Effectiveness of a surveillance program of upper endoscopy for upper gastrointestinal cancers in Lynch syndrome patients.

BACKGROUND AND AIMS: Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer and is associated with an increased lifetime risk of gastric and duodenal cancers of 8-16% and 7%, respectively; therefore, we aim to describe an esophagogastroduodenoscopy (EGD) surveillance program for upper gastrointestinal (GI) precursor lesions and cancer in LS patients. METHODS: Patients who either had positive genetic testing or met clinical criteria for LS who had a surveillance EGD at our institution from 1996 to 2017 were identified. Patients were included if they had at least two EGDs or an upper GI cancer detected on the first surveillance EGD. EGD and pathology reports were extracted manually. RESULTS: Our cohort included 247 patients with a mean age of 47.1 years (SD 12.6) at first EGD. Patients had a mean of 3.5 EGDs (range 1-16). Mean duration of follow-up was 5.7 years. Average interval between EGDs was 2.3 years. Surveillance EGD detected precursor lesions in 8 (3.2%) patients, two (0.8%) gastric cancers and two (0.8%) duodenal cancers. Two interval cancers were diagnosed: a duodenal adenocarcinoma was detected 2 years, 8 months after prior EGD and a jejunal adenocarcinoma was detected 1 year, 9 months after prior EGD. CONCLUSIONS: Our data suggest that surveillance EGD is a useful tool to help detect precancerous and cancerous upper GI lesions in LS patients. To our knowledge, this is the first study to examine a program of surveillance EGDs in LS patients. More data are needed to determine the appropriate surveillance interval.

Bevacizumab does not increase risk of perforation in patients undergoing percutaneous endoscopic gastrostomy or jejunostomy placement.

INTRODUCTION: Bevacizumab is a humanized anti-vascular endothelial growth factor monoclonal antibody used in the treatment of cervical cancer, ovarian cancer, colorectal cancer, lung cancer, renal cell cancer, and recurrent glioblastomas. Its approval by US FDA was issued with a black box warning that its use has been associated with a risk of gastrointestinal (GI) tract perforation and that it should be discontinued in patients who have experienced such. The reported incidence of GI perforation in those receiving bevacizumab is as high as 3%. However, the incidence of GI perforation in those receiving bevacizumab undergoing GI endoscopic procedures has not been well studied. METHODS: A retrospective, single-center observational study was conducted at Memorial Sloan Kettering Cancer Center (MSKCC) between 2011 and 2018. All patients who underwent upper GI endoscopy with percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) tube placement and received bevacizumab within 6 months of their endoscopic procedure were included. RESULTS: We identified 176 patients who underwent PEG or PEJ tube placement and received bevacizumab within 6 months. Eighty-one percent of patients were female (n = 144) and the median age was 61 years. Prior to endoscopic procedures, patients received a median of seven doses of bevacizumab. Patients received bevacizumab from 170 days before to 170 days after their endoscopic procedures (median 44 days). No GI perforations were observed during or after the time of the endoscopic procedures. CONCLUSION: Our study demonstrated that receiving bevacizumab within 6 months prior to their endoscopic procedure was not associated with an increased risk of GI tract perforation and thus not an absolute contraindication to proceeding with PEG and PEJ tube placement in these patients.

Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.

PURPOSE: Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. METHODS: Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. RESULTS: We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). CONCLUSION: Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

Direct Percutaneous Endoscopic Jejunostomy: Procedural and Nutrition Outcomes in a Large Patient Cohort.

BACKGROUND: Direct percutaneous endoscopic jejunostomy (DPEJ) is used for enteral nutrition (EN) in patients with postoperative anastomotic leaks after esophagectomy/gastrectomy and at high risk for aspiration. We characterized the indications, technical success, procedural/nutrition outcomes, and adverse events in a large cohort of patients undergoing DPEJ insertion. METHODS: Patients undergoing DPEJ insertion between January 2009 and March 2015 were identified from an institutional endoscopy database. Demographic, procedural, and nutrition outcome data were collected from electronic medical records. Regression analyses were used to identify predictors of adverse events and procedural success. RESULTS: A total of 452 patients underwent 480 attempts at DPEJ insertion. Indications included preoperative or postoperative weight loss (64%), postoperative upper gastrointestinal (UGI) anastomotic leak (13%), aspiration prevention (10%), and other (13%). Of attempted procedures, 398 (83%) were successful. Feeding was initiated in 389 (98%) of patients; a median of 1775 calories was delivered daily. Median body mass index (BMI) at baseline was 22.9 (11.4-44.7) and did not change over follow-up. Median change in BMI after DPEJ was similar in groups that received EN with palliative and curative intent. Adverse events following 480 attempted DPEJ insertions included 13 (3%) immediate and 74 (15%) delayed, 13 (3%) of which were serious. Patients with head and neck cancer had more adverse events than those with esophageal cancer (P = .020). CONCLUSION: DPEJ is a successful and safe procedure that effectively provides access for EN support in malnourished patients and patients with postoperative UGI cancer.

Predictors of clinical outcome of colonic stents in patients with malignant large-bowel obstruction because of extracolonic malignancy.

BACKGROUND AND AIMS: Colonic stent placement in patients with large-bowel obstruction (LBO) secondary to extracolonic malignancy (ECM) has been evaluated in small series with heterogeneous results. Our aim is to better characterize the technical and clinical success of colonic stent placement and to identify factors that affect this success in ECM patients. METHODS: All patients at a single high-volume center who presented for colonic stent placement for LBO because of ECM between 2001 and 2012 were retrospectively identified. The outcomes of interest were technical success, clinical success, stent occlusion rate, and overall survival. RESULTS: A total of 187 patients were identified. Mean age was 61.9 years (range, 23-89), and 150 (80.2%) were women. The most common malignancy type was urogynecologic (n = 104) and most common location sigmoid colon (n = 128). Overall, 142 patients (75.9%) achieved technical success and 102 patients (54.5%) clinical success. Radiographic presence of peritoneal carcinomatosis (P < .001) and multifocal disease (P < .001) were associated with both decreased technical and clinical success. Procedure-related adverse events were seen in 12 patients (6.4%). In patients with clinical success, the incidence of stent occlusion at 3 months was 14.7% (95% confidence interval, 7.8%-21.6%) and was higher in patients with prior radiation therapy (P = .011). The median overall survival for all patients from time of attempted stent placement was 3.3 months (95% confidence interval, 3.0-4.1). CONCLUSIONS: This study represents the largest retrospective series of colonic stent placement for LBO in ECM patients in the literature. Our technical success rate of 75.9%, clinical success rate of 54.5%, and 3-month stent occlusion rate of 14.7% suggest that stent placement is a viable palliative option for patients with advanced disease because of ECM. Patients with peritoneal carcinomatosis and multifocal disease have reduced technical and clinical success. However, these factors should not dissuade an attempt at stent placement, if risk-to-benefit analysis is favorable.

A potential association between exposure to hepatitis B virus and small bowel adenocarcinoma.

Chronic infection with hepatitis B virus (HBV) has never been described as a risk factor for small bowel adenocarcinoma, although infection is a known risk factor for hepatocellular carcinoma. From May 2009 to December 2014, we implemented an institution-wide screening program for hepatitis B viral serologies prior to starting chemotherapy. Evidence of exposure [hepatitis B core antibody (anti-HBc) positivity in the absence of hepatitis B surface antigen (HBsAg) positivity] was highest in patients with hepatocellular carcinoma (21.1%), followed by small bowel cancer (12.5%). The small bowel adenocarcinoma cases with anti-HBc positivity were reviewed. Special attention was paid to known risk factors for small bowel cancers. One patient had a diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC). However, the other patients had no genetic syndromes, history of inflammatory bowel disease or other chronic inflammation to explain their risk. We postulate exposure to bile acids, tumorigenesis of hepatocytes and cholangiocytes, and/or damage to the intestinal mucosa secondary to HBV exposure/infection as potential mechanisms for development of small bowel adenocarcinoma. More research is warranted to further elucidate this association.

Endoscopic Management of Esophageal Anastomotic Leaks After Surgery for Malignant Disease.

BACKGROUND: Esophageal anastomotic leaks after cancer surgery remain a major cause of morbidity and mortality. Endoscopic interventions, including covered metal stents (cSEMS), clips, and direct percutaneous endoscopic jejunostomy (dPEJ) tubes are increasingly used despite limited published data regarding their utility in this setting. This study aimed to determine the efficacy and safety of a multimodality endoscopic approach to anastomotic leak management after operation for esophageal or gastric cancer. METHODS: We performed a retrospective review of prospectively maintained databases of gastric and esophageal operations at our hospital between January 2003 and December 2012. Included patients had an operation for esophageal or gastric cancer, demonstrated evidence of an anastomotic leak at the esophageal anastomosis, and underwent attempted endoscopic therapy. Healing was defined as clinical and radiographic leak resolution. RESULTS: Forty-nine patients with leaks underwent endoscopic management. Of the 49 patients, 31 (63%) received cSEMS, 40 (82%) had dPEJ tubes inserted, and 3 (6%) received clips. Twenty-three (47%) patients underwent a combined approach. Overall, 88% of patients achieved healing in a median of 83 days. Twenty-two of 23 patients (96%) who underwent a multimodality endoscopic approach healed. Only 1 patient had a major complication associated with stent erosion into the pulmonary artery, which was successfully treated with operative repair. CONCLUSIONS: Esophageal anastomotic leaks after esophageal and gastric cancer operations can be managed successfully and safely with endoscopic therapy. Combining cSEMS for leak control and dPEJ tube placement for nutritional support was highly effective in achieving healing, without the need for surgical repair.

Palliation of malignant gastric outlet obstruction with simultaneous endoscopic insertion of afferent and efferent jejunal limb enteral stents in patients with recurrent malignancy.

BACKGROUND: Patients with prior pancreaticobiliary or distal gastric cancer treated surgically may have local anastomotic recurrence with obstruction of the afferent and efferent jejunal limbs. This report describes the efficacy and safety of simultaneous endoscopic insertion of self-expanding metal stents into the afferent and efferent jejunal limbs in patients with gastric outlet obstruction (GOO) of post-surgical anatomy for palliation of recurrent malignancy. METHODS: Patients were identified from an endoscopic database at a specialized cancer center between September 2007 and March 2014. Technical success was defined as single-session insertion of afferent and efferent jejunal limb enteral stents. Clinical success was defined as immediate symptom relief and ability to advance diet. A durable response was defined as symptom relief of at least 60 days or until hospice placement or death. RESULTS: Twenty-three patients were identified who underwent insertion of two 22-mm-diameter uncovered duodenal stents. Stent length varied from 60 to 120 mm. Stents were placed under endoscopic and fluoroscopic guidance. Three patients required balloon dilation to facilitate stent insertion. Average procedure time was 58.8 min (range 28-120). Technical success was achieved in 23/24 (96%) patients. Clinical success was achieved in 19/23 (83%) patients. Following initial stent insertion and prior to subsequent re-intervention, 11/19 (58%) patients had a durable response with a median duration of 70 days (range 4-315). Eight (42%) patients underwent subsequent re-intervention at a median of 22 days (range 11-315). Five patients had stent revision and were able to tolerate oral intake. Two patients had percutaneous endoscopic gastrostomy/jejunostomy insertion. One patient required surgical diversion for persistent obstruction. Complications included stent migration and post-stent insertion bacteremia due to food bolus obstruction. CONCLUSIONS: Recurrent malignant GOO in patients with post-surgical anatomy treated with simultaneous endoscopic enteral stenting of afferent and efferent jejunal limbs has a high rate of technical and clinical success and low rate of complications and provides effective palliation.

Fatal hepatitis B reactivation in a patient with islet cell tumor on octreotide and sirolimus.

Reactivation of hepatitis B viral infection (HBVr) is a known risk in cancer patients with a history of chronic hepatitis B infection receiving cytotoxic or immunosuppressive therapies. Patients with hematologic malignancies or those who have received stem cell transplantation seem to be most at risk but reactivation has been reported with various malignancies. Reactivation can present as asymptomatic liver function test abnormalities (LFTs), with symptoms of abdominal pain, encephalopathy, or as fulminant hepatitis and liver failure. Here we report the first case of a patient with islet cell tumor on octreotide and sirolimus who developed hepatitis B reactivation with fulminant liver failure and death.

Allergies and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium.

In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between-study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (Pheterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age.

Endoluminal high-dose-rate brachytherapy for early stage and recurrent esophageal cancer in medically inoperable patients.

PURPOSE: The management of superficial primary and recurrent esophageal cancer (EC) in medically inoperable patients is complex. Endoluminal high-dose-rate (HDR) brachytherapy has shown mixed results in terms of toxicity and local control. In this study, we examined the outcomes and toxicities in a set of patients with superficial primary and recurrent EC treated with a consistent HDR technique. METHODS AND MATERIALS: Between 8/2008 and 7/2011, 14 patients were treated with HDR intraluminal brachytherapy, 10 (71.4%) with recurrent disease, and 4 (28.6%) with previously unirradiated lesions. Patients received three weekly fractions to a median dose of 12 Gy (range, 10-15 Gy); dose was prescribed to 7-mm median depth with mucosal dose limited to 8-10 Gy using a 12-14-mm applicator. RESULTS: Median followup was 15.4 months. Overall freedom from failure (OFFF) and overall survival (OS) at 18 months were 30.8% (95% confidence interval [CI]: 5.2, 56.4) and 72.7% (95% CI: 45.3, 100), respectively. For patients with recurrent disease, OFFF and OS at 18 months were 11.1% (95% CI: 0, 32.1) and 55.6% (95% CI: 15.4, 95.8), respectively. For patients with previously unirradiated disease, OFFF and OS at 18 months were 75.0% (95% CI: 31.6, 100) and 100.0%, respectively. Eight (57.1%) patients had Grade 1 acute adverse effects; 6 (42.9%) patients had chronic Grade 1 adverse effects; 1 (7.1%) patient developed Grade 2 stricture. Grade 3 tracheoesophageal fistula occurred in 1 (7.1%) patient. One patient died before completion of treatment of unrelated causes. CONCLUSIONS: HDR endoluminal brachytherapy is a well-tolerated treatment for superficial primary and recurrent EC in medically inoperable patients.

An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions.

BACKGROUND: BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported. METHODS: Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center. RESULTS: Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. CONCLUSION: BRCA mutation-associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC.

Including additional controls from public databases improves the power of a genome-wide association study.

Though genome-wide association studies (GWAS) have identified numerous susceptibility loci for common diseases, their use is limited due to the expense of genotyping large cohorts of individuals. One potential solution is to use 'additional controls', or genotype data from control individuals deposited in public repositories. While this approach has been used by several groups, the genetically heterogeneous nature of the population of the United States makes this approach potentially problematic. We empirically investigated the utility of this approach in a US-based GWAS. In a small GWAS of pancreatic cancer in New York, we observed clear population structure differences relative to controls from the database of Genotypes and Phenotypes (dbGaP). When we conduct the GWAS using these additional controls, we find large inflation of the test statistic that is properly corrected by using eigenvectors from principal components analysis as covariates. To deal with errors introduced due to different sources, we propose simultaneously genotyping a small number of controls along with cases and then comparing this group to the additional controls. We show that removing SNPs that show differences between these control groups reduces false-positive findings. Thus, through an empirical approach, this report provides practical guidance for using additional controls from publicly available datasets.

Studying cancer in minorities: a look at the numbers.

BACKGROUND: Inclusion of minorities is an important but challenging aspect of epidemiologic studies in the United States. One aspect of this challenge that has received little attention is the actual number of minorities with specific cancers. The authors aimed to understand how population characteristics affect the numbers of minority cancer cases in Surveillance, Epidemiology, and End Results (SEER) regions. METHODS: By using SEER data, the authors identified 6 cancers with higher incidence rates in racial and ethnic minorities and reviewed the annual number of cases of those cancers in SEER areas where there are large numbers of blacks, Hispanics, and Asians. The authors examined the age characteristics of the populations in SEER areas using data from the US Census. RESULTS: Although there are substantial numbers of cases for the most common cancers with higher incidence in blacks, their numbers are quite small for other cancers, <150 cases, and in many areas, <100 per year. Few registries have substantial numbers of Hispanics or Asians. As expected, the proportion of minority populations is lower in older age groups, whereas the proportion of non-Hispanic whites is larger. CONCLUSIONS: Because of the sharp decline in minority populations associated with age and the high age-specific incidence rates of most cancers, the actual number of minority cases is quite small for several cancers. Thus, the inclusion of minority groups in studies of any but the most common cancers presents a challenge.

Feasibility and yield of screening in relatives from familial pancreatic cancer families.

OBJECTIVES: Pancreatic adenocarcinoma is a lethal disease. Over 80% of patients are found to have metastatic disease at the time of diagnosis. Strategies to improve disease-specific outcome include identification and early detection of precursor lesions or early cancers in high-risk groups. In this study, we investigate whether screening at-risk relatives of familial pancreatic cancer (FPC) patients is safe and has significant yield. METHODS: We enrolled 309 asymptomatic at-risk relatives into our Familial Pancreatic Tumor Registry (FPTR) and offered them screening with magnetic resonance cholangiopancreaticogram (MRCP) followed by endoscopic ultrasound (EUS) with fine needle aspiration if indicated. Relatives with findings were referred for surgical evaluation. RESULTS: As of 1 August 2009, 109 relatives had completed at least one cycle of screening. Abnormal radiographic findings were present on initial screening in 18/109 patients (16.5%), 15 of whom underwent EUS. A significant abnormality was confirmed in 9 of 15 patients, 6 of whom ultimately had surgery for an overall diagnostic yield of 8.3% (9/109). Yield was greatest in relatives >65 years old (35%, 6/17) when compared with relatives 55-65 years (3%, 1/31) and relatives <55 years (3%, 2/61). CONCLUSIONS: Screening at-risk relatives from FPC families has a significant diagnostic yield, particularly in relatives >65 years of age, confirming prior studies. MRCP as initial screening modality is safe and effective.