Clinical Risk Prediction Model for Neoadjuvant Therapy in Resectable Esophageal Adenocarcinoma.

GOALS AND BACKGROUND: Clinical staging with endoscopic ultrasound (EUS) and positron emission tomography (PET) is used to identify esophageal adenocarcinoma (EAC) patients with locally advanced disease and therefore, benefit from neoadjuvant therapy. However, EUS is operator dependent and subject to interobserver variability. Therefore, we aimed to identify clinical predictors of locally advanced EAC and build a predictive model that can be used as an adjunct to current staging methods. STUDY: This was a cross-sectional study of patients with EAC who underwent preoperative staging with EUS and PET scan followed by definitive therapy at our institution from January 2011 to December 2017. Demographic data, symptoms, endoscopic findings, EUS, and PET scan findings were obtained. RESULTS: Four hundred and twenty-six patients met the study criteria, of which 86 (20.2%) patients had limited stage EAC and 340 (79.8%) had locally advanced disease. The mean age was 65.4±10.3 years of which 356 (83.6%) were men and 393 (92.3%) were White. On multivariable analysis, age (above 75 or below 65 y), dysphagia [odds ratio (OR): 2.84], weight loss (OR: 2.06), protruding tumor (OR: 2.99), and tumor size >2 cm (OR: 3.3) were predictive of locally advanced disease, while gastrointestinal bleeding (OR: 0.36) and presence of visible Barrett's esophagus (OR: 0.4) were more likely to be associated with limited stage. A nomogram for predicting the risk of locally advanced EAC was constructed and internally validated. CONCLUSIONS: We constructed a nomogram to facilitate an individualized prediction of the risk of locally advanced EAC. This model can aid in decision making for neoadjuvant therapy in EAC.

Chemoprevention Considerations in Patients with Hereditary Colorectal Cancer Syndromes.

Secondary prevention of colorectal neoplasia with chemoprevention is long-studied area of research and clinical use in patients with the 2 most common hereditary colorectal cancer syndromes including Lynch syndrome and familial adenomatous polyposis. No medication is currently approved for use for the prevention of colorectal polyps or cancer in either the general population or individuals with the hereditary colorectal cancer syndromes. Emerging data in animal models and limited data in humans suggest vaccines may be the next breakthrough for neoplasia prevention in patients with hereditary colorectal cancer. Clinicians must acknowledge chemoprevention is an adjunct and does not supplant endoscopic surveillance.

Clinical Predictors of Locally Advanced Pathology in Esophageal Adenocarcinoma.

Background In patients with resectable esophageal adenocarcinoma (EAC), the decision for neoadjuvant treatment depends on clinical staging with endoscopic ultrasound (EUS) and positron-emission tomography (PET) scan. Patients with locally advanced EAC pathology misclassified as early EAC by clinical staging are missing the opportunity to receive neoadjuvant therapy. We aim to identify predictors of locally advanced pathology in EAC to determine more accurately those who benefit from neoadjuvant therapy.  Methods Retrospective study of patients who underwent upfront endoscopic or surgical resection for EAC without neoadjuvant therapy from January 2011 to December 2017 was performed. Clinical characteristics, EUS, PET scan and histologic findings were analyzed. Multivariable analysis of predictors of locally advanced stage was performed and a risk prediction score was developed. Results A total of 97 patients were included; 68 patients were staged as early EAC (pT1 or pT2 and pN0) and 29 patients were staged as locally advanced EAC (pT1 or pT2 with pN1 and pT3 or pT4 irrespective of N status). In a predictive model of EAC, patients presenting with dysphagia, tumor size >2 cm, exophytic mass appearance on endoscopy and absence of hiatal hernia were more likely to be have locally advanced pathology with a probability of 70% (C-statistic 0.766). Conclusions A risk prediction model based on the presence of dysphagia, tumor size >2 cm, exophytic mass appearance and absence of hiatal hernia can be used to identify locally advanced pathology in EAC patients.

Dual Targeted Therapy for the Management of Inflammatory Bowel Disease.

The burden of inflammatory bowel disease (IBD) is increasing globally and imposes a high morbidity in patients with IBD. Advances have been made in medical management of IBD with the advent of novel therapies such as the biologics and small molecule drugs (SMDs). However, response to these medications is limited; with only 40% of patients achieving clinical remission at 1 year with a biologic. Hence, medical management of IBD is a rapidly evolving paradigm in which not only are new medications being developed but understanding how, when and in whom to use them is evolving. Dual targeted therapy (DTT), which is the combination of biologics and/or SMDs is an attractive concept as it is theoretically a potent and multidimensional anti-inflammatory treatment strategy. In this review, we present the published literature on the use of DTT and highlight its utility in clinical practice. The majority of studies on DTT are case reports and case series on the combination of dual biologic therapy. From the limited evidence available in patients with IBD, dual biologic therapy may be a safe option for patients with refractory IBD who have failed multiple biologic therapies and to manage extraintestinal manifestation of IBD. There are a handful of reports of combination therapy with a biologic and a SMD in patients with IBD. Further studies and randomized control trials are required to comprehensivretain hereely evaluate the safety and efficacy of DTT in IBD.

Retrospective observational study of temporal trends and outcomes of hepatitis B screening in patients receiving rituximab.

OBJECTIVE: Hepatitis B reactivation (HBr) is strongly associated with rituximab therapy. Guidelines advise hepatitis B screening and use of preventive nucleoside analogue (NA) in patients at risk. In this study, we examined screening trends, post-screening interventions and outcomes in patients receiving rituximab in light of recommendations. DESIGN: Retrospective, observational study. SETTING: Single, tertiary care centre in the USA. PARTICIPANTS: Patients receiving rituximab from January 2005 to December 2017. PRIMARY OUTCOME: Trends of hepatitis B screening prior to initiation of rituximab. SECONDARY OUTCOME: Results of hepatitis B screening, use of preventive NA therapy and HBr incidence. RESULTS: Over 13 years, 2219 patients received rituximab. Screening, with at least hepatitis B core antibody (anti-HBc) prior to the first dose of rituximab, improved from 20% to 97%. Because only 4.5% of patients had a positive anti-HBc, the overall HBr incidence was very low (0.42%). In susceptible patients, the incidence of HBr was 8%. In at-risk patients given preventive NA, 96% remained free of HBr. However, only 23% received a preventive NA and no temporal improvement in compliance was seen. Of those with HBr, 87.5% were hepatitis B surface antigen (HbsAg-)/anti-HBc+. CONCLUSIONS: In those treated with rituximab, we demonstrated near-universal anti-HBc screening. Screening unlinked to preventive NA use, in those who are anti-HBc+, is ineffective in reducing HBr. HBr has a high fatality rate. The majority of cases occurred in those who were HBsAg negative. Efforts are needed to educate providers who use rituximab not only to screen for anti-HBc, but to provide preventive NA to those who test positive.

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia.

About 85% of patients with essential thrombocythemia (ET) harbor one of three driver mutations: JAK2, calreticulin (CALR), and MPL; the remaining ( ∼15%) are wild type for all three mutations and are referred to as being "triple negative." Furthermore, CALR mutations in ET are structurally classified as type 1/type 1-like or type 2/type 2-like variants. The objective of the current study was to examine the impact of CALR mutation variant stratified driver mutational status on overall (OS), myelofibrosis-free (MFFS), thrombosis-free, and leukemia-free survival (LFS) in ET; 495 patients (median age 58 years; 61% females) with ET were fully annotated for the their driver mutational status: 321 (65%) harbored JAK2, 109 (22%) CALR, and 12 (2%) MPL mutations and 11% were triple-negative. Among the 109 CALR-mutated cases, 52% were classified as type 1/type 1-like and 48% as type 2/type 2-like. In univariate analysis, triple-negative patients displayed the best and MPL mutated the worst OS (P = 0.007); however, the difference in OS was no longer apparent on multivariable analysis that included age and sex as covariates (P = 0.5). LFS was also similar among the different mutational groups (P = 0.6) whereas MFFS was significantly shorter in MPL-mutated patients on both univariate and multivariable analyses (age-adjusted P = 0.02; HR 7.9, 95% CI 2.0-31.5). Also in multivariable analysis that included thrombosis history, age, and cardiovascular risk factors, the presence of JAK2 or MPL mutations was independently associated with higher risk of thrombosis (P = 0.02; HR 1.9, 95% CI 1.1-3.4). In conclusion, driver mutational status in ET does not appear to influence overall or LFS, even after CALR variant stratification. However, the presence of MPL mutations might be associated with a higher risk of fibrotic transformation and the presence of JAK2/MPL mutations with higher risk of thrombosis.

Validation of the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) in 585 Mayo Clinic patients.

The primary objective of treatment in essential thrombocythemia (ET) is to prevent thromboembolic complications. In this regard, advanced age and thrombosis history have long distinguished "low" from "high" risk patients. More recently, JAK2V617F and cardiovascular (CV) risk factors were identified as additional modifiers, leading to the development of a 3-tiered International Prognostic Score of Thrombosis for ET (IPSET-thrombosis): "low," "intermediate," and "high". The international data set used to develop IPSET-thrombosis was recently re-analyzed in order to quantify the additional pro-thrombotic effect of JAK2V617F and CV risk factors in specific risk subcategories. The revised IPSET-thrombosis identified four risk categories based on three adverse variables (thrombosis history, age >60 years and JAK2V617F): very low (no adverse features), low (presence of JAK2V617F), intermediate (age >60 years) and high (presence of thrombosis history or presence of both advanced age and JAK2V617F). In this study of 585 patients with ET (median age 68 years; 61% female), we validated the revised IPSET-thrombosis by confirming significant differences in thrombosis risk between "very low" and "low" (HR 2.4, 95% CI 1.1 - 5.3) and between "intermediate" and "high" (HR 2.3, 95% CI 1.1 - 5.2) risk patients. Furthermore, in multivariable analysis, only JAK2V617F (HR=1.8, CI= 1.07 - 2.94) and history of thrombosis (HR=2.1, CI= 1.20 - 3.58) were independently predictive of future thrombotic events. The revised IPSET-thrombosis needs confirmation in prospective studies, especially in terms of risk-adapted therapy that includes the need for aspirin therapy in very low risk, twice-daily aspirin therapy for low risk and cytoreductive therapy for low or intermediate risk patients.

Nelarabine associated myotoxicity and rhabdomyolysis.

Nelarabine (ara-G; Arranon; compound 506U78) is an antineoplastic purine analog used for the treatment of refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). The drug was granted accelerated approval in October 2005 by the US Food and Drug Administration (FDA) given the efficacy (induction of complete responses) noted in 2 single-arm trials (one in pediatric setting and one in adult patient population). The main spectra of toxicities that have been reported in these clinical trials and subsequent studies are hematological and neurological. Nelarabine induced rhabdomyolysis and increased creatinine phosphokinase (CK; CPK) levels apparently have been reported and this side effect has been added as an adverse reaction in the product monograph from the drug company during postmarketing surveillance. However, the true extent and incidence of the myotoxicity from the drug are unclear. In this paper we report a grade IV CK elevation and rhabdomyolysis in a patient with T-ALL treated with nelarabine. Given the reported finding, we examined the literature further for myotoxicity, increased CK, and/or rhabdomyolysis associated with the use of the nelarabine and report our findings.

Hyper-reactive malarial splenomegaly in the absence of raised IgM antibodies.

Hyper-reactive malarial splenomegaly (HMS) is diagnosed by the presence of massive splenomegaly, raised IgM and antimalarial antibodies and a response to antimalarial therapy. Although malaria is endemic to Pakistan, HMS is uncommon. We report on HMS in a patient with massive splenomegaly, positive Plasmodium falciparum polymerase chain reaction but normal immunoglobulin M antibody levels. The investigations were not consistent with any other diagnosis. HMS is also briefly reviewed.