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Michael H Storandt,1 Zhaohui Jin,2 Amit Mahipal3 1Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; 2Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA; 3Department of Medical Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USACorrespondence: Amit Mahipal, University Hospitals Seidman Cancer Center, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH, 44106, USA, Tel +1 216-844-3951, Email Amit.mahipal@UHhospitals.orgAbstract: Advanced biliary tract cancers (BTCs) have historically been managed with chemotherapy but, in recent years, this treatment paradigm has begun to shift with the introduction of immune checkpoint inhibitors in addition to standard of care chemotherapy. The tumor microenvironment of BTC may be enriched with regulatory T lymphocytes and immune checkpoint expression in some patients. Durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, in combination with gemcitabine and cisplatin, has now received United States Food and Drug Administration approval for treatment of advanced BTC. Regulatory approval was based on the Phase III, randomized TOPAZ-1 trial that demonstrated survival benefit with addition of durvalumab to gemcitabine plus cisplatin compared to chemotherapy alone. The combination of chemotherapy and immunotherapy was well tolerated, and a subset of patients were able to achieve a durable response, with a 2-year overall survival rate of 23.6%. However, limitations remain in identifying which patients are most likely to benefit from immune checkpoint inhibition. Future study should aim to identify biomarkers predictive of substantial benefit, as well as the role of immune checkpoint inhibition in combination with targeted therapies and radiotherapy in the management of advanced BTC.Keywords: durvalumab, immunotherapy, cholangiocarcinoma, bile duct cancers

Michael H Storandt,1 Amit Mahipal,2 Sri Harsha Tella,2 Anuhya Kommalapati,2 Zhaohui Jin2 1Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; 2Department of Medical Oncology, Mayo Clinic, Rochester, MN, USACorrespondence: Zhaohui Jin, Department of Medical Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA, Tel +1 507-293-0487, Email jin.zhaohui@mayo.eduAbstract: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Most patients with HCC have advanced disease at initial diagnosis, and sorafenib has been the only systemic treatment option for more than a decade in patients with advanced, unresectable HCC. However, there has been a dramatic change in the treatment algorithm in the last several years, given new drug approvals in the field. Most importantly, the combination of atezolizumab and bevacizumab has demonstrated clinically meaningful benefits in terms of response rate, progression-free survival, and overall survival compared to sorafenib in the first-line setting. Recently a phase III trial showed that the combination of durvalumab with a single dose of tremelimumab improved overall survival compared to sorafenib, while durvalumab monotherapy was found to be noninferior to sorafenib, making it an attractive alternative single agent in selected patient populations. As immunotherapy makes its way into the therapeutic landscape of HCC, other novel targeted therapies, such as lenvatinib, cabozantinib, ramucirumab, and regorafenib, have also been approved by regulatory authorities for treatment of advanced, unresectable HCC. This review article focuses on the first-line systemic treatment options for HCC while addressing some of the most important questions aimed at optimization of HCC treatment.Keywords: hepatocellular carcinoma, advanced hepatocellular carcinoma

Background: Atezolizumab plus bevacizumab is the standard of care for advanced hepatocellular carcinoma (HCC) in the first-line setting, although was only evaluated in patients with Child-Pugh (CP) A liver function in the IMbrave150 trial. We sought to determine the outcomes of these patients based on CP score and ALBI grade in the US population., Methods: This multicenter cohort study included patients with HCC who received atezolizumab with bevacizumab as first-line systemic therapy between March 2018 and November 2023. Overall survival (OS) was determined using the Kaplan-Meier method and multivariate analyses were performed using Cox proportional hazard regression method., Results: Among 322 patients, 226, 86, and 10 patients had CP-A, CP-B, and CP-C liver function, respectively. Median age was 66.5 years, 78.6% were male, and 82.6% were White. Median OS (mOS) was 21.6 months for those with CP-A, 9.1 months for those with CP-B7, and 4.7 months for those with CP-B8-C12 (P < .0001). Among patients with CP-A, those with ALBI grade 1 had an mOS of 34.9 months versus 14.2 months in those with grade 2. In multivariate analyses, CP score, ALBI grade, hepatitis B, performance status, and macrovascular invasion were significantly associated with survival., Conclusions: CP score is an important prognostic tool for patients with HCC receiving atezolizumab plus bevacizumab, and this regimen remains a viable option for patients with CP-B7 with no additional safety concern, although the benefit is significantly less than those with CP-A. ALBI score has independent predictive value in patients with CP-A liver function., (© The Author(s) 2024. Published by Oxford University Press.)

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan-Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar's test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients ( p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA ( p < 0.097). Post-intervention systemic therapy was not associated with improved DFS ( p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

Background: The predictive and prognostic role of BRAF alterations has been evaluated in colorectal cancer (CRC); however, BRAF alterations have not been fully characterized in non-CRC gastrointestinal (GI) malignancies. In the present study, we report the frequency and spectrum of BRAF alterations among patients with non-CRC GI malignancies., Methods: Patients with CRC and non-CRC GI malignancies who underwent somatic tumor profiling via a tissue-based or liquid-based assay were included in this study. Gain-of-function BRAF alterations were defined as pathogenic/likely pathogenic somatic short variants (SVs), copy number amplifications ≥8, or fusions (RNA or DNA)., Results: Among 51,560 patients with somatic profiling, 40% had CRC and 60% had non-CRC GI malignancies. BRAF GOF alterations were seen more frequently in CRC (8.9%) compared to non-CRC GI malignancies (2.2%) ( p < 0.001). Non-CRC GI malignancies with the highest prevalence of BRAF GOF alterations were bile duct cancers (4.1%) and small intestine cancers (4.0%). Among BRAF GOF alterations, class II (28% vs. 6.8%, p < 0.001) and class III (23% vs. 14%, p < 0.001) were more common in non-CRC GI malignancies. Among class II alterations, rates of BRAF amplifications (3.1% vs. 0.3%, p < 0.001) and BRAF fusions (12% vs. 2.2%, p < 0.001) were higher in non-CRC GI malignancies compared to CRC., Conclusions: Non-CRC GI malignancies demonstrate a distinct BRAF alteration profile compared to CRC, with a higher frequency of class II and III mutations, and more specifically, a higher incidence of BRAF fusions. Future studies should evaluate clinical implications for the management of non-CRC GI patients with BRAF alterations, especially BRAF fusions.

Introduction: Colorectal cancer (CRC) is the third most diagnosed cancer globally and despite therapeutic strides, the prognosis for patients with metastatic disease (mCRC) remains poor. Fruquintinib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) targeting VEGFR -1, -2, and -3, and has recently received approval by the U.S. Food and Drug Administration for treatment of mCRC refractory to standard chemotherapy, anti-VEGF therapy, and anti-epidermal growth factor receptor (EGFR) therapy., Areas Covered: This article provides an overview of the pre-clinical data, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib, as well as the management of clinical toxicities associated with fruquintinib., Expert Opinion: Fruquintinib is a valuable additional treatment option for patients with refractory mCRC. The pivotal role of vigilant toxicity management cannot be understated. While fruquintinib offers a convenient and overall, well-tolerated treatment option, ongoing research is essential to determine its efficacy in different patient subsets, evaluate it in combination with chemotherapy and immunotherapy, and determine its role in earlier lines of therapy.

Background: Identifying the projected incidence of hepatobiliary cancers and recognizing patient cohorts at increased risk can help develop targeted interventions and resource allocation. The expected incidence of subtypes of hepatobiliary cancers in different age groups, races, and genders remains unknown., Methods: Historical epidemiological data from the Surveillance, Epidemiology, and End Results (SEER) database was used to project future incidence of hepatobiliary malignancies in the United States and identify trends by age, race, and gender. Patients ≥18 years of age diagnosed with a hepatobiliary malignancy between 2001 and 2017 were included. US Census Bureau 2017 National Population projects provided the projected population from 2017 to 2029. Age-Period-Cohort forecasting model was used to estimate future births cohort-specific incidence. All analyses were completed using R Statistical Software., Results: We included 110381 historical patients diagnosed with a hepatobiliary malignancy between 2001 and 2017 with the following subtypes: hepatocellular cancer (HCC) (68%), intrahepatic cholangiocarcinoma (iCCA) (11.5%), gallbladder cancer (GC) (8%), extrahepatic cholangiocarcinoma (eCCA) (7.6%), and ampullary cancer (AC) (4%). Our models predict the incidence of HCC to double (2001 to 2029) from 4.5 to 9.03 per 100,000, with the most significant increase anticipated in patients 70-79 years of age. In contrast, incidence is expected to continue to decline among the Asian population. Incidence of iCCA is projected to increase, especially in the white population, with rates in 2029 double those in 2001 (2.13 vs. 0.88 per 100,000, respectively; p < 0.001). The incidence of GC among the black population is expected to increase. The incidence of eCCA is expected to significantly increase, especially among the Hispanic population, while that of AC will remain stable., Discussion: The overall incidence of hepatobiliary malignancies is expected to increase in the coming years, with certain groups at increased risk. These findings may help with resource allocation when considering screening, treatment, and research in the coming years.

Primary tumor resection and liver transplantation are the only curative treatment options for the management of cholangiocarcinoma (CCA). However, for patients with advanced or metastatic disease, palliative systemic therapy remains the only treatment option. The development of targeted therapeutics has begun to shift the treatment paradigm in CCA. Targets of interest in CCA include mutated isocitrate dehydrogenase-1 (mIDH-1), human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and fibroblast growth factor receptor 2 ( FGFR2 ) fusion, in addition to less frequently observed targets such as BRAF V600E , deficient mismatch repair/high microsatellite instability (dMMR/MSI-H), and high tumor mutation burden (TMB-H). These targets are observed in varying frequency among patients with intrahepatic CCA and extrahepatic CCA. Multiple novel therapies have been developed to exploit each of these targets, with some having received United States Food and Drug Administration approval for use in the second-line setting. In the current review, we discuss targets of interest in CCA and summarize current evidence evaluating available therapies directed at these targets.

Background: Lenvatinib, a multikinase inhibitor, is an FDA-approved treatment for advanced hepatocellular carcinoma (HCC) in the first-line setting. Recent trial data have established atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab as preferred first-line treatment options for advanced HCC. The role of lenvatinib following progression on immunotherapy in patients with advanced HCC remains unclear., Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at the Mayo Clinic in Minnesota, Arizona, and Florida who received immunotherapy followed by lenvatinib. Median overall survival and progression-free survival analyses were performed using the Kaplan-Meier method, and responses were determined using RECIST 1.1. Adverse events were determined using CTCAE v 4.0., Results: We identified 53 patients with advanced HCC who received lenvatinib following progression on immunotherapy. Forty five (85%) patients had a Child Pugh class A at diagnosis, while 30 (58%) patients were still Child Pugh A at time of lenvatinib initiation. Lenvatinib was administered as a second-line treatment in 85% of the patients. The median PFS was 3.7 months (95% CI: 3.2-6.6), and the median OS from the time of lenvatinib initiation was 12.8 months (95% CI: 6.7-19.5). In patients with Child Pugh class A, the median OS and PFS was 14 and 5.2 months, respectively. Race, gender, and Child Pugh class was associated with OS on multivariate analysis., Discussion: Our study, using real-world data, suggests that patients benefit from treatment with lenvatinib following progression on immunotherapy in advanced HCC. The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown, and these results need to be validated in a clinical trial.

Over the past 20 years, rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased, with 16-25% associated with a pathogenic germline variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we sought to further characterize PGVs observed in patients with eoCRC. We conducted a retrospective analysis of patients with a history of CRC referred for genetic counseling at Mayo Clinic Rochester between April 2019 and April 2022. Three hundred and three CRC patients were referred to medical genetics, including 124 with a history of eoCRC. Only 84 patients (68%) with eoCRC referred for genetic counseling completed genetic testing, with an average of 48 genes evaluated. PGVs were identified in 27.4% with eoCRC, including 8.3% with Lynch syndrome (LS). Other detected PGVs known to increase the risk of CRC included MUTYH (4.8%), CHEK2 (3.6%), APC , BMPR1A , and TP53 (1.3% each). Among those with aoCRC, 109 patients (61%) completed genetic testing, among which 88% had either a dMMR tumor, personal history of an additional LS malignancy, or family history of LS malignancy, with PGVs detected in 23% of patients. This study reinforces the importance for all patients with CRC, especially those with eoCRC, to undergo germline testing.

Background: Pembrolizumab confers minimal benefit to most patients with pancreas cancer. We explored survival and patient treatment burden (for example, death within 14 days of therapy) in a subgroup who had early access to pembrolizumab ., Methods: This multisite study examined consecutive pancreas cancer patients, who received pembrolizumab from 2004 through 2022. Median overall survival of > 4 months was to be deemed favorable. Patient treatment burden and medical record quotations are presented descriptively., Results: Forty-one patients (median age 66 years; range 36, 84) are included. Fifteen (37%) had dMMR, MSI-H, TMB-H, or Lynch syndrome; and 23 (56%) received concurrent therapy. The median overall survival was 7.2 months (95% confidence interval (CI): 5.2, 12.7 months); 29 were deceased at the time of reporting. Patients with dMMR, MSI-H, TMB-H, or Lynch syndrome had a lower risk of death: hazard ratio (HR): 0.29 (95% CI: 0.12, 0.72); p = 0.008. Medical record phrases ("brilliant response") aligned with the above. One patient died within 14 days of therapy, and one was in an intensive care unit within 30 days of death. Fifteen patients enrolled in hospice; four of these died < 3 days later., Conclusions: These unexpectedly favorable findings underscore the need for healthcare providers-including palliative care providers-to knowledgeably guide patients about cancer therapy even near the end of life., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely considered a nonimmunogenic malignancy; however, approximately 1%, of patients may have tumors with deficient mismatch repair, high microsatellite instability, or high tumor mutational burden (TMB ≥10 mutations/Mb), which may be predictive of response to immune checkpoint inhibitor (ICI) therapy. We sought to analyze outcomes of patients with high-TMB and pathogenic genomic alterations observed in this population., Methods: This study included patients with PDAC who underwent comprehensive genomic profiling (CGP) at Foundation Medicine (Cambridge, MA). Clinical data were obtained from a US-wide real-world clinicogenomic pancreatic database. We report genomic alterations in those with high and low TMB, and compare outcomes on the basis of receipt of single-agent ICI or therapy regimens not containing ICI., Results: We evaluated 21,932 patients with PDAC who had tissue CGP data available, including 21,639 (98.7%) with low-TMB and 293 (1.3%) with high-TMB. Among patients with high-TMB, a greater number of alterations were observed in BRCA2 , BRAF , PALB2 , and genes of the mismatch repair pathway, whereas fewer alterations were observed in KRAS . Among patients who received an ICI (n = 51), those with high-TMB had more favorable median overall survival when compared with the low-TMB subset (25.7 v 5.2 months; hazard ratio, 0.32; 95% CI, 0.11 to 0.91; P = .034)., Conclusion: Longer survival was observed in patients with high-TMB receiving ICI compared with those with low-TMB. This supports the role of high-TMB as a predictive biomarker for efficacy of ICI therapy in PDAC. Additionally, we report higher rates of BRAF and BRCA2 mutations and lower rates of KRAS mutation among patients with PDAC and high-TMB, which to our knowledge, is a novel finding.

Background: Bevacizumab-induced gastrointestinal perforation is a rare but potentially devastating adverse event that has generated limited data on overall survival. Yet, such survival data are critical in guiding management., Methods: This multi-site, single-institution retrospective study focused on all cancer patients who had received bevacizumab and who had suffered a well-documented gastrointestinal perforation from January 1, 2004 through January 20, 2022.The main goal was to report survival outcomes; Kaplan Meier curves and Cox survival models were used for this purpose., Results: Eighty-nine patients are included in this report with a median age of 62 years (range 26-85). Colorectal cancer was the most common malignancy (n = 42). Thirty-nine patients underwent surgery for the perforation. Seventy-eight were deceased at the time of reporting with an overall median survival of all patients of 2.7 months (range 0-45 months), and 32 (36%) died within 30 days of perforation. In univariable survival analyses, no statistically significant associations were observed for age, gender, corticosteroid use, and time since last bevacizumab dose. However, surgically treated patients manifested a better survival (hazard ratio (HR) 0.49 (95% CI 0.31-0.78); p = 0.003). In multivariable analyses, surgery continued to be associated with improved survival (HR 0.47 (95% CI 0.29-0.74); p = 0.002), and corticosteroid use was associated with worse survival (HR 1.75 (95% CI 1.02-2.99); p = 0.04)., Conclusion: Although gastrointestinal perforation after bevacizumab should be managed on a case-by-case basis, these descriptive survival data can help inform patients, their families, and healthcare providers as challenging management decisions arise., (© 2023. The Author(s).)

Circulating tumor cells (CTCs) are tumor cells shed from the primary tumor into circulation, with clusters of CTCs responsible for cancer metastases. CTC detection and isolation from the bloodstream are based on properties distinguishing CTCs from normal blood cells. Current CTC detection techniques can be divided into two main categories: label dependent, which depends upon antibodies that selectively bind cell surface antigens present on CTCs, or label-independent detection, which is detection based on the size, deformability, and biophysical properties of CTCs. CTCs may play significant roles in cancer screening, diagnosis, treatment navigation, including prognostication and precision medicine, and surveillance. In cancer screening, capturing and evaluating CTCs from peripheral blood could be a strategy to detect cancer at its earliest stage. Cancer diagnosis using liquid biopsy could also have tremendous benefits. Full utilization of CTCs in the clinical management of malignancies may be feasible in the near future; however, several challenges still exist. CTC assays currently lack adequate sensitivity, especially in early-stage solid malignancies, due to low numbers of detectable CTCs. As assays improve and more trials evaluate the clinical utility of CTC detection in guiding therapies, we anticipate increased use in cancer management.

Septic arthritis is a medical emergency that requires prompt diagnosis to prevent long-term intra-articular complications. Prevotella bivia is an anaerobic gram-negative rod which has been infrequently reported to cause septic arthritis. We present a 49-year-old female that presented with spontaneous left knee pain and swelling without history of insult to the knee. She was initially misdiagnosed with patellar tendinitis and gout but later underwent joint aspiration due to worsening symptoms, which demonstrated 60 800/µL nucleated cells with a polymorphonuclear burden consistent with septic arthritis. Arthroscopy with irrigation and drainage was subsequently performed, and the patient was started on empiric antibiotics while awaiting cultures. Cultures grew Prevotella bivia , and antibiotics were deescalated to ertapenem alone followed by oral metronidazole. Prevotella species as a source of septic arthritis is rare, and its occurrence in a patient without known insult to the knee is even more uncommon. It is essential that it is recognized to treat appropriately and prevent long-term loss of function in the joint.

Purpose: Medical financial hardship, encompassing material, behavioral, and psychologic domains, has been shown to impair quality of life during and after cancer therapy. We sought to evaluate the change in financial concerns in breast cancer survivors over time and identify those at risk of worsening financial concerns., Methods: In Mayo Clinic Breast Disease Registry (MCBDR), a prospective cohort of consenting patients seen at Mayo Clinic Rochester within 1 year of their initial breast cancer diagnosis, consenting participants were asked to complete baseline and annual follow-up surveys that included an item on which respondents were asked to report their financial concerns on a linear analogue scale from 0 ("none") to 10 ("constant concerns"). We compared patient-reported financial concern at baseline to that on each patient's most recent survey, with worsening concerns defined as a 1+-point increase. Logistic regression analysis evaluated for possible predictors of worsening financial concerns., Results: One-thousand nine-hundred fifty-seven participants responded to financial concern questions on the baseline and at least one follow-up survey between 2015 and 2020. Three-hundred fifty-seven (18.2%) reported worsening financial concerns. Only baseline financial situation of "enough to pay the bills, but little spare money to buy extra or special things," was associated with a greater likelihood of worsening financial concerns., Conclusions: More than one in seven breast cancer survivors develop worsening financial concerns within 5 years of diagnosis, and those with less financial security at baseline appear to be most vulnerable., Implication for Cancer Survivors: Financial concerns may worsen over time for breast cancer survivors, and therefore, oncology providers must continue to assess the financial well-being of survivors over time., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Chemotherapy can cause hiccups but few randomized controlled trials have focused on hiccups. This trial examined the feasibility of such research., Methods: This single-institution, multi-site trial used phone recruitment for patients: (1) 18 years or older, (2) able to speak/read English, (3) with a working e-mail address, (4) with hiccups 4 weeks prior to contact, and (5) with ongoing oxaliplatin or cisplatin chemotherapy. The primary outcome was feasibility. Patients were randomly assigned to one of two sets of educational materials, each of which discussed hiccups and palliative options. The experimental materials were almost identical to the standard materials but provided updated content based on the published medical literature. At 2 weeks, patients responded by phone to a 5-item verbally administered questionnaire., Results: This trial achieved its primary endpoint of recruiting 20 eligible patients within 5 months; 50 patients were recruited in 3 months. Among the 40 patients who completed the follow-up questionnaire, no statistically significant differences between arms were observed in hiccup incidence since initial contact, time spent reviewing the educational materials, and the troubling nature of hiccups. Twenty-five patients tried palliative interventions (13 in the experimental arm and 12 in the standard arm), most commonly drinking water or holding one's breath. Eleven and 10 patients, respectively, described hiccup relief after such an intervention., Conclusions: Clinical trials for chemotherapy-induced hiccups are feasible and could address an unmet need., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Cholangiocarcinoma (CCA) accounts for approximately 3% of gastrointestinal malignancies and is associated with a high mortality rate. Recent progress in the understanding of cholangiocarcinoma tumorigenesis and molecular markers has led to the development of several targeted therapies applicable to this disease. Fibroblast growth factor receptor 2 (FGFR2) gene fusion or translocation, resulting in constitutive activation of the FGFR tyrosine kinase, has been identified as a driver of oncogenesis in 10-15% of intrahepatic CCA. Pemigatinib is an FGFR inhibitor that has demonstrated survival benefit in the second line setting for treatment of CCA with FGFR2 fusion or rearrangement refractory to chemotherapy. Pemigatinib was the first targeted therapy to be approved by the FDA for treatment of cholangiocarcinoma., Areas Covered: This article reviews FGFR and its dysregulation in oncogenesis, FGFR inhibitors, especially pemigatinib, utilized in treatment of CCA, common adverse events associated with FGFR inhibitors, and future directions in the field of targeted drug development for CCA., Expert Opinion: FGFR inhibitors, including pemigatinib, have shown promise in the management of CCA with FGFR2 fusion or rearrangement; however, acquired resistance remains a major barrier in the field of FGFR inhibitors and requires further study.

(1) Background: Cabozantinib, a multikinase inhibitor, is approved by the Food and Drug Administration (FDA) for the treatment of advanced hepatocellular carcinoma (HCC) following progression on sorafenib. Recently, atezolizumab plus bevacizumab has been approved in the first line setting for advanced HCC and has become the new standard of care. Whether cabozantinib improves outcomes following progression on immunotherapy remains unknown. We describe the clinical outcomes following treatment with immunotherapy in patients with advanced HCC who received cabozantinib. (2) Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic in Minnesota, Arizona, and Florida who received cabozantinib. Median overall survival and progression free survival analyses were performed using the Kaplan-Meier method. Adverse events were determined using Common Terminology Criteria for Adverse Events (CTCAE). (3). Results: We identified 26 patients with advanced HCC who received cabozantinib following progression on immunotherapy. Median progression free survival on cabozantinib therapy was 2.1 months (95% CI: 1.3-3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3-14.9). (4) Conclusion: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. Our study demonstrates that patients may benefit from treatment with cabozantinib following progression on immunotherapy.

Objective: The aim of this study was to examine the trends and risk factors of antibiotic treatment for skin and soft tissue infections (SSTIs), in the United States., Methods: We conducted a retrospective analysis of SSTIs visits utilizing the 2011-2016 National Ambulatory Medical Care Survey., Results: There were over 43 million visits for SSTIs in the US. We found no association between antibiotic treatment and gender, age, race, insurance, region, and metropolitan statistical area. Methicillin-resistant Staphylococcus aureus (MRSA) antibiotics were prescribed at 34.8% of SSTI visits, methicillin-sensitive Staphylococcus aureus (MSSA) antibiotics at 27.5%, and other antibiotics at 21.7%. Among visits treated with an antibiotic, 40.4% ( n  = 378) received an antibiotic with MSSA coverage, while 59.6% ( n  = 558) received an antibiotic with MRSA coverage. Region where the visit occurred was associated with the use of MSSA versus MRSA antibiotics ( p  = .013). Mean age of visits receiving MSSA antibiotics was significantly older than visits receiving MRSA antibiotics, 53.8 ± 1.2 vs. 50.9 ± 0.9 ( p  = .045)., Conclusions: This study found that providers more frequently utilize antibiotics with MRSA coverage for SSTIs. Antibiotic class chosen was associated with region, with MRSA coverage antibiotics more likely to be prescribed in the South. Additionally, individuals receiving antibiotics with MSSA coverage were older than those receiving antibiotics with MRSA coverage.

Theory: Burnout is prevalent among medical students and is correlated with negative feelings, behaviors, and outcomes. Empathy is a desired trait for medical students that has been correlated with reduced burnout. The concept of guilt is closely related to concern about the well-being of others; therefore, feelings of guilt may be associated with empathy. Excessive guilt poses an increased risk for internalized distress, symptoms such as anhedonia, and may be related to burnout. The relationship between pathogenic guilt and burnout in medical students is unknown., Hypothesis: We hypothesize that pathogenic guilt is present and related to both burnout and empathy in medical students., Methods: We conducted a cross-sectional survey study of all students in one medical school. Data were collected in February 2020. The Oldenburg Burnout Inventory (OBLI), Toronto Empathy Questionnaire (TEQ), and Interpersonal Guilt Questionaire-67 (IGQ-67) were used. A modified version of IGQ-67 was used to measure four subscales of pathogenic guilt: survival guilt, separation guilt, omnipotence guilt, and self-hate guilt. Data analyses for this study including screening, evaluation of assumptions, descriptive statistics, reliabilities, one-way ANOVA, and correlation coefficients, were conducted using SPSS version 26., Results: Of 300, 168 (56.0%) students participated in the study. Survival, omnipotence, and self-hate classes of pathogenic guilt were positively correlated with burnout. Empathy was correlated with two classes of pathogenic guilt: survival and omnipotence. Empathy was inversely related to burnout (disengagement)., Conclusions: Pathogenic guilt may be a contributor to burnout in medical students. Guilt should be a target of prevention and treatment in burnout in medical students., Supplemental data for this article is available online at https://doi.org/10.1080/10401334.2021.1891544.