Publications by authors named "Anuhya Kommalapati"

49 Publications

Aspirin and Statin Use and the Risk of Gallbladder Cancer.

Cancers (Basel) 2021 Mar 9;13(5). Epub 2021 Mar 9.

Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA.

Aspirin and statin drugs have been associated with reduced risk of several gastrointestinal cancers, but their association with gallbladder cancer (GBC) has not been well established. We evaluated the association of aspirin and statins with the risk of GBC. Patients with GBC managed at Mayo Clinic between 2000 and 2019 were matched 1:2 with a general patient pool by age and sex. Univariable and multivariable logistic regression models were used to assess associations between GBC and aspirin or statin use. The analysis included 795 cases and 1590 controls, with a median age of 67 years. Aspirin or statin use alone or in combination was higher in controls ( < 0.001). Univariate analysis showed that the use of aspirin [odds ratio (OR): 0.11; 95%CI: 0.08-0.15] or statins (OR: 0.29; 95%CI: 0.20-0.40) and their combined use (OR: 0.18; 95%CI: 0.13-0.24) was associated with lower risk of GBC. Multivariable analysis revealed that aspirin (OR: 0.12; 95%CI: 0.09-0.16) and combined statins and aspirin (OR: 0.46; 95%CI: 0.31-0.67) were associated with lower risk of GBC. Aspirin alone or in combination with statins is associated with a strongly reduced risk of GBC. Further prospective studies are needed to confirm these results and to elucidate their mechanisms.
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http://dx.doi.org/10.3390/cancers13051186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967123PMC
March 2021

Quality of life in caregivers of patients receiving chimeric antigen receptor T-cell therapy.

Psychooncology 2021 Mar 19. Epub 2021 Mar 19.

Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, USA.

Objective: Informal family caregivers provide critical support for patients receiving chimeric antigen receptor (CAR) T-cell therapy. However, caregivers' experiences are largely unstudied. This study examined quality of life (QOL; physical functioning, pain, fatigue, anxiety, and depression), caregiving burden, and treatment-related distress in caregivers in the first 6 months after CAR T-cell therapy, when caregivers were expected to be most involved in providing care. Relationships between patients' clinical course and caregiver outcomes were also explored.

Methods: Caregivers completed measures examining QOL and burden before patients' CAR T-cell therapy and at days 90 and 180. Treatment-related distress was assessed at days 90 and 180. Patients' clinical variables were extracted from medical charts. Change in outcomes was assessed using means and 99% confidence intervals. Association of change in outcomes with patient clinical variables was assessed with backward elimination analysis.

Results: A total of 99 caregivers (mean age 59, 73% female) provided data. Regarding QOL, pain was significantly higher than population norms at baseline but improved by day 180 (p < .01). Conversely, anxiety worsened over time (p < .01). Caregiver burden and treatment-related distress did not change over time. Worsening caregiver depression by day 180 was associated with lower patient baseline performance status (p < .01). Worse caregiver treatment-related distress at day 180 was associated with lower performance status, intensive care unit admission, and lack of disease response at day 90 (ps < 0.01).

Conclusions: Some CAR T-cell therapy caregivers experience pain, anxiety, and burden, which may be associated patients' health status. Further research is warranted regarding the experience of CAR T-cell therapy caregivers.
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http://dx.doi.org/10.1002/pon.5674DOI Listing
March 2021

Collateral damage of COVID-19 pandemic on oncology clinical trials.

Chin Clin Oncol 2020 12 18;9(6):80. Epub 2020 Nov 18.

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.21037/cco-20-200DOI Listing
December 2020

Prevention and treatment of FGFR inhibitor-associated toxicities.

Crit Rev Oncol Hematol 2020 Nov 1;155:103091. Epub 2020 Sep 1.

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. Electronic address:

Fibroblast growth factor receptor (FGFR) inhibitors have shown promising results in terms of objective response rates in phase I/II trials in various malignancies that harbor FGFR genetic aberrations. The class of medications brings in the concept of 'personalized' treatment by targeting susceptible FGFR genetic alterations in some rare but dismal cancers such as cholangiocarcinoma. Despite the fact that FGFR inhibitors are well-tolerated, these drugs are associated with toxicities that are distinct from that of other small-molecule tyrosine kinase inhibitors. These toxicities can result in dose reductions, interruptions, and even drug discontinuation as reported in the clinical trials. The prevention and effective management of the FGFR inhibitor-associated toxicities will allow patients to stay on these medications without the therapy interruptions. The current work is focused on summarizing the available literature on unique FGFR inhibitor-associated toxicities with a special emphasis in managing the unique adverse events.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103091DOI Listing
November 2020

Epigenetic modulation of immunotherapy cofactors to enhance tumor response in lung cancer.

Hum Vaccin Immunother 2021 Jan 27;17(1):51-54. Epub 2020 May 27.

Department of Thoracic Oncology, Moffitt Cancer Center , Tampa, USA.

Immunotherapy with a checkpoint inhibitor has revolutionized the treatment of advanced non-small cell lung cancer. Replacing cytotoxic chemotherapy in some settings, immunotherapy with checkpoint inhibitors enables many patients to live longer with much fewer side effects. Nonetheless, immunotherapy alone only works for about one-fifth of unselected patients and despite the durability of response, treatment will eventually fail. There are several important cofactors within the tumor microenvironment which can contribute to the efficacy of immunotherapy. These include T-cells, chemokines, and antigen presentations. Preliminary research has shown that these cofactors can be altered by epigenetic modulation. Specifically, hypomethylating agents or histone deacetylase inhibitors can lead to changes in the compositions and characteristics within the tumor microenvironment in a way that enhances the efficacy of checkpoint inhibitor. In recent clinical trials of combined immuno-epigenetic therapy, tumor responses were observed among patients who were previously resistant or refractory to immunotherapy. Furthermore, biological correlative studies also confirmed the mechanism of action of these agents, especially among patients who derived benefit. Nonetheless, at present, the efficacy in terms of tumor response seems modest and side effects, though mostly not serious, can result in treatment interruption or interfere with the quality of life.
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http://dx.doi.org/10.1080/21645515.2020.1764273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872084PMC
January 2021

Systemic therapy for advanced hepatocellular carcinoma: targeted therapies.

Chin Clin Oncol 2021 Feb 14;10(1):10. Epub 2020 May 14.

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

Therapeutic options for advanced, unresectable hepatocellular carcinoma (HCC) have changed dramatically over the last 3 years. While surgical resection, orthotropic liver transplantation, and localized therapeutic options such as ablation, radiation therapy, and embolization remain therapeutics of choice in localized disease, systemic therapy is the only option in advanced, metastatic HCC. Since the United States Food and Drug Administration (US FDA) approval of sorafenib in 2008, targeted therapies such as sunitinib, tivantinib, brivanib, erlotinib, and linifanib; monoclonal antibody- bevacizumab showed no meaningful improvement in treatment of HCC. However, with improved understanding on the molecular pathophysiology and tumor heterogeneity of HCC, we have made progress in expanding the therapeutic options in advanced HCC. Targeted therapy with lenvatinib, cabozantinib, and regorafenib; monoclonal antibody ramucirumab; immunotherapies nivolumab and pembrolizumab have demonstrated promising results in the clinical trials. The current work outlines the molecular mechanisms and tumorigenesis of HCC, a detailed discussion of the trial results of the approved therapies in HCC, future perspectives and potential options to overcome the challenges of systemic therapy in HCC.
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http://dx.doi.org/10.21037/cco-20-117DOI Listing
February 2021

Survival and prognostic factors in patients with rectal squamous cell carcinoma.

Eur J Surg Oncol 2020 06 4;46(6):1111-1117. Epub 2020 Mar 4.

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: Squamous cell carcinoma (SCC) of the rectum is a rare form of gastrointestinal malignancy. The current knowledge on the natural history is primarily derived from case series.

Methods: Using the National Cancer Data Base (NCDB), we determined the prognostic factors and overall survival (OS) outcomes of rectal SCC reported to NCDB between 2004 and 2015. Kaplan-Meier method and log-rank test were used to perform OS analysis. Propensity matched analysis was undertaken to compare the OS outcomes between rectal and anal SCC.

Results: Of the 3405 cases included in our analysis, 67% were female. Median age at diagnosis was 61 years and did not differ by sex. In stages I-III, patients who received definitive chemoradiation only (108 months) had a better median OS as compared to surgery alone (76 months) (p = 0.012). On multivariate analysis, age <60 years, female sex, and receipt of chemoradiation with or without surgery were independent predictors of better OS in stage I-III disease. Administration of chemoradiation was associated with better OS in stage IV disease. On propensity matched analysis comparing outcomes to anal SCC, OS of rectal SCC was inferior (79 months) to anal SCC (113 months) (p < 0.001), no such difference in OS was noted in the cohorts that received surgery plus post-surgical chemoradiation (p = 0.12).

Conclusion: Outcomes of rectal SCC were dependent upon age, sex, comorbidity score, and therapy received. Chemoradiation alone or in combination with surgery was associated with a better median OS in patients with stages I-III.
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http://dx.doi.org/10.1016/j.ejso.2020.02.039DOI Listing
June 2020

A Novel Clinically Based Staging System for Gallbladder Cancer.

J Natl Compr Canc Netw 2020 02;18(2):151-159

Department of Oncology, Mayo Clinic, Rochester, Minnesota.

Background: Current staging systems for gallbladder cancer (GBC) are primarily based on surgical pathology and therefore are not relevant for unresectable patients and those undergoing neoadjuvant chemotherapy.

Methods: Patients with a confirmed diagnosis of GBC managed at a tertiary referral center (2000-2016) were included. Independent predictors of overall survival (OS) were identified using multivariable analysis (MVA). A combination of these variables was then assessed to identify a set of factors that provided maximal accuracy in predicting OS, and a nomogram and a new staging system were created based on these factors. Harrell's C-statistic was calculated to evaluate the predictive accuracy of the nomogram and staging system.

Results: A total of 528 patients were included in the final analysis. On MVA, factors predictive of poor OS were older age, ECOG performance status, hemoglobin level <9 g/dL, presence of metastases, and alkaline phosphatase (ALP) level >200 U/L. A nomogram and a 4-tier staging system predictive of OS were created using age at diagnosis, ECOG status, tumor size, presence or absence of metastasis, and ALP level. The C-statistic for this novel staging system was 0.71 compared with 0.69 for the TNM staging system (P=.08). In patients who did not undergo surgery, the C-statistics of the novel and TNM staging systems were 0.60 and 0.51, respectively (P<.001).

Conclusions: We created a novel, clinically based staging system for GBC based on nonoperative information at the time of diagnosis that was superior to the TNM staging system in predicting OS in patients who did not undergo surgery, and that performed on par with TNM staging in surgical patients.
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http://dx.doi.org/10.6004/jnccn.2019.7357DOI Listing
February 2020

The Impact of Ramucirumab Treatment on Survival and Quality of Life in Patients with Gastric Cancer.

Cancer Manag Res 2020 7;12:51-57. Epub 2020 Jan 7.

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

Gastric cancer is the sixth most common cancer and is known to be the fifth-leading cause of cancer-related deaths globally in 2018. Systemic therapy remains the only curative option in advanced gastric carcinoma with the primary goal of improving the Health-related Quality of Life (HRQoL) (including palliation of symptoms such as dysphagia) and prolonging overall survival. Recently, ramucirumab is approved by the United States Food and Drug Administration (US-FDA) as a second-line agent either as monotherapy or in combination with paclitaxel in advanced or metastatic gastric and gastro-esophageal junction adenocarcinoma patients who have progressed on prior treatment with fluoropyrimidine or platinum containing chemotherapy. HRQoL is a subjective term that typically constitutes four components - psychological, social, occupational and physical well being. This has been evaluated as secondary endpoint in the pivotal Phase III trials with ramucirumab. HRQoL measurement can potentially provide additional information for clinical decision making beyond that of traditional medical outcomes. The present work is primarily focused on discussing HRQoL in gastric cancer patients and the impact of ramucirumab on the HRQoL in the patients with advanced gastric cancer. We also summarized the studies that evaluated the benefits of systemic therapies on HRQoL in advanced gastric cancer.
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http://dx.doi.org/10.2147/CMAR.S199827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954857PMC
January 2020

Novel staging system using carbohydrate antigen (CA) 19-9 in extra-hepatic cholangiocarcinoma and its implications on overall survival.

Eur J Surg Oncol 2020 05 11;46(5):789-795. Epub 2020 Jan 11.

Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: CA19-9 elevation has shown to be associated with poor prognosis in extrahepatic cholangiocarcinoma (ECCA). However, the role of CA19-9 in staging of ECCA has not been evaluated. We hypothesized that CA19-9 elevation is a marker of aggressive biology in ECCA and that inclusion of CA19-9 in the staging system may improve overall survival (OS) discrimination.

Methods: Patients with ECCA whose CA19-9 levels, irrespective of surgical status, were reported to the National Cancer Database (2004-2015) were included. The patients were classified based on their CA19-9 levels and a new staging system was proposed. Net reclassification improvement (NRI) model was used to assess the predictive improvement in the proposed survival model as compared to AJCC-TNM staging.

Results: Of the 2100 patients included in the study, 626 (32%) and 1474 (68%) had normal and elevated CA19-9 levels (>38 U/ml), respectively. Median OS was lower among patients with elevated CA19-9 level compared to those with CA19-9 level ≤38 U/ml (8.5 vs 16 months, p < 0.01). On multivariate analysis, CA19-9 elevation independently predicted poor prognosis [HR:1.72 (1.46-2.02); p < 0.01] with similar impact as node-positivity, positive resection margins and non-receipt of chemotherapy. We developed a new staging system by incorporating CA19-9 into the 7th edition AJCC TNM staging system. NRI of 46% (95%CI: 39-57%) indicates that the new staging system is substantially effective at re-classifying events at 12 months as compared to AJCC 7th edition.

Conclusion: Elevated CA19-9 was found to be an independent risk factor for mortality in ECCA and its inclusion in the proposed staging system improved OS discrimination.
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http://dx.doi.org/10.1016/j.ejso.2020.01.016DOI Listing
May 2020

Second-line therapies in advanced biliary tract cancers.

Lancet Oncol 2020 01;21(1):e29-e41

Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Biliary tract cancers constitute approximately 3% of gastrointestinal malignancies with poor prognosis. Surgical therapy is the main form of treatment in localised disease; however, for patients with advanced stage or unresectable disease, locoregional and systemic chemotherapeutics are primary treatment options. Although the combination of gemcitabine and cisplatin is a standard regimen of choice, there are no consensus guidelines that help in choosing an appropriate second-line therapy. Substantial progress has been made in the past decade to understand the tumorigenesis and genetic landscape of each biliary tract cancer subtype, which facilitates precision medicine for this cancer. Common genes implicated in biliary tract cancer tumorigenesis include IDH1, IDH2, FGFR1, FGFR2, FGFR3, EPHA2, BAP1, ARID1B, ELF3, PBRM1, PRKACA, PRKACB, HER2, and BRAF. With the advancements in molecular pathogenesis of biliary tract cancer, especially in an era of personalised medicine, many questions are yet to be answered in advanced stages of the cancer: what subset of patients might benefit from second-line drugs, how to choose an optimal second-line regimen, and their effects on quality of life. This Review seeks to summarise available literature and discuss the potential second-line systemic therapy options for advanced biliary tract cancer on the basis of advancements of our knowledge on molecular pathogenesis and tumorigenesis.
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http://dx.doi.org/10.1016/S1470-2045(19)30733-8DOI Listing
January 2020

Evaluating the Safety and Efficacy of Nivolumab in Patients with Advanced Hepatocellular Carcinoma: Evidence to Date.

Onco Targets Ther 2019 28;12:10335-10342. Epub 2019 Nov 28.

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a dismal prognosis, especially when diagnosed at advanced stages. Surgical resection of the primary lesion, liver-directed therapies, and orthotropic liver transplantation are employed in localized disease depending upon the clinical status, underlying liver function, the size, and location of the liver lesions. Systemic therapy plays a critical role in the management of advanced HCC. Sorafenib had remained as the only United States Food and Drug Administration (US-FDA)-approved systemic therapeutic agent for approximately a decade since its approval in 2007, until the advent of immunotherapy and a better understanding of HCC molecular pathogenesis changed the landscape of advanced HCC management. Lenvatinib was approved as an alternative first-line agent, whereas regorafenib, nivolumab, pembrolizumab, ramucirumab, and cabozantinib were approved as second-line agents for HCC patients who could not tolerate or whose disease progressed on sorafenib. Nivolumab and pembrolizumab are the two immunotherapeutic agents that were conditionally approved by the US-FDA based on the encouraging results in Phase I/II trials. This review discusses the potential role of immunotherapy in advanced HCC with a special focus on nivolumab.
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http://dx.doi.org/10.2147/OTT.S214870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886547PMC
November 2019

Red cell transfusion in chronic kidney disease in the United States in the current era of erythropoiesis stimulating agents.

J Nephrol 2020 Apr 28;33(2):267-275. Epub 2019 Nov 28.

Division of Nephrology, Department of Medicine, Georgetown University/Washington Hospital Center, 110 Irving Street, Suite 2A 50, Washington, DC, NW, 20010, USA.

Anemia is a major complication of chronic kidney disease (CKD) that leads to many symptoms of this disease and worsens cardiovascular health. Treatment of this condition was revolutionized three decades ago by the commercial availability of recombinant human erythropoietin which held the promise of completely eliminating the need for red blood cell transfusion (RBCT). Despite specific therapy now available for anemia in CKD, clinical data accumulated in the last 2 decades suggests that there is a continued need for RBCT, which, we surmise, is due to underutilization of Erythropoietin Stimulating Agents (ESA) or clinical settings such as active bleed, bone marrow resistance such as myelofibrosis or infections where ESAs are ineffective. The purpose of this narrative review is to highlight the adverse effects and summarize the current patterns of RBCT use in all stages of CKD while elaborating on the clinical characteristics of patients that increases their risks of transfusion exposure. We discuss, briefly, salient features of the pathophysiology of anemia in CKD and its contemporary therapies while presenting our perspectives on how to optimize transfusion strategies without compromising patient safety.
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http://dx.doi.org/10.1007/s40620-019-00680-5DOI Listing
April 2020

Association between facility volume and mortality of patients with classic Hodgkin lymphoma.

Cancer 2020 02 12;126(4):757-764. Epub 2019 Nov 12.

Division of Hematology, Mayo Clinic, Rochester, Minnesota.

Background: Prior studies in oncology have shown that a higher annual facility patient volume is associated with reduced mortality. Because classic Hodgkin lymphoma is uncommon but highly curable, this study used the National Cancer Database (2003-2014) to analyze whether such a relationship exists for this disease.

Methods: The facilities were classified by quartiles, and random intercepts were used to account for clustering of patients within facilities. A Cox regression model was used to determine the volume-outcome relationship.

Results: There were 47,633 patients with classic Hodgkin lymphoma treated at 1310 facilities. The first quartile (Q1), which included 58.4% of the facilities, treated 3 or fewer patients per year, whereas the fourth quartile (Q4), which included 5.9% of the facilities, treated more than 9 patients per year. Compared with the patients treated at Q4 facilities, those treated at lower quartile facilities had a higher risk of death (hazard ratio for the third quartile [HR], 1.19; 95% confidence interval [CI], 1.1-1.29; HR for the second quartile, 1.28; 95% CI, 1.19-1.38; HR for Q1, 1.29; 95% CI, 1.2-1.39) after adjustments for all other factors (P < .0001). Compared with facilities treating 10 patients per year, facilities treating 40 patients per year had approximately 27% lower overall mortality rates.

Conclusions: Patients with classic Hodgkin lymphoma treated at high-volume centers had lower overall mortality than those treated at lower volume centers. Because this is a highly curable malignancy, such differences may suggest a benefit from referral to higher volume facilities or the emulation of their care models.
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http://dx.doi.org/10.1002/cncr.32584DOI Listing
February 2020

Association Between Hospital Volume, Therapy Types, and Overall Survival in Stage III and IV Cutaneous Malignant Melanoma.

J Natl Compr Canc Netw 2019 11;17(11):1334-1342

Department of Hematology and Oncology, University of Nebraska Medical Center, and.

Background: The advent of targeted therapies and immunomodulatory agents has revolutionized the management of advanced cutaneous malignant melanoma (MMel) by prolonging overall survival. This study evaluated the therapeutic and survival disparities among patients with advanced MMel based on hospital volume using the National Cancer Database (NCDB).

Methods: A retrospective analysis using regression models and Kaplan-Meier estimates was performed from the data obtained from the NCDB on patients with MMel diagnosed in 2004 through 2015.

Results: A total of 40,676 patients with MMel were treated at 1,260 facilities. Multivariable analysis showed that facility volume was an independent predictor of overall survival (P<.0001). Compared with patients treated at high-volume facilities (tertile 3 [T3]), those with stage III disease (n=27,528) treated at intermediate- and low-volume facilities (T2 and T1, respectively) had a significantly higher risk of death (T2 hazard ratio [HR], 1.15; 95% CI, 1.09-1.20; T1 HR, 1.23; 95% CI, 1.17-1.29). Compared with patients treated at T3 facilities, those with stage IV disease (n=13,148) treated at lower-tertile facilities had a significantly higher risk of death (T2 HR, 1.16; 95% CI, 1.10-1.21; T1 HR, 1.29; 95% CI, 1.23-1.36). Further, patients with stage IV disease treated at T3 facilities (vs T1 facilities) were more likely to receive chemotherapy (38% vs 28%) and immunotherapy (23% vs 10%) (P<.0001).

Conclusions: Patients with advanced-stage MMel treated at high-volume facilities had significantly improved survival and were more likely to receive chemotherapy and immunotherapy.
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http://dx.doi.org/10.6004/jnccn.2019.7320DOI Listing
November 2019

Immunotherapy in Hepatocellular Carcinoma: Is There a Light at the End of the Tunnel?

Cancers (Basel) 2019 Jul 30;11(8). Epub 2019 Jul 30.

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic reserve and baseline functional status of the patient. Liver directed therapies such as portal vein embolization (PVE), trans-arterial chemoembolization (TACE), and systemic chemotherapy are employed in non-surgical candidates. Sorafenib was the only approved systemic therapeutic agent for almost a decade until the recent approval of lenvatinib by the United States Food and Drug Administration (FDA) as an alternate first-line agent. Regorafenib, nivolumab, pembrolizumab and cabozantinib are approved by the FDA as second-line agents in patients who failed or could not tolerate sorafenib. Ramucirumab was recently FDA approved for the subset of patients that have high alfa-fetoprotein levels (>400 ng/mL). A better understanding of tumorigenesis and encouraging clinical trial results that evaluated immune-checkpoint inhibitors opened doors for immunotherapy in HCC. Immune checkpoint inhibitors have demonstrated a prolonged median overall and progression-free survival in a subset of patients with HCC. On-going translational and clinical research will hopefully provide us with a better understanding of tumor markers, genetic aberrations and other factors that determine the immunotherapy response in HCC. In this review, we sought to summarize the potential role and future directions of immunotherapy in the management of HCC.
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http://dx.doi.org/10.3390/cancers11081078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721326PMC
July 2019

FGFR2 genomic aberrations: Achilles heel in the management of advanced cholangiocarcinoma.

Cancer Treat Rev 2019 Aug 22;78:1-7. Epub 2019 Jun 22.

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, United States. Electronic address:

Cholangiocarcinoma is the most common aggressive biliary tract malignancy with dismal prognosis. Though surgical resection of the primary tumors yields better prognosis, majority of patients present at advanced, inoperable stages rendering systemic therapy as the only option. A significant progress has been made in understanding the cholangiocarcinoma tumorigenesis and molecular markers over the last decade, which opens doors to precision medicine in this dismal cancer. Intrahepatic cholangiocarcinomas are most likely to harbor mutations in isocitrate dehydrogenase genes (IDH1, IDH2), fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3), Eph receptor 2 (EPHA2), and BAP1 (gene involved in chromatin remodeling) genes, whereas ARID1B, ELF3, PBRM1, cAMP dependent protein kinase (PRKACA, and PRKACB) genetic mutations were implicated more commonly in distal and perihilar subtypes. Genomic studies have shown that FGFR2 aberrations are implicated in approximately 15% of intrahepatic cholangiocarcinomas, which make FGFR2 aberrations (Achilles heel) as potential novel targets in the management of cholangiocarcinoma. The current review comprehensively focuses on the role of FGFR2 inhibition either alone or in combination with other targeted therapy that act on down-stream and alternate kinase pathways in cholangiocarcinoma.
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http://dx.doi.org/10.1016/j.ctrv.2019.06.003DOI Listing
August 2019

Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma.

J Gastrointest Oncol 2019 Jun;10(3):554-561

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

Background: Clinicopathological features and the outcomes of patients with fibrolamellar hepatocellular carcinoma (FLHCC) are not clearly defined.

Methods: Data were collected by retrospective chart review on 42 patients with FLHCC treated between 1990 and 2017 at Mayo Clinic.

Results: Of 42 patients (median age at diagnosis 22 years), 10 patients (23.8%) had stage I disease and 32 patients (76.2%) had stage II to IVB disease. All 10 patients with stage I disease and 21 of 32 patients with stage II-IVB disease underwent resection at presentation. In stage I patient group, 6 patients experienced recurrence with a median time to recurrence of 30.5 months and a 5-year overall survival (OS) of 86%. Patients with stage II to IVB disease who underwent resection (n=21) upfront had a median OS of 32.5 months and 5-year OS of 44%. In the upfront surgery group, 71% of patients experienced recurrence. The median OS of patients with unresectable disease (n=11) was 10 months. Four out of nine patients treated with sorafenib had stable disease and one patient with programmed cell death ligand-1 (PD-L1) expressing tumor had a near complete response after 2 months of therapy with nivolumab.

Conclusions: In FLHCC, surgical resection was associated with prolonged OS; although most patients had a disease recurrence regardless of disease stage and resection margin status. The response to kinase inhibitor, sorafenib, was variable. In select cases, therapy with a checkpoint inhibitor may provide a viable treatment option.
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http://dx.doi.org/10.21037/jgo.2019.01.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534717PMC
June 2019

Survival and prognostic factors in patients with pancreatic squamous cell carcinoma.

Eur J Surg Oncol 2019 Sep 15;45(9):1700-1705. Epub 2019 May 15.

Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Objectives: Squamous cell carcinoma (SCC) of pancreas is rare entity with poorly defined prognostic factors and therapeutic outcomes. We sought to determine the overall survival (OS) and prognostic factors of patients with pancreatic SCC using National Cancer Database (NCDB) (2004-15).

Methods: Kaplan-Meier method and log-rank test were used to perform OS analysis. Propensity-matched analysis was used to compare the OS of pancreatic SCC and adenocarcinoma.

Results: Of the 515 cases included in our analysis, 46% were female. Approximately half of the cohort (48%) received chemotherapy or radiation therapy or both. Twenty six percent (33/125) of stage I and II disease (localized disease), 11% (8/72) of stage III, and 2% (6/318) of stage IV disease underwent surgical resection of the primary tumor. Median OS for the entire cohort was 4 months and was significantly higher in patients who underwent surgical resection of the primary tumor (17 vs 4 months, p < 0.001). In localized disease, adjuvant chemotherapy was not associated with improved OS in early stage disease (20 vs 24 months, p = 0.60). Stage IV patients treated with chemotherapy had a better OS than those without (5 vs 2 months, p < 0.0001). Propensity matched analysis demonstrated no significant differences in median OS between pancreatic adenocarcinoma (4.8 months) and SCC (4 months, p = 0.09).

Conclusions: Pancreatic SCC had a diverse OS that varied significantly according to increasing age (>70 years) and stage of the disease at presentation (p < 0.01). Surgical resection of primary tumor was associated with longer OS in stages I-II, whereas chemotherapy was associated with longer OS in stage IV disease.
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http://dx.doi.org/10.1016/j.ejso.2019.05.011DOI Listing
September 2019

Incidence, Clinical Features, and Outcomes of Langerhans Cell Sarcoma in the United States.

Clin Lymphoma Myeloma Leuk 2019 07 1;19(7):441-446. Epub 2019 Apr 1.

Division of Hematology, Mayo Clinic, Rochester, MN. Electronic address:

Background: Limited knowledge exists on the incidence, treatment patterns, and long-term outcomes of Langerhans cell sarcoma (LCS) in the United States.

Patients And Methods: We performed a retrospective study of LCS patients diagnosed between 2001 and 2014 using the Surveillance, Epidemiology, and End Results (SEER) and National Cancer Data Base (NCDB) databases. Incidence was calculated from SEER, and treatment patterns and outcomes were calculated from NCDB.

Results: A total of 25 and 52 cases of LCS were reported to SEER and NCDB, respectively. The overall incidence of the disease was 0.2 per 10,000,000 and did not differ by race (P = .56) or sex (P = .33). The median age at diagnosis was 62 (range, 19-90) years. Of the 52 patients from NCDB, 20 (39%) received chemotherapy as first-line therapy, 24 (46%) received surgery, and 15 (29%) received radiotherapy. The 1-year overall survival (OS) rate was 62%, and the median OS was 19 months. After censoring the patients with bone marrow and reticuloendothelial system involvement, no significant difference in OS was noted between the patients who were managed with or without surgery (P = .75). Postsurgical radiation or chemotherapy were not associated with improvement in median OS (P = .25). Patients who were managed with radiotherapy had a better OS compared to those who received no radiotherapy (P = .03).

Conclusion: This dual-national registry study shows that LCS is extremely rare and has a poor prognosis. Radiotherapy may offer a survival advantage to patients with locoregional disease without bone marrow and reticuloendothelial system involvement.
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http://dx.doi.org/10.1016/j.clml.2019.03.026DOI Listing
July 2019

Association Between Treatment Facility Volume, Therapy Types, and Overall Survival in Patients With Stage IIIA Non-Small Cell Lung Cancer.

J Natl Compr Canc Netw 2019 03;17(3):229-236

Department of Hematology and Oncology, VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska.

Background: There is significant heterogeneity in the treatment of stage IIIA non-small cell lung cancer (NSCLC). This study evaluated the therapeutic and survival disparities in patients with stage IIIA NSCLC based on the facility volume using the National Cancer Database.

Methods: Patients with stage IIIA NSCLC diagnosed from 2004 through 2015 were included. Facilities were classified by tertiles based on mean patients treated per year, with low-volume facilities treating ≤8 patients, intermediate-volume treating 9 to 14 patients, and high-volume treating ≥15 patients. Cox multivariate analysis was used to determine the volume-outcome relationship.

Results: Analysis included 83,673 patients treated at 1,319 facilities. Compared with patients treated at low-volume facilities, those treated at high-volume centers were more likely to be treated with surgical (25% vs 18%) and trimodality (12% vs 9%) therapies. In multivariate analysis, facility volume was independently associated with all-cause mortality (P<.0001). Median overall survival by facility volume was 15, 16, and 19 months for low-, intermediate-, and high-volume facilities, respectively (P<.001). Compared with patients treated at high-volume facilities, those treated at intermediate- and low-volume facilities had a significantly higher risk of death (hazard ratio, 1.09 [95% CI, 1.07-1.11] and 1.11 [95% CI, 1.09-1.13], respectively).

Conclusions: Patients treated for stage IIIA NSCLC at high-volume facilities were more likely to receive surgical and trimodality therapies and had a significant improvement in survival.
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http://dx.doi.org/10.6004/jnccn.2018.7086DOI Listing
March 2019

Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Oncologist 2019 04 6;24(4):537-548. Epub 2019 Mar 6.

South Carolina Center of Economic Excellence for Medication Safety, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.
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http://dx.doi.org/10.1634/theoncologist.2018-0341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459242PMC
April 2019

Type 2M Von Willebrand Disease: A Case Report.

Cureus 2018 Aug 6;10(8):e3112. Epub 2018 Aug 6.

Internal Medicine, University of South Carolina, Columbia, USA.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is divided into three types, namely type 1, type 2 (2A, 2B, 2M, 2N), and type 3. We report a case of a 24-year-old Caucasian woman with a rare variety of type 2M VWD. Her von Willebrand factor versus antigen ratio was 0.44 (normal ratio is greater than 0.7) . She was asymptomatic and hence not treated but followed up regularly. VWD is not life-threatening when treated timely.
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http://dx.doi.org/10.7759/cureus.3112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175265PMC
August 2018

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

Invest New Drugs 2019 06 9;37(3):473-481. Epub 2018 Oct 9.

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

Background 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 3 + 3 dose escalation design with cohort expansion to evaluate 2 dose levels of enzalutamide: 80 mg and 160 mg/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 19.6 ± 4.7 h. Conclusions Enzalutamide 160 mg 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.
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http://dx.doi.org/10.1007/s10637-018-0676-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771270PMC
June 2019

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

HPB (Oxford) 2019 03 25;21(3):379-386. Epub 2018 Sep 25.

Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: To determine the association between the number of patients with intra-hepatic cholangiocarcinoma (IHCC) treated annually at a treatment facility (volume) and overall survival (outcome).

Methods: Patients 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.

Results: There were 11,344 IHCC patients treated at 1106 facilities. On multivariable analysis, facility volume was independently associated with all-cause mortality (p < 0.001). The unadjusted median OS by facility volume was: T1: 5 months (m), T2: 8.1 m, and T3: 13.1 m (p < 0.001). 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.

Conclusion: IHCC 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.
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http://dx.doi.org/10.1016/j.hpb.2018.08.004DOI Listing
March 2019

Upper Limb Phlegmasia Cerulea Dolens Secondary to Heparin-induced Thrombocytopenia Leading to Gangrene.

Cureus 2018 Jun 21;10(6):e2853. Epub 2018 Jun 21.

Hematology and Oncology, University of Nebraska, Omaha, USA.

We present a case of a dialysis-dependent end-stage renal disease patient who originally presented with sepsis and later developed heparin-induced thrombocytopenia-related upper extremity deep venous thrombosis that rapidly progressed to phlegmasia. Argatroban, a direct thrombin inhibitor, was initiated without delay. Argatroban restored the venous patency completely but did not reverse his two gangrenous fingers. The patient finally underwent digital amputation. The management of this uncommon, but life-threatening, situation of upper limb phlegmasia cerulea dolens secondary to heparin-induced thrombocytopenia leading to gangrene is discussed in this case report.
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http://dx.doi.org/10.7759/cureus.2853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104908PMC
June 2018

Novel targeted treatment options for advanced cholangiocarcinoma.

Expert Opin Investig Drugs 2018 09 30;27(9):709-720. Epub 2018 Aug 30.

d Department of Gastrointestinal Oncology , H. Lee Moffitt Cancer Center , Tampa , FL , USA.

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.
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http://dx.doi.org/10.1080/13543784.2018.1512581DOI Listing
September 2018

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

Lung Cancer 2018 08 19;122:214-219. Epub 2018 Jun 19.

Division of Hematology, Mayo Clinic, Rochester, MN, United States; Robert D. & Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Prior 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.

Patients And Methods: This 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.

Results: There 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 (p < .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]).

Conclusions: Patients 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.
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http://dx.doi.org/10.1016/j.lungcan.2018.06.025DOI Listing
August 2018