Anuhya Kommalapati

Contemporary Management of Localized Resectable Pancreatic Cancer

Pancreatic cancer is the third most common cause of cancer deaths in the United States. Surgical resection with negative margins still constitutes the cornerstone of potentially curative therapy, but is possible only in 15–20% of patients at the time of initial diagnosis. Accumulating evidence suggests that the neoadjuvant approach may improve R0 resection rate in localized resectable and borderline resectable diseases, and potentially downstage locally advanced disease to achieve surgical resection, though the impact on survival is to be determined. Despite advancements in the last decade in developing effective combinational chemo-radio therapeutic options, preoperative treatment strategies, and better peri-operative care, pancreatic cancer continues to carry a dismal prognosis in the majority. Prodigious efforts are currently being made in optimizing the neoadjuvant therapy with a better toxicity profile, developing novel agents, imaging techniques, and identification of biomarkers for the disease. Advancement in our understanding of the tumor microenvironment and molecular pathology is urgently needed to facilitate the development of novel targeted and immunotherapies for this setting. In this review, we detail the current literature on contemporary management of resectable, borderline resectable and locally advanced pancreatic cancer with a focus on future directions in the field.

Histiocytic sarcoma: a population-based analysis of incidence, demographic disparities, and long-term outcomes

TO THE EDITOR:nnHistiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system that is diagnosed using immunohistochemistry markers, such as CD68, lysozyme, CD4, and CD163, on the tissue biopsies.[1][1] HS can occur in

Thyrotoxic Periodic Paralysis: An Underdiagnosed and Under-recognized Condition.

Thyrotoxic hypokalemic periodic paralysis (TPP) is a condition characterized by the triad of acute hypokalemia without total body potassium deficit, episodic muscle paralysis, and thyrotoxicosis. We describe two cases of thyrotoxic periodic paralysis who presented to our hospital with potassium values of 1.3 MeQ/l and 1.2 MeQ/l, respectively. Surprisingly, the two patients had no documented past medical history. Based on the clinical features of high heart rate, palpitations (seen in both the patients), and exophthalmos (seen in one patient), thyrotoxic periodic paralysis was suspected. A thorough laboratory workup confirmed the diagnosis of thyrotoxicosis. Beta blockers were initiated promptly, along with intravenous potassium chloride, and the patients eventually improved symptomatically. These patients were eventually diagnosed with Graves’ disease and were placed on methimazole, which prevented further attacks. Thyroid periodic paralysis (TPP) is a rare clinical manifestation of hyperthyroidism. Patients present with sudden onset paralysis associated with severe hypokalemia. The presence of paralysis and hypokalemia in a patient who has a history of hyperthyroidism should prompt the physician about thyrotoxic periodic paralysis. A high index of suspicion, prompt diagnosis, and management of the condition can prevent severe complications, such as cardiac arrhythmias.

Predictors of survival in Adrenocortical Carcinoma: An analysis from the National Cancer Database (NCDB).

ContextnAdrenocortical carcinoma (ACC) is rare; knowledge about prognostic factors and survival outcomes is limited.nnnObjectivenTo describe predictors of survival and overall survival (OS) outcomes.nnnDesign and PatientsnRetrospective analysis of data from the National Cancer Database (NCDB) from 2004 to 2015 on 3185 patients with pathologically confirmed ACC.nnnMain Outcome MeasuresnBaseline description, survival outcomes, and predictors of survival were evaluated in patients with ACC.nnnResultsnMedian age at ACC diagnosis was 55 (range: 18 to 90) years; did not differ significantly by sex or stage of the disease at diagnosis. On multivariate analysis, increasing age, higher Charlson-Deyo comorbidity index score, high tumor grade, and no surgical therapy (all P < 0.0001); and stage IV disease (P = 0.002) and lymphadenectomy during surgery (P = 0.02) were associated with poor prognosis. Patients with stage I-III disease treated with surgical resection had significantly better median OS (63 vs 8 months; P < 0.001). In stage IV disease, better median OS occurred in patients treated with surgery (19 vs 6 months; P < 0.001), and postsurgical radiation (29 vs 10 months; P < 0.001) or chemotherapy (22 vs 13 months; P = 0.004).nnnConclusionnOS varied with increasing age, higher comorbidity index, grade, and stage of ACC at presentation. There was improved survival with surgical resection of primary tumor, irrespective of disease stage; postsurgical chemotherapy or radiation was of benefit only in stage IV disease.

Predictors of survival, treatment patterns, and outcomes in histiocytic sarcoma

Histiocytic sarcoma (HS) is an aggressive hematologic malignancy derived from non-dendritic, non-Langerhans histiocytic cells of the monocyte/macrophage system [1]. The diagnosis of HS is made base...

Novel targeted treatment options for advanced cholangiocarcinoma

ABSTRACT Introduction: Surgical resection remains the mainstay of potentially curative treatment in the early stages of cholangiocarcinoma, whereas for the advanced stage, systemic chemotherapeutics and experimental targeted therapies are the primary treatment options. The molecular heterogeneity of the tumor is based on location, liver dysfunction, and relative rarity of the disease and confers challenges for clinical trial enrollment. The advancements in the understanding of molecular pathogenesis of cholangiocarcinoma have led to the development of targeted therapies that are currently being evaluated in the clinical trials. Areas covered: This review summarizes the current understanding and future directions of targeted therapeutic options in the management of advanced cholangiocarcinoma. Expert opinion: Advanced cholangiocarcinoma has a dismal prognosis; improved understanding of the molecular pathogenesis and advancements in development of targeted therapy offers hope that we may improve outcomes in this rare, but highly lethal cancer. Among the newly discovered molecular alterations, targeting FGFR2 fusions, IDH1/2 mutations and HER2 receptors hold great promise for improving the future management of cholangiocarcinoma. Immunotherapy in combination with targeted agents and chemotherapy may improve outcomes. In addition, drugs targeting the MEK, EGFR, KRAS, BRAF, and ROS1 pathways and neo-angiogenesis may also provide new horizons in the management of cholangiocarcinoma.

Association between hospital volume and mortality of patients with metastatic non-small cell lung cancer

BACKGROUNDnPrior studies have shown superior surgical outcomes of stage I-III non-small cell lung cancer (NSCLC) in centers with higher patient volumes. However, there is a lack of such information in stage IV NSCLC.nnnPATIENTS AND METHODSnThis is a retrospective study of stage IV NSCLC patients diagnosed between 2004 and 2014 using the National Cancer Data Base (NCDB). We classified the total number of patients treated at facilities into quartiles: quartile 1 (Q1): ≤23; quartile 2 (Q2): 24-36, quartile 3 (Q3): 37-55, and quartile 4 (Q4): ≥56 cases/year. Cox regression was used to assess whether risk of death differed between quartiles after adjusting for demographics, insurance type, Charlson-Deyo score, and type of therapy received.nnnRESULTSnThere were 338, 445 patients with stage IV NSCLC treated at 1326 facilities. We included the patients who received any form of therapy in the survival analysis. The unadjusted median overall survival by facility volume was: Q1: 6 months, Q2: 6 months, Q3: 7 months, and Q4: 8 months (pu202f<u202f.001). Multivariable analysis showed that facility volume was independent predictor of all-cause mortality. Compared with patients treated at Q4 facilities, patients treated at lower-quartile facilities had a small but significantly higher risk of death (Q3 hazard ratio [HR], 1.05 [95%CI, 1.04-1.06]; Q2 HR, 1.12 [95%CI, 1.11-1.14]; Q1 HR, 1.11 [95%CI, 1.10-1.12]).nnnCONCLUSIONSnPatients who were treated for stage IV NSCLC at highest-volume facilities had less risk of all-cause mortality compared with those who were treated at lower-volume facilities. Although the survival advantage of being treated at highest-volume facilities appeared small, the results of this study suggest differences in cancer care delivery models among various facilities, and may become more relevant in the future era of personalized treatment of stage IV NSCLC.

Incidence, racial disparities and survival outcomes of mast cell malignancies: analysis from a national database

Mastocytosis is a group of rare heterogeneous clonal disorders of mast cells (MCs) characterized by their abnormal accumulation in the skin, bone marrow and internal organs (liver, spleen, gastrointestinal tract and lymph nodes). Mastocytosis is now classified as its own major category in the revised 2016 World Health Organization Classification of hematolymphoid neoplasms due to unique clinicopathologic characteristics [1]. The category of mastocytosis is sub divided into five major groups based on the clinical features, aggressiveness and extent of disease: indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). Patients with ASM, SM-AHN and MCL are known to have an aggressive clinical course with endorgan damage [2]. Mast cell sarcoma (MCS) is a rare but aggressive solid tumor that is composed of atypical mast cells that have destructive infiltration and metastatic potential. The exact incidence and survival data of malignant mast cell disorders are unclear, and contemporary clinical data are mostly limited to institutional case series [3–6]. The three aggressive forms – ASM, MCL and MCS – are reportable to Surveillance, Epidemiology and End Results (SEER) program database based on WHO ICD-0-3 codes. In this study, we utilized the SEER Program database (https://seer.cancer.gov/) to analyze the incidence, racial disparities, and outcomes of aggressive forms of mast cell neoplasms. SEER, a program of the U.S. National Cancer Institute, collects cancer incidence and survival data from population-based cancer registries covering approximately 28% of the US population. We identified mast cell tumors (ASM, MCS and MCL) that were reported to SEER using International Classification of Diseases for Oncology edition 3 (ICD-O-3) histology codes 9741/3, 9740/3 and 9742/3, respectively from SEER 18 (1973–2014) registry. As mast cell neoplasms are reportable to SEER after 1978, we included the cases that were diagnosed only after 1978. We excluded the cases that received a diagnosis at death certificate/autopsy or unknown sex. Since indolent forms of the disease (ISM, SSM) are not reportable to SEER, they are not included in our analysis. We calculated the incidence rates (case/1,000,000) using the 2000–2014 SEER 9 registries and age-adjusted those to the US 2000 standard population. Disease-specific survival (DSS) analysis was calculated using the 1973–2013 SEER 18 registry. The SEER Stat Multiple Primary-SIR tool was used to calculate standard incidence ratios (SIRs) and absolute excess risk (AER) for secondary malignancies by comparing these patients’ subsequent cancer diagnoses with the number of cancers that would be expected based on incidence rates for the general U.S. population. We excluded Second primary malignancies diagnosed within 12 months of ASM diagnosis from the analyzes (to make sure that they are not classifiable under SM-AHN). Patient-level data were analyzed to determine demographic findings and clinical outcome. We used SEER Stat (v 8.3.4; https://seer.cancer.gov/seerstat/) for incidence and survival statistical calculations. The patient characteristics of ASM, MCL and MCS are summarized in Table 1. A total of 523 cases of ASM were reported in the SEER database between 1978 and 2014. The overall incidence was found to be 0.37 per 1,000,000 individuals [95% confidence interval (CI): 0 34–0 40]. Compared to that of Caucasians, the incidence was significantly lower among African Americans (AA) (incidence rate ratio: 0.30; 95% CI: 0.17–0.48; p< .0001) and Asian/ Pacific Islander (incidence rate ratio: 0.16; 95% CI: 0.07–0.31; p< .0001). The median age at diagnosis was similar in males and females (55 years) (range, 1–88 years). After a median follow-up of 45 months (range, 0–368), 183 patients died, of which 47 (26%) died due to this malignancy. The median overall survival (OS) in the

Phase 1 trial of enzalutamide in combination with gemcitabine and nab-paclitaxel for the treatment of advanced pancreatic cancer

SummaryBackground Androgens were shown to play a key role in the growth and progression of pancreatic cancer. We evaluated the safety and tolerability of the combination of enzalutamide, a novel androgen receptor (AR) antagonist with gemcitabine and nab-paclitaxel as a first-line treatment in advanced pancreatic cancer. Methods We used the standard 3u2009+u20093 dose escalation design with cohort expansion to evaluate 2 dose levels of enzalutamide: 80xa0mg and 160xa0mg/day orally (phase 1a) in combination with gemcitabine and nab-paclitaxel in metastatic pancreatic cancer patients. In the expansion phase (phase 1b), AR+ was a pre-requisite criterion. We also evaluated the full pharmacokinetic (PK) profile for nab-paclitaxel and enzalutamide. Results We enrolled 24 patients, 12 patients in phase 1a and 12 patients in phase 1b. The median age was 68 (range, 32–84) years. No DLTs were observed. Grade 3/4 treatment related adverse events included neutropenia (44%), anemia (40%), leukopenia (24%), nausea and vomiting (20%), diarrhea (16%), infections (12%), thrombocytopenia (8%), thromboembolic event (8%), hypertension (8%), hypokalemia (8%), hyponatremia (8%), and ALT elevation (8%). Median overall survival and progression-free survival was 9.73 [95%CI:9.73–13.5] and 7.53 (95%CI:6.05–12.8) months, respectively. PK analysis suggests that the combination therapy does not impact the kinetics of either drug evaluated. Enzalutamide reached steady-state levels between day 22 and 29 and the mean half-life of nab-paclitaxel was 19.6u2009±xa04.7xa0h. Conclusions Enzalutamide 160xa0mg daily in combination with gemcitabine and nab-paclitaxel can be safely administered with no unexpected toxicities. We also noticed preliminary signals of efficacy with this combination.

Association between treatment facility volume, therapy types and overall survival in patients with intrahepatic cholangiocarcinoma

BACKGROUNDnTo determine the association between the number of patients with intra-hepatic cholangiocarcinoma (IHCC) treated annually at a treatment facility (volume) and overall survival (outcome).nnnMETHODSnPatients with IHCC reported to the National Cancer Database (years 2004-2015) were included. We classified facilities by tertiles (T; mean IHCC patients treated/year): T1: <2.56; T2: 2.57-5.39 and T3: ≥5.40. Volume-outcome relationship was determined by using Cox regression adjusting for patient demographics, comorbidities, tumor characteristics, insurance type and therapy received.nnnRESULTSnThere were 11,344 IHCC patients treated at 1106 facilities. On multivariable analysis, facility volume was independently associated with all-cause mortality (pxa0<xa00.001). The unadjusted median OS by facility volume was: T1: 5 months (m), T2: 8.1xa0m, and T3: 13.1xa0m (pxa0<xa00.001). Compared with patients treated at T3 facilities, patients treated at lower-tertile facilities had significantly higher risk of death [T2 hazard ratio (HR), 1.12 [95% CI, 1.05-1.23]; T1 HR, 1.21 [95% CI, 1.11-1.33]. Patients treated at high-volume centers were more likely to get surgery (34.6 vs 13.1%) and adjuvant therapy.nnnCONCLUSIONnIHCC patients treated at high-volume facilities had a significant improvement in OS and were more likely to receive surgery and adjuvant therapy as compared to that of patients at low-volume facilities.