) that require hospital admission are not uncommon in patients treated with immune checkpoint inhibitors (ICIs). The clinical and hematological parameters are attractive biomarkers as potential predictors of irAE. Methods: This is a retrospective study of patients with melanoma and lung cancer treated with ICIs between 2015 and 2019 at the University of South Alabama Mitchell Cancer Institute. Fisher’s exact test, Pearson Chi-squared test, log-rank test, and Cox proportional hazard model were used to evaluate clinical and hematological parameters as possible predictors of irAE. Results: The cohort consisted of 160 patients treated with at least two doses of ICI, of which 54 (33.8%) patients had melanoma and 106 (66.3%) had lung cancer. Incidence of irAE did not have any bearing on the overall survival (OS) or progression-free survival (PFS) of the cohort. The clinical factors associated with irAE were dual-agent therapy (ipilimumab/nivolumab combination) and high disease burden (? 2 metastatic sites). The irAE-group had a lower mean platelet-to-lymphocyte ration (PLR, 200 vs. 257, P = 0.04). Although not statistically significant at the level of 0.05, other factors such as type of cancer (lung cancer > melanoma (P = 0.06)), stage at treatment (stage IV > stage II and III disease (P = 0.06)), and higher absolute lymphocyte counts (P = 0.07) showed a considerable association with irAE and warrants further review with different patient data. Conclusions: Irrespective of ICI used to treat lung cancer and melanoma, patients with high disease burden and dual-agent ICI therapy were more prone to irAE. The only hematological parameter that may predict the incidence of irAE is low baseline PLR. J Clin Med Res. 2021;13(5):268-275 doi: https://doi.org/10.14740/jocmr4511

Management of hepatocellular carcinoma (HCC) is complicated. Barcelona Clinic Liver Cancer (BCLC) staging system is widely used in risk stratifying HCC. It is different from anatomic staging (TNM) used in other cancers and is based on the liver function (Child-Pugh Score) and performance status at diagnosis along with tumor characteristics like size/number of primary, vascular invasion, and distant metastasis. Guidelines proposed by various liver societies help the treating physician select first-line therapy, but there are many limitations to them. Lack of reliable biomarkers that give objective information to monitor the response other than alpha-fetoprotein or radiological response is hurting the management strategies. There are no ideal predictors for recurrence and residual microscopic disease, especially after locoregional therapy (LRT) like surgical resection, ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic radiation therapy (SBRT). Also, there is no convincing evidence to use adjunct therapy along with LRT in localized HCC. There is a need to identify the subset of HCC that would benefit from peri-procedural therapy. Recommendations for treating advanced HCC with macrovascular invasion is not uniform across the guidelines. Some propose LRT (TACE and/or TARE) or recommend systemic therapy only like tyrosine-kinase inhibitors (TKI) or Immune-checkpoint inhibitors (ICI). A considerable portion of patients have poor liver function (Child-Pugh Score C) at diagnosis. In this era of medicine, we should give them options other than supportive care, but unfortunately, it is the preferred option. This population needs special attention in trials. In current practice, there only 2-3 classes of drugs available like TKI, ICI, and vascular endothelial growth factor (VEGF) inhibitors. There is a need to explore more classes of liver-friendly drugs in treating HCC, and the enrolment of patients in clinical trials must be advised in the guidelines.

Pseudo-thrombotic microangiopathy (pseudo-TMA) is a recognized, yet uncommon, clinical presentation of vitamin B12 deficiency. Patients with pseudo-TMA present with microangiopathic hemolytic anemia (MAHA), thrombocytopenia and schistocytes. They are often misdiagnosed as thrombotic thrombocytopenia purpura (TTP) and receive unnecessary therapy. Here, we report a case of a 60-year-old male who presented with thrombocytopenia and normocytic normochromic anemia. Anemia work-up was remarkable for severe B12 deficiency (

Carcinomatous meningitis (CM), also known as neoplastic meningitis or leptomeningeal metastasis, refers to the invasion of meninges protecting the brain and spinal cord by tumor cells. It should be distinguished from brain metastasis where there is an infiltration of brain parenchyma by metastatic cells. With improved overall survival in a majority of cancers with advances in cancer management, more cases of CM are being diagnosed lately. Cancer cells from the primary source can migrate to the meninges through various ways: vertebral and paravertebral metastasis (breast and lung cancers), perineural spaces (gastrointestinal cancers), arteries from parenchymal metastasis, and rarely by direct invasion (primary central nervous system tumors). Patients often present with non-specific symptoms, like a headache and altered mental status, or focal neurological signs, depending on the area of the central nervous system involved. Due to poor prognosis and limited success in treating it, early detection is key. Diagnosis in suspected cases by cerebrospinal fluid (CSF) cytology (identifying malignant cells) and/or imaging has limited success. In this review, we discuss the need for using various biomarkers in CSF to increase the probability of a diagnosis of CM in solid tumors. Biomarkers can also help in predicting the disease burden, response to treatment, and in detecting the recurrence. We also discuss utilizing Fluorescence in situ hybridization (FISH), Rare cell capture technology (RCCT) and circulating tumor DNA (CtDNA) in identifying malignant cells in CSF for diagnosing CM. However, the definitive role of these modalities in combination needs further validation in larger cohorts.

Primary malignancy of the liver or hepatocellular carcinoma (HCC) is unique in its presentation, disease process, and management. Unlike breast or colon cancer, the staging of HCC depends on performance status and baseline liver function along with pathological characteristics. Apart from traditional options like surgery and systemic therapy, effective management can be achieved in selected cases with liver transplant and locoregional therapy (LRT) like transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and ablation. Liver study societies and cancer groups across the globe proposed guidelines to aid the treating physicians in choosing first-line treatment for liver cancer. It is tough to compare these guidelines as they differ not only in treatment recommendations but also in risk assessment (and staging). The approach to the same patient may be different in the country he or she is managed. In clinical practice, decisions are usually taken on the consensus of multidisciplinary tumor boards and do not necessarily adhere to any guidelines. In the early (and very early) stage HCC, curative options like surgery, transplant, and ablation are recommended. In intermediate stage HCC, LRT (TACE and TARE) is preferred in the first line and systemic therapy for treatment failure or residual disease. Systemic therapy, including the atezolizumab/bevacizumab combination and tyrosine kinase inhibitors (TKI) like sorafenib and lenvatinib, is used for advanced stages. Supportive care is advised for terminal stage HCC.

Background: Despite measures taken to control traditional risk factors like increased rectal disease activity, anorectal stenosis, and, to a lesser extent, obesity, rates of poor outcomes after rectovaginal fistula (RVF) surgery in women with Crohn’s disease (CD) are still high and require further elucidation. To bridge the gap, we sought to identify risk factors beyond the aforementioned determinants that may be associated with poor outcomes in these patients. Methods: We designed a retrospective, unmatched, case-control study to test our hypothesis. The population comprised women with CD who underwent RVF surgery between the years of 2000 and 2013. Cases were defined as surgeries with an unsuccessful outcome at 4 weeks post-surgery, and controls represented those with a successful outcome at 4 weeks post-surgery. With multivariable logistic regression models, we sought to identify pertinent risk factors for poor outcomes after RVF surgery in these women. Results: Of the 108 women with CD who were referred to our institution for evaluation of RVFs between 2000 and 2013, 39 underwent a total of 63 surgeries, of which 16 were cases and 47 were controls. There were no significant differences between them with regard to medications and clinical or mucosal disease severity, but a significantly higher proportion of poor outcomes arose from the group of women who underwent a mucosal flap procedure (88%) compared to those who had a seton placed (13%; P = 0.0004). The final adjusted logistic regression model demonstrated that women who underwent a mucosal flap procedure instead of a seton placement were 17.5 times more likely to have a poor surgical outcome (odds ratio (OR): 17.51; 95% confidence interval (CI): 3.12 - 98.43; P = 0.0012). Moreover, it was seen that women with active colonic mucosal disease, independent of rectal disease activity, were 4.4 times more likely to have a poor outcome (OR: 4.40; 95% CI: 1.06 - 18.26). Conclusion: Mucosal flap procedures, representing the second, or definitive, stage in surgical treatment of RVF are associated with much worse outcomes and therefore should be preceded by aggressive medical optimization of the patient. J Clin Med Res. 2016;8(2):126-129 doi: http://dx.doi.org/10.14740/jocmr2421w

e16609 Background: The Barcelona-Clinic Liver Cancer (BCLC) staging based management proposed by AASLD depends on baseline liver function and performance status of the patient in addition to tumor characteristics. Low adherence to AASLD guidelines, especially in advanced staged tumors, can be ascribed to suboptimal revision/updates of the guidelines reflecting the advancements in hepatocellular carcinoma (HCC) management. Here, in addition to the adherence rate, we explored the overall survival of patients with HCC according to first-line treatment modality compliance to AASLD guidelines. Methods: This is a retrospective study conducted at the University of South Alabama/Mitchell Cancer Institute. Between 2017 and 2019, 148 unique treatment-naïve patients with HCC were identified. Patients were staged according to the BCLC staging system and their compliance with suggested first-line treatment modality according to AASLD guidelines was noted. Overall survival was explored and differences between overall survival rates of compliant and non-complaint patients were compared using the log-rank Wilcoxon test. Results: In our cohort, the median age was 72.5 years (range 38-90). Males represented 80%. Caucasians, African Americans, and other ethnicities (e.g. Asians) represented 68%, 30% and 2% respectively. The overall adherence rate was 83%. The adherence rate according to BCLC stage 0, A, B, C and D was 100%, 97%, 77%, 77% and 38% respectively. Compliance vs. non-compliance to AASLD guidelines showed no significant difference in overall survival of patients with BCLC stage 0-A, B and C. In patients with BCLC stage D (N = 13), compared to patients treated in compliance to AASLD guidelines (N = 5), patients treated in non-compliance (N = 8) had better overall survival (2.2 vs. 5.2 months, p = 0.0012). Conclusions: In our cohort, the adherence rate to AASLD treatment guidelines in patients with BCLC stage D was very low at 38%. Lack of adherence in this group of patients translated into better overall survival. The current AASLD guidelines for the management of HCC have several limitations, especially for advanced stages. In the last few years, the FDA approved several tyrosine kinase inhibitors, immune checkpoint inhibitors and the monoclonal antibody, ramucirumab. This expansion generated the need for periodic updates/revisions of consensus guidelines.

e16096 Background: Adenocarcinomas arising from the distal one third of the transverse colon, splenic flexure, descending colon, sigmoid colon and rectum are often grouped together due to their hindgut embryologic origin and referred to as left-sided colorectal cancer (CRC). Rectal cancer represents a subset of CRC that has distinct differences in anatomical location, clinical behavior, prognosis and molecular background. In patients with left sided colon cancer (LSCC), the expression of exosomal marker CD63 was reported to be higher in the adjacent normal mucosa (ANM) compared to the tumor (224 vs 154, p = 0.0001). Here, we explored the pattern of CD63 expression using immunohistochemistry in patients with rectal cancer in comparison with patients with LSCC. Methods: Between 2015 and 2018, 53 patients underwent rectal cancer biopsy/resection and had available tissues for CD63 IHC staining. Two pathologists independently scored CD63 expression in the tumor and ANM. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean quick-score (Q-score) was calculated (intensity x percentage). Paired t test was used for statistical analysis. Results: Median age was 60 (range 34-80). Females represented 26%. Caucasians and African Americans represented 74% and 26%, respectively. In patients with rectal cancer, the mean CD63 expression was higher in ANM compared to their expression in the tumor (147 vs 113, p = 0.0012). Compared to patients with LSCC (N = 30), the mean CD63 expression in patients with rectal cancer was lower in the ANM (224 vs 147, p < 0.0001) and in the tumor (154 vs 113, p = 0.01). Conclusions: In our cohort of patients with rectal cancer, exosomal marker CD63 expression was lower in tumor compared to ANM. This observation was similar to our previously reported findings in patients with LSCC. Compared to patients with LSCC, patients with rectal cancer had lower expression of CD63 in the tumor and ANM. To our knowledge, this is the first study to explore exosomal marker CD63 expression using IHC in patients with rectal cancer.

546 Background: For advanced hepatocellular cancers (HCCs) and colorectal cancers (CRCs) with liver metastasis, the impact of selective internal radiation therapy(SIRT) with yttrium-90 on survival outcomes is not established. A meta-analysis of randomized clinical trials (RCT) was performed to determine the relative risk (RR) of hepatic and hematological toxicities with the use of SIRT, compared to therapies not including SIRT. For patients with advanced HCC or CRC, we assessed the RR of high grade (grades 3 and 4) hyperbilirubinemia, fatigue, leucopenia, thrombocytopenia and elevated liver enzymes (AST and ALT) with use of SIRT. Methods: Citations from PubMed/Medline, clinical trials.gov, package inserts, and abstracts from major conferences were reviewed to include RCTs comparing arms with or without SIRT. Potential publication bias was assessed using the Egger test for funnel plot asymmetry. There was no publication bias and the trials were of high quality per Jadad scoring. Patients in control arms received trans-arterial chemo-embolization (TACE) or sorafenib for HCC or FOLFOX for CRC. The proportion and 95% confidence intervals (CIs) for patients with adverse events were derived for each arm of each study and used to calculate the RR. For the meta-analysis, both the fixed-effects model and the random-effects model were considered; the method proposed by DerSimonian and Laird was used to estimate the random-effects model. Results: The RR of grade 3/4 leucopenia was consistently high across high with the use of SIRT across all the studies (RR 2.05, 95% CI (1.22-3.42), p-value 0.027). The risk of hepatic dysfunction and fatigue was higher with SIRT but not statistically significant. Conclusions: Since SIRT is associated with increased risk of high-grade leukopenia, caution is advised in selecting patients with HCC’s with underlying decompensated cirrhosis or with CRCs and on cytotoxic therapy. Proper selection of patients would reduce toxicities from SIRT alone or SIRT in combination with systemic chemotherapy.

Background: Evidence suggests that obesity (body mass index (BMI) > 30 kg/m 2 ) adversely affects several outcomes in Crohn’s disease (CD). CD-associated perianal fistula (CDPF) represents a debilitating phenotype with a clinical course that may be affected by obesity. We hypothesized that obese CD patients would be more likely to have poor outcomes following CDPF surgery. Methods: We designed a case-control study of CD patients who underwent surgery for CDPF between 2000 and 2013 with documented pre-operative BMI and post-operative outcome. Cases and controls were defined based on the outcome of CDPF surgery. Poor outcomes were designated as cases. Results: Of the 317 patients diagnosed with CDPF, 73 patients underwent 120 surgeries for CDPF. Eighty-nine (74%) of the surgeries comprised fistulotomy with or without Seton placement, whereas 31 (26%) were mucosal flap procedures. Twenty-five (21%) cases and 95 (79%) controls were identified. Unadjusted odds ratio (OR) for the association between obesity and outcome demonstrated a trend towards a poor surgical outcome among obese patients that did not reach statistical significance (OR: 1.86; 95% confidence interval (CI): 0.58 - 5.98; P = 0.295). Multivariable logistic regression analysis demonstrated an even stronger trend towards a poor outcome among obese CD patients, albeit without reaching statistical significance (OR: 2.83; 95% CI: 0.64 - 12.49; P = 0.169). Conclusion: In patients undergoing Seton placement, fistulotomy or mucosal flap procedure for CDPF, there is a trend towards poor outcomes in the obese; however, as this trend did not reach statistical significance, this association should be examined further. Gastroenterol Res. 2015;8(6):291-295 doi: http://dx.doi.org/10.14740/gr698e

e15714 Background: Although combination of fluorouracil, irinotecan, Leucovorin and oxaliplatin [FOLFIRINOX] significantly increases survival in metastatic pancreatic cancer (MPC) compared to gemcitabine based on ACCORD trial, the efficacy and toxicities may be different in non-metastatic setting. We reviewed our institution’s experience with FOLFIRINOX in locally advanced pancreatic cancer (LAPC). Methods: We performed a retrospective review of clinical outcomes in patients diagnosed with LAPC and receiving between June 2010 and July 2015, with at least one year of follow up from diagnosis, at University of Alabama at Birmingham. Results: Total of 41 patients with ECOG performance scale of 0 or 1, who underwent neoadjuvant chemotherapy with FOLFIRINOX were assessed for clinical and pathological characteristics. Median age was 61 years (range 38-81) with 23 (56.1%) males, 28 (68.3%) Caucasians and 16 (39.0%) underwent surgery (whipple operation) post-neoadjuvant. Median OS (time of diagnosis to last follow up/death) is 83.5 months for whole cohort, survival rates are 94.9% at 1 year, 58.4% at 2 year, and 33.3% at 5 year.Median OS for those who underwent surgical resection following the chemotherapy is 38.6 months; 100% at one year, 85.1% at 2 year, 55.3% at 5 year; while median OS for those who did not undergo surgery is 21.8 months; 91.7% at one year, 41.5% at 2 year, 20.7% at 5 years. Among those who underwent surgery, the median recurrence free survival (time from surgery to relapse/progression) is 19.9 months with liver being common recurrence site (81%). There was no post-operative mortality in 30 days. Grade 3-4 toxicity occurred in 46% ( vomiting (12%), fatigue (28%) and neutropenia (54%), febrile neutropenia (9%)). There is a significant difference between surgery and non-surgery groups (p = 0.012) for improved OS by log-rank test. Conclusions: Neoadjuvant FOLFIRINOX treatment associated with high response rates leading to surgical resection in our cohort. Patients who underwent neoadjuvant chemotherapy followed by resection for LAPC have statistically significant improved OS compared to those who did not.

456 Background: Ampullary carcinoma [AC] is a rare malignancy associated with favorable prognosis among pancreatobiliary tumors. Pancreaticoduodenectomy [PDY] is considered to be curative for early stage cancers. The role of adjuvant chemotherapy [CT] or combination chemoradiation [CRT] remains uncertain for stage I/II. In this analysis we reviewed our institution’s experience with AC. Methods: From 2005 to 2015, 62 patients with stage 1 and 2 AC with at least one year follow up after PDY were reviewed. Clinical and pathologic factors and disease status were obtained from chart review. The patients’ demographical and oncological characteristics are summarized. The univariate Cox proportional hazard model was conducted for evaluating the parameters associated with overall survival. Kaplan-Meier method and log-rank was used to compare the time-to-events. Results: Adjuvant treatment was administered in 61%: CT (32%), CRT (29%) 39% surgical alone. The median overall survival [OS] for the study cohort is 60 months with 3 yr OS at 58% and 5 yr OS at 50%. Recurrence noted in 21% of patients. About half of patients surviving five years were alive at 10 years. Lymph node [LN] metastases (57%) predicted worse PFS (HR 2.29, 95% CI (1.13-4.61), p = 0.021) but did not significantly affect OS (HR 1.2, 95% CI (0.84-3.61);p = 0.13). There were no postoperative deaths following surgery.Peri- pancreatic extension [PPE] (20%) and peri-neural invasion [PNI] (16%) was also found to be determinants for poor OS. Current data did not suggest lympho-vascular invasion (24%) predict OS (HR 1.20, 95% CI (0.49, 2.96);p = 0.63 or PFS(HR 1.45 (0.65, 3.20),p = 0.36). When compared to surgery alone adjuvant CT or CRT had no statistically significant difference in terms of PFS (p = 0.53) or OS (p = 0.96). Conclusions: The use of adjuvant treatment may be most useful at improving long-term disease control in patients with high-risk features; however, no significant difference between CT and CRT was demonstrated in our series. This could be due to small sample size and needs further validation in larger cohort. PDY with regional lymphadenectomy is appropriate for early-stage AC, but worst outcomes seen in patients with PPE, PNI and LN involvement.

Background: Published data suggest a link between obesity and adverse outcomes in Crohn ’ s disease (CD). We aimed to test the hypothesis that obese CD patients would be more likely than non-obese CD patients to have poor surgical outcome when undergoing surgery for a complication of CD. Methods: We designed a retrospective cohort study to test our hypothesis. The population comprised of adult CD patients who underwent CD related surgery at a tertiary referral center. The exposed and unexposed cohorts were represented by patients who were obese vs. non-obese at the pre-op visit respectively. Outcome was represented by successful vs. unsuccessful surgical outcome as deemed by the treating clinician. Results: Ninety CD patients were eligible for inclusion into this cohort study of which 36 were obese (exposed cohort) and 54 were non-obese (unexposed cohort). Among obese CD patients, 64% had an unsuccessful surgical outcome vs. 41% with unsuccessful surgical outcome among the non-obese. Based on unadjusted bivariate analysis, potential confounders identified included age and type of surgery. Gender distribution, disease duration, ethnicity, tobacco use, steroid use, traditional and biological immune modulator use and clinical disease activity were similar between the two groups. Logistic regression adjusted for age and type of surgery revealed that obese CD patients were approximately 2.5 times more likely to have a poor surgical outcome than patients with CD who were not obese (P = 0.05 OR 2.53 95% CI 0.99 - 6.52). BMI as a continuous variable (adjusted for age and type of surgery) appeared to be associated with poor surgical outcome (P = 0.06 OR 1.07 95% CI 0.99 - 1.15). Conclusions: Obesity may be associated with poor surgical outcome in CD patients. doi: http://dx.doi.org/10.4021/gr553w

In this report, we seek to shed light on a 44-year-old Caucasian male with a known history of an esophageal diverticulum, who was transferred to our facility after an upper endoscopy at an outside hospital suggested a purulent discharge emanating from the mouth of a mid-esophageal diverticulum. A barium swallow done at the outside institution had reportedly demonstrated an 8 cm long barium collection parallel to and anterolateral to the mid-and distal esophagus which terminated several centimeters proximal to the gastroesophageal junction. At our facility, antibiotics (piperacillin/tazobactam) were continued, and a double-contrast esophagram was performed. The presence of an unusual mid-esophageal diverticulum was confirmed. He clinically improved after a 3-day course of intravenous broad-spectrum antibiotics. No surgical or endoscopic repair was elected as the patient opted for continued medical management. While esophageal diverticula are not rare in humans, to our knowledge, this is the first report of development of esophageal diverticulitis in humans. We believe that antibiotic coverage in addition to dietary restriction is the logical mainstay of acute therapy. Optimal antibiotic coverage should likely include oral flora aerobes and anaerobes. Once symptoms resolve, diverticula may be managed expectantly.