Publications by authors named "Daniel Ahn"

78 Publications

Mismatch Repair (MMR) Gene Alteration and BRAF V600E Mutation Are Potential Predictive Biomarkers of Immune Checkpoint Inhibitors in MMR-Deficient Colorectal Cancer.

Oncologist 2021 Feb 25. Epub 2021 Feb 25.

Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia, USA.

Background: Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC.

Materials And Methods: Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test.

Results: A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001).

Conclusion: BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings.

Implications For Practice: The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.
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http://dx.doi.org/10.1002/onco.13741DOI Listing
February 2021

Advance care planning among African American patients on haemodialysis and their end-of-life care preferences.

J Ren Care 2021 Feb 22. Epub 2021 Feb 22.

General Internal Medicine, University of Chicago Medicine, Section of Nephrology, Chicago, Illinois, USA.

Background: African Americans in the general population have been shown to be less likely than White ethnic groups to participate in advance care planning; however, advance care planning in the population receiving dialysis has not been well explored.

Objective: We examined the prevalence of African American patients receiving haemodialysis' advance care planning discussions, and whether advance care planning impacts end-of-life care preferences.

Design: In-person interviewer-administered surveys of African American patients receiving in-centre haemodialysis.

Setting/participants: About 101 participants at three large dialysis organisation units in Chicago.

Outcomes: Self-reported advance care planning and preferences for life-extending treatments at end-of-life.

Results: Most patients (69%) report no advance care planning discussions with their healthcare providers. Nearly all patients (92%) without prior advance care planning reported their healthcare providers approached them about advance care planning. While the majority of patients indicated preference for aggressive life-extending care, prior conversations about end-of-life care wishes either with family members or a healthcare provider significantly decreased patients' likelihood of choosing aggressive life-extending care across three scenarios (all p < 0.05). Significantly more patients reported that common end-of-life scenarios related to increased dependence/disability were "not worth living through" compared with those associated with increased burden on family, decreased cognitive function, and severe pain/discomfort.

Conclusion: African Americans with end-stage renal disease need more frequent, culturally-sensitive advance care planning discussions. Despite a preference for aggressive life-sustaining treatments, individuals with prior advance care planning discussions were significantly less likely to support aggressive end-of-life care. End-of-life care discussions that focus on the impact of life-extending care on patients' independence could be more concordant with the values and priorities of the African American patients.
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http://dx.doi.org/10.1111/jorc.12368DOI Listing
February 2021

Preemptive Versus Reactive Topical Clobetasol for Regorafenib-Induced Hand-Foot Reactions: A Preplanned Analysis of the ReDOS Trial.

Oncologist 2021 Feb 18. Epub 2021 Feb 18.

Mayo Clinic, Scottsdale, Arizona, USA.

Background: Hand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation.

Materials And Methods: The Regorafenib Dose Optimization Study (ReDOS), a four-arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib.

Results: Sixty-one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p = .03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p = .35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p = .02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p = .12). Patient-reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol-induced adverse events were reported.

Conclusion: Preemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort.

Implications For Practice: Regorafenib causes hand-foot skin reactions. Preemptive clobetasol, a high-potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients.
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http://dx.doi.org/10.1002/onco.13730DOI Listing
February 2021

Circulating Tumor DNA-Based Testing and Actionable Findings in Patients with Advanced and Metastatic Pancreatic Adenocarcinoma.

Oncologist 2021 Feb 8. Epub 2021 Feb 8.

Mayo Clinic, Scottsdale, Arizona, USA.

Purpose: Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings.

Materials And Methods: From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation.

Results: All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease.

Conclusion: Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis.

Implications For Practice: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.
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http://dx.doi.org/10.1002/onco.13717DOI Listing
February 2021

Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-analysis.

JAMA Oncol 2020 12 10;6(12):e204930. Epub 2020 Dec 10.

Mayo Clinic Cancer Center, Phoenix, Arizona.

Importance: The treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials.

Objective: To evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy.

Data Sources: We searched various databases for abstracts and full-text articles published from database inception through March 2020.

Study Selection: We included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting.

Data Extraction And Synthesis: The reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model.

Main Outcomes And Measures: Outcomes of interest included overall (OS) and progression-free survival (PFS).

Findings: Fourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others.

Conclusions And Relevance: This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.
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http://dx.doi.org/10.1001/jamaoncol.2020.4930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582230PMC
December 2020

Acute Toxicities and Short-Term Patient Outcomes After Intensity-Modulated Proton Beam Radiation Therapy or Intensity-Modulated Photon Radiation Therapy for Esophageal Carcinoma: A Mayo Clinic Experience.

Adv Radiat Oncol 2020 Sep-Oct;5(5):871-879. Epub 2020 May 19.

Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona.

Purpose: Intensity modulated proton beam radiation therapy (IMPT) has a clinically significant dosimetric advantage over intensity modulated photon radiation therapy (IMRT) for the treatment of patients with esophageal cancer, particularly for sparing the heart and lungs. We compared acute radiation therapy-related toxicities and short-term clinical outcomes of patients with esophageal cancer who received treatment with IMPT or IMRT.

Methods And Materials: We retrospectively reviewed the electronic health records of consecutive adult patients with esophageal cancer who underwent concurrent chemoradiotherapy with IMPT or IMRT in the definitive or neoadjuvant setting from January 1, 2014, through June 30, 2018, with additional follow-up data collected through January 31, 2019. Treatment-related toxicities were evaluated per the Common Terminology Criteria for Adverse Events, version 4. Survival outcomes were estimated with the Kaplan-Meier method.

Results: A total of 64 patients (32 per group) were included (median follow-up time: 10 months for IMPT patients vs 14 months for IMRT patients). The most common radiation therapy regimen was 45 Gy in 25 fractions, and 80% of patients received a simultaneous integrated boost to a median cumulative dose of 50 Gy. Similar numbers of IMPT patients (n = 15; 47%) and IMRT patients (n = 18; 56%) underwent surgery ( = .07), with no difference in pathologic complete response rates (IMPT: n = 5; 33% vs IMRT: n = 7; 39%; = .14). At 1 year, the clinical outcomes also were similar for IMPT and IMRT patients, respectively. Local control was 92% versus 84% ( = .87), locoregional control 92% versus 80% ( = .76), distant metastasis-free survival 87% versus 65% ( = .08), progression-free survival 71% versus 45% ( = .15), and overall survival 74% versus 71% ( = .62). The rate of acute treatment-related grade 3 toxicity was similar between the groups ( = .71).

Conclusions: In our early experience, IMPT is a safe and effective treatment when administered as part of definitive or trimodality therapy. Longer follow-up is required to evaluate the effectiveness of IMPT.
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http://dx.doi.org/10.1016/j.adro.2020.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557123PMC
May 2020

Homologous Recombination Repair Defect May Predict Treatment Response to Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors.

Oncologist 2020 08 1;25(8):e1246-e1248. Epub 2020 Jul 1.

Mayo Clinic, Phoenix, Arizona, USA.

Lutetium-177-dotatate ( Lu-dotatate), a form of peptide receptor radionuclide therapy, was approved by the U.S. Food and Drug Administration for the treatment of advanced somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs) in 2018 based on the promising results of the NETTER-1 trial for grade 1-2 midgut NETs. Here, we present a patient with a grade 3 pancreatic neuroendocrine tumor and BRCA1 germline mutation who had a significant response to Lu-dotatate.
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http://dx.doi.org/10.1634/theoncologist.2020-0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418337PMC
August 2020

The Role of Immune Checkpoint Inhibitors in Colorectal Adenocarcinoma.

BioDrugs 2020 Jun;34(3):349-362

Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA.

Over the past decade, immune checkpoint inhibitors (ICI) have proven to be promising agents in a number of solid tumor malignancies. Pembrolizumab and nivolumab are ICIs that target programmed cell death protein 1 and both have been approved by the US Food and Drug Administration for the treatment of microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) colorectal cancer (CRC). In MSI-H/dMMR CRC, these agents were found to have considerable antitumor activity and are now used in the treatment of this disease. However, MSI-H/dMMR tumors account for only 5% of metastatic CRC and the remaining patients are identified as being microsatellite stable/DNA mismatch repair proficient (MSS/pMMR). In MSS/pMMR CRC, ICIs were found to have no antitumor activity and they are not currently used in the treatment of the disease. However, ongoing research is expanding our knowledge of how the human immune system interacts with cancer cells. Identifying mechanisms to improve our immune response to MSS/pMMR CRC is of utmost importance. In this review, we discuss available clinical data and the emerging role of immune-based strategies to overcome the resistance to ICI therapy in the treatment of MSS/pMMR CRC.
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http://dx.doi.org/10.1007/s40259-020-00420-3DOI Listing
June 2020

Biliary tract cancer and genomic alterations in homologous recombinant deficiency: exploiting synthetic lethality with PARP inhibitors.

Chin Clin Oncol 2020 Feb 20;9(1). Epub 2020 Feb 20.

Mayo Clinic, Phoenix, AZ, USA.

Biliary tract cancers (BTC) are a group of rare, chemoresistant solid tumor malignancies that arise from the bile ducts. BTC are typically associated with poor outcomes. Most patients present with advanced disease, where treatment is palliative with platinum based cytotoxic therapy. Response to chemotherapy is variable with limited duration of response. A subset of patients that will receive durable and meaningful responses to platinum-based chemotherapy is deemed to be platinum sensitive. The availability and implementation of next-generation sequencing allowed genomic profiling of BTC, which have identified potential targetable somatic genetic aberrations, which include kinases (FGFR, BRAF, ALK, ERBB2), oncogenes (IDH1/2, CCND1) and tumor suppressor genes, including germline or somatic mutations involved in DNA damage response (DDR) genes. These genes include, but are not limited to: ATM, ATR, BRCA1/2, RAD51, PALB2, PTEN, FANC, NBN, EMSY, MRE11, ARID1A. In BTC, alterations in DDR genes are identified in up to 20% of patients, with a higher proportion identified in those with extrahepatic cholangiocarcinoma. Patients harboring mutations exhibit varying patterns of clinical behavior and response to therapy. The presence of these mutations typically predicts for susceptibility to DNA damaging chemotherapy, such as platinum agents.
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http://dx.doi.org/10.21037/cco.2020.02.02DOI Listing
February 2020

Real-World Dosing Patterns and Outcomes of Patients With Metastatic Pancreatic Cancer Treated With a Liposomal Irinotecan Regimen in the United States.

Pancreas 2020 02;49(2):193-200

Division of Medical Oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, AZ.

Objectives: Liposomal irinotecan (nal-IRI) is a topoisomerase inhibitor proven to improve survival in metastatic pancreatic cancer (mPC). This study describes real-world characteristics of patients treated with nal-IRI for mPC.

Methods: Patients 18 years or older diagnosed with stage IV mPC and treated with nal-IRI were selected retrospectively from a deidentified electronic health record database of more than 2 million US cancer patients. Demographics, clinical and dosing characteristics, and treatment outcomes were collected.

Results: Of 257 total patients, 145 (57%) received nal-IRI as first- or second-line therapy. Median nal-IRI treatment duration was 51 days, longer when nal-IRI was used as first/second versus as third-line therapy or later (62 vs 44.5 days). Seventy patients (27.2%) experienced dose modification. Median time to treatment discontinuation was 2.3 versus 1.6 months for first-/second- versus third-line therapy or later, respectively. Median overall survival from nal-IRI initiation was 5.6 versus 4.1 months for first-/second- versus third-line therapy or later, respectively. Prior irinotecan treatment, baseline serum albumin less than 40 g/L, and baseline neutrophil-to-lymphocyte ratio greater than 5 were associated with reduced overall survival.

Conclusions: This is the first large US study of real-world US mPC patients treated with nal-IRI. These results, comparable to the NAPOLI-1 trial, can help inform future studies and the efficacy of nal-IRI in mPC therapy.
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http://dx.doi.org/10.1097/MPA.0000000000001479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028474PMC
February 2020

The Role of Maintenance Strategies in Metastatic Colorectal Cancer: A Systematic Review and Network Meta-analysis of Randomized Clinical Trials.

JAMA Oncol 2020 03 12;6(3):e194489. Epub 2020 Mar 12.

Division of Hematology/Oncology, Mayo Clinic, Phoenix, Arizona.

Importance: In metastatic colorectal cancer, induction combination chemotherapy with a targeted agent is considered the mainstay of treatment. Multiple randomized clinical trials have examined different strategies of continuing cytotoxic therapy until progression compared with a period of either observation or the use of various maintenance agents. However, those randomized clinical trials have shown inconsistent efficacy results that make it challenging to draw any conclusion on which strategy is preferred. Therefore, a network meta-analysis is helpful to compare different agents across randomized clinical trials.

Objective: To evaluate the comparative effectiveness of different treatment strategies for patients with metastatic colorectal cancer.

Evidence Review: MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for randomized clinical trials evaluating different strategies for patients with previously untreated metastatic colorectal cancer. Trials of interest included those including patients with metastatic colorectal cancer who were treated with an initial period of cytotoxic chemotherapy (with or without a biologic) and then switched to one of the following strategies: observation; maintenance with bevacizumab (Bev), fluoropyrimidine (FP), or both (FP + Bev); or continuing the induction regimen until progression. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian and Laird random-effects model. Network meta-analysis was conducted using a random-effects consistency model to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Initial analysis was performed on December 18, 2018. An updated search was performed in April 2019, and no additional studies were added.

Findings: Twelve trials at low risk of bias (5540 patients; age range, 23-85 years; 64.4 % male) were included. Network meta-analysis showed no benefit of continuing full cytotoxic chemotherapy until progression vs observation in terms of PFS (hazard ratio, 0.71; 95% CI, 0.46-1.09) and OS (hazard ratio, 0.95; 95% CI, 0.85-1.07). Compared with observation, maintenance therapy showed a PFS benefit (hazard ratio, 0.58; 95% CI, 0.43-0.77) but not an OS benefit (hazard ratio, 0.91; 95% CI, 0.83-1.01). All maintenance strategies (FP, FP + Bev, and Bev) showed significant improvement in PFS vs observation. On SUCRA analysis, maintenance treatment (FP or FP + Bev) had the highest likelihood of achieving improved PFS (67.1% for FP, 99.8% for FP + Bev, and 36.5% for Bev) and OS (81.3% for FP, 73.2% for FP + Bev, and 32.6% for Bev).

Conclusions And Relevance: For patients with metastatic colorectal cancer, there is no benefit to continuing the full induction regimen until progression, without a period of either observation or maintenance treatment. A maintenance strategy with a fluoropyrimidine, with or without the addition of bevacizumab, is preferred. However, given the lack of a clear OS benefit, shared decision-making should include observation as an acceptable alternative.
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http://dx.doi.org/10.1001/jamaoncol.2019.4489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990730PMC
March 2020

Phase II Trial of Trifluridine/Tipiracil in Patients with Advanced, Refractory Biliary Tract Carcinoma.

Oncologist 2020 05 11;25(5):380-e763. Epub 2019 Dec 11.

Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Lessons Learned: Trifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5-fluorouracil refractory tumors. FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first-line therapy.

Background: Patients with advanced biliary tract carcinoma (BTC) refractory to first-line therapy lack an established second-line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine-sensitive and -resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC.

Methods: Patients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression-free survival (PFS), and toxicity.

Results: Of 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%-53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2-5.8 months) and 6.1 (95% CI, 4.4-11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted.

Conclusion: FTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.
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http://dx.doi.org/10.1634/theoncologist.2019-0874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216452PMC
May 2020

ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5.

Nat Chem Biol 2019 12 18;15(12):1232-1240. Epub 2019 Nov 18.

Department of Chemistry, The University of Chicago, Chicago, IL, USA.

S-Palmitoylation is a reversible lipid post-translational modification that has been observed on mitochondrial proteins, but both the regulation and functional consequences of mitochondrial S-palmitoylation are poorly understood. Here, we show that perturbing the 'erasers' of S-palmitoylation, acyl protein thioesterases (APTs), with either pan-active inhibitors or a mitochondrial-targeted APT inhibitor, diminishes the antioxidant buffering capacity of mitochondria. Surprisingly, this effect was not mediated by the only known mitochondrial APT, but rather by a resident mitochondrial protein with no known endogenous function, ABHD10. We show that ABHD10 is a member of the APT family of regulatory proteins and identify peroxiredoxin-5 (PRDX5), a key antioxidant protein, as a target of ABHD10 S-depalmitoylase activity. We then find that ABHD10 regulates the S-palmitoylation status of the nucleophilic active site residue of PRDX5, providing a direct mechanistic connection between ABHD10-mediated S-depalmitoylation of PRDX5 and its antioxidant capacity.
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http://dx.doi.org/10.1038/s41589-019-0399-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871660PMC
December 2019

AJCC 8th edition staging system for pathologically versus clinically staged intrahepatic cholangiocarcinoma (iCCA): ready for prime time?

Chin Clin Oncol 2019 Oct 6;8(S1):S19. Epub 2019 May 6.

Department of Internal Medicine, Division of Hematology/Medical Oncology, Mayo Clinic, Phoenix, AZ, USA.

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http://dx.doi.org/10.21037/cco.2019.04.04DOI Listing
October 2019

Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.

Lancet Oncol 2019 08 28;20(8):1070-1082. Epub 2019 Jun 28.

West Cancer Center, Memphis, TN, USA.

Background: Regorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules.

Methods: In this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov, number NCT02368886. This study is fully accrued but remains active.

Findings: Between June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98-1·57). The primary endpoint was met: 23 (43%, 95% CI 29-56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15-37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3-4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction).

Interpretation: The dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data.

Funding: Bayer HealthCare Pharmaceuticals.
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http://dx.doi.org/10.1016/S1470-2045(19)30272-4DOI Listing
August 2019

A Systematic Review and Network Meta-Analysis of Regorafenib and TAS-102 in Refractory Metastatic Colorectal Cancer.

Oncologist 2019 09 4;24(9):1174-1179. Epub 2019 Jun 4.

Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA

Background: Regorafenib at different dosing strategies and TAS-102 are treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these different strategies.

Materials And Methods: We searched different databases for randomized controlled trials evaluating TAS-102 or regorafenib in patients with refractory mCRC who failed prior oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White's multivariate meta-regression to pool evidence from direct and indirect comparisons.

Results: Six trials at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to best-supportive care (BSC) in terms of PFS (Rego 160: hazard ratio [HR], 0.4; 95% confidence ratio [CI], 0.26-0.63; TAS-102: HR, 0.46 CI, 0.40-0.52) and OS (Rego 160: HR, 0.67; CI, 0.48-0.93; TAS-102: HR, 0.67; CI, 0.57-0.80). Network analysis showed no statistically difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR, 0.44; CI, 0.23-0.84) and PFS (HR, 0.37; CI, 0.21-0.66). Rego 80+ was associated with statistically nonsignificant improvement in OS and PFS compared with TAS-102 and Rego 160.

Conclusion: Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102.

Implications For Practice: Regorafenib at a dose of 160 mg and TAS-102 appear to have similar efficacy in patients with refractory metastatic colorectal cancer. Regorafenib with a dose escalation strategy is superior to best-supportive care. Given its tolerability and the observed trend in survival benefit compared with regorafenib 160, dose escalation strategy of regorafenib (80+) may be the preferred option in this setting.
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http://dx.doi.org/10.1634/theoncologist.2019-0189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738316PMC
September 2019

Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial.

JAMA Oncol 2019 Jun;5(6):824-830

Department of Medical Oncology, Mayo Clinic, Phoenix, Arizona.

Importance: Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed.

Objective: To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer.

Design, Setting, And Participants: This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017.

Interventions: Patients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients.

Main Outcomes And Measures: The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population.

Results: Of 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment.

Conclusions And Relevance: Treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial.

Trial Registration: ClinicalTrials.gov identifier: NCT02392637.
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http://dx.doi.org/10.1001/jamaoncol.2019.0270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567834PMC
June 2019

Watch and Wait in Rectal Cancer: Who's In and Who's Out?

J Oncol Pract 2019 03;15(3):133-134

1 Mayo Clinic Arizona, Phoenix, AZ.

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http://dx.doi.org/10.1200/JOP.19.00071DOI Listing
March 2019

Therapeutic Targeting Strategies of Cancer Stem Cells in Gastrointestinal Malignancies.

Biomedicines 2019 Mar 10;7(1). Epub 2019 Mar 10.

Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ 85054, USA.

Cancer stem cells (CSCs) are thought to be a distinct population of cells within a tumor mass that are capable of asymmetric division and known to have chemoresistant characteristics. The description and identification of CSC models in cancer growth and recurrence has inspired the design of novel treatment strategies to overcome treatment resistance by targeting both CSCs and non-CSC tumor cells. Several cellular signaling pathways have been described as playing a role in the induction and maintenance of stemness in CSCs, such as the Wnt/β-catenin, Notch, STAT3, and Hedgehog pathways. In this review, we aim to review some of the ongoing CSC therapeutic targeting strategies in gastrointestinal malignancies.
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http://dx.doi.org/10.3390/biomedicines7010017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466109PMC
March 2019

Phase I Immunotherapy Trial with Two Chimeric HER-2 B-Cell Peptide Vaccines Emulsified in Montanide ISA 720VG and Nor-MDP Adjuvant in Patients with Advanced Solid Tumors.

Clin Cancer Res 2019 06 25;25(12):3495-3507. Epub 2019 Feb 25.

Arthur G. James Cancer Hospital/Comprehensive Cancer Center, Columbus, Ohio.

Purpose: This first-in-human phase I study (NCT01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines.

Patients And Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a "promiscuous T-cell epitope." Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks.

Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease.

Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159438PMC
June 2019

CanStem111P trial: a Phase III study of napabucasin plus nab-paclitaxel with gemcitabine.

Future Oncol 2019 Apr 15;15(12):1295-1302. Epub 2019 Feb 15.

Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ 85054, USA.

Napabucasin (also known as BBI-608 or BBI608) is an investigational, oral agent hypothesized to inhibit multiple oncogenic pathways. In this article, we describe the design and rationale for the CanStem111P clinical trial, a multicenter, randomized, open-label, Phase III study designed to determine the efficacy and safety of combining napabucasin with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma (NCT02993731). Patients were randomized in a 1:1 fashion to receive weekly gemcitabine and nab-paclitaxel with or without napabucasin. The results of this study will help define the role of this novel agent in the management of advanced pancreatic cancer.
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http://dx.doi.org/10.2217/fon-2018-0903DOI Listing
April 2019

Circulating interleukin-6 is associated with disease progression, but not cachexia in pancreatic cancer.

Pancreatology 2019 Jan 10;19(1):80-87. Epub 2018 Nov 10.

Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

Background: Cachexia is a wasting syndrome characterized by involuntary loss of >5% body weight due to depletion of adipose and skeletal muscle mass. In cancer, the pro-inflammatory cytokine interleukin-6 (IL-6) is considered a mediator of cachexia and a potential biomarker, but the relationship between IL-6, weight loss, and cancer stage is unknown. In this study we sought to evaluate IL-6 as a biomarker of cancer cachexia while accounting for disease progression.

Methods: We retrospectively studied 136 subjects with biopsy-proven pancreatic ductal adenocarcinoma (PDAC), considering the high prevalence of cachexia is this population. Clinical data were abstracted from subjects in all cancer stages, and plasma IL-6 levels were measured using a multiplex array and a more sensitive ELISA. Data were evaluated with univariate comparisons, including Kaplan-Meier survival curves, and multivariate Cox survival models.

Results: On multiplex, a total of 43 (31.4%) subjects had detectable levels of plasma IL-6, while by ELISA all subjects had detectable IL-6 levels. We found that increased plasma IL-6 levels, defined as detectable for multiplex and greater than median for ELISA, were not associated with weight loss at diagnosis, but rather with the presence of metastasis (p < 0.001 for multiplex and p = 0.007 for ELISA). Further, while >5% weight loss was not associated with worse survival, increased plasma IL-6 by either methodology was.

Conclusion: Circulating IL-6 levels do not correlate with cachexia (when defined by weight loss), but rather with advanced cancer stage. This suggests that IL-6 may mediate wasting, but should not be considered a diagnostic biomarker for PDAC-induced cachexia.
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http://dx.doi.org/10.1016/j.pan.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613190PMC
January 2019

Terrorism, geopolitics, and oil security: Using remote sensing to estimate oil production of the Islamic State.

Energy Res Soc Sci 2018 Oct 16;44:411-418. Epub 2018 Apr 16.

Payne Institute, Colorado School of Mines, United States.

As the world's most traded commodity, oil production is typically well monitored and analyzed. It also has established links to geopolitics, international relations, and security. Despite this attention, the illicit production, refining, and trade of oil and derivative products occur all over the world and provide significant revenues outside of the oversight and regulation of governments. A prominent manifestation of this phenomenon is how terrorist and insurgent organizations-including the Islamic State group, also known as ISIL/ISIS or Daesh-use oil as a revenue source. Understanding the spatial and temporal variation in production can help determine the scale of operations, technical capacity, and revenue streams. This information, in turn, can inform both security and reconstruction strategies. To this end, we use satellite multi-spectral imaging and ground-truth pre-war output data to effectively construct a real-time census of oil production in areas controlled by the ISIL terrorist group. More broadly, remotely measuring the activity of extractive industries in conflict-affected areas without reliable administrative data can support a broad range of public policy and decisions and military operations.
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http://dx.doi.org/10.1016/j.erss.2018.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241310PMC
October 2018

Emerging role of precision medicine in biliary tract cancers.

NPJ Precis Oncol 2018 3;2:21. Epub 2018 Oct 3.

1Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ USA.

Biliary tracts cancers (BTCs) are a diverse group of aggressive malignancies with an overall poor prognosis. Genomic characterization has uncovered many putative clinically actionable aberrations that can also facilitate the prognostication of patients. As such, comprehensive genomic profiling is playing a growing role in the clinical management of BTCs. Currently however, there is only one precision medicine approved by the US Food and Drug Administration (FDA) for the treatment of BTCs. Herein, we highlight the prevalence and prognostic, diagnostic, and predictive significance of recurrent mutations and other genomic aberrations with current clinical implications or emerging relevance to clinical practice. Some ongoing clinical trials, as well as future areas of exploration for precision oncology in BTCs are highlighted.
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http://dx.doi.org/10.1038/s41698-018-0064-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170410PMC
October 2018

Pathway-Specific Asymmetries between ON and OFF Visual Signals.

J Neurosci 2018 11 24;38(45):9728-9740. Epub 2018 Sep 24.

Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710,

Visual processing is largely organized into ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways exhibit natural pairings based on morphological and physiological similarities, such as ON and OFF α-ganglion cells in the mammalian retina. Several studies have noted asymmetries in the properties of ON and OFF pathways. For example, the spatial receptive fields (RFs) of OFF α-cells are systematically smaller than ON α-cells. Analysis of natural scenes suggests that these asymmetries are optimal for visual encoding. To test the generality of ON/OFF asymmetries, we measured the spatiotemporal RF properties of multiple RGC types in rat retina. Through a quantitative and serial classification, we identified three functional pairs of ON and OFF RGCs. We analyzed the structure of their RFs and compared spatial integration, temporal integration, and gain across ON and OFF pairs. Similar to previous results from the cat and primate, RGC types with larger spatial RFs exhibited briefer temporal integration and higher gain. However, each pair of ON and OFF RGC types exhibited distinct asymmetric relationships between RF properties, some of which were opposite to the findings of previous reports. These results reveal the functional organization of six RGC types in the rodent retina and indicate that ON/OFF asymmetries are pathway specific. Circuits that process sensory input frequently process increments separately from decrements, so-called ON and OFF responses. Theoretical studies indicate that this separation, and associated asymmetries in ON and OFF pathways, may be beneficial for encoding natural stimuli. However, the generality of ON and OFF pathway asymmetries has not been tested. Here we compare the functional properties of three distinct pairs of ON and OFF pathways in the rodent retina and show that their asymmetries are pathway specific. These results provide a new view on the partitioning of vision across diverse ON and OFF signaling pathways.
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http://dx.doi.org/10.1523/JNEUROSCI.2008-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222062PMC
November 2018

Novel immunotherapy strategies for hepatobiliary cancers.

Immunotherapy 2018 09;10(12):1077-1091

Department of Medicine, Division of Hematology & Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA.

Despite recent advancements in therapeutic options for advanced hepatobiliary cancers, there remains an unmet need for innovative systemic treatments. Immunotherapy has shown an ability to provide prolonged clinical benefit, but this benefit remains limited to a small subset of patients. Numerous ongoing endeavors are investigating novel immunotherapy concepts. Immunotherapies that have demonstrated clinical efficacy in hepatobiliary cancers include PD-1 inhibitor therapy and CTLA-4 inhibitor therapy. Novel immunotherapy concepts include targeting emerging checkpoint proteins, bispecific T-cell engagers, combinatorial trials with checkpoint inhibitors, oncolytic virotherapy and chimeric antigen receptor T cells. The goal for these new treatment strategies is to achieve a meaningful expansion of patients deriving prolonged clinical benefit from immunotherapy.
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http://dx.doi.org/10.2217/imt-2018-0024DOI Listing
September 2018

Emerging Therapies and Future Directions in Targeting the Tumor Stroma and Immune System in the Treatment of Pancreatic Adenocarcinoma.

Cancers (Basel) 2018 Jun 11;10(6). Epub 2018 Jun 11.

Department of Hematology/Medical Oncology, Mayo Clinic Cancer Center, 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA.

Pancreatic adenocarcinoma is typically refractory to conventional treatments and associated with poor prognosis. While therapeutic advances over the past several years have improved patient outcomes, the observed benefits have been modest at best, highlighting the need for continued development of alternate treatment strategies. The tumor microenvironment has been identified as being integral to oncogenesis through its direct effect on cellular pathway communication, immune inhibition, and promoting chemo-resistance. A more in depth understanding of the biology of the disease, in addition with our ability to develop more effective novel therapies have led to ongoing studies that are investigating several promising treatment options in this disease. Herein, we highlight and review the therapeutic landscape in pancreatic adenocarcinoma.
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http://dx.doi.org/10.3390/cancers10060193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025083PMC
June 2018

Small Intestine Neuroendocrine Tumor in a Patient With MUTYH Adenomatous Polyposis-Case Report and SEER Analysis.

Clin Colorectal Cancer 2018 09 9;17(3):e545-e548. Epub 2018 May 9.

Department of Surgery, Mayo Clinic, Phoenix, AZ. Electronic address:

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http://dx.doi.org/10.1016/j.clcc.2018.05.002DOI Listing
September 2018