Metabolism, toxicity and management of fruquintinib: a novel drug for metastatic colorectal cancer.

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.

Projected Incidence of Hepatobiliary Cancers and Trends Based on Age, Race, and Gender in the United States.

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.

Tumor-Informed Circulating Tumor DNA for Minimal Residual Disease Detection in the Management of Colorectal Cancer.

PURPOSE: Recurrence after curative-intent treatment occurs in 20%-50% of patients with stage II-IV colorectal cancer (CRC), underscoring the need for early detection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA). Here, we examined the pattern of use of a tumor-informed ctDNA assay in CRC MRD monitoring in routine clinical practice at Mayo Clinic, Rochester. METHODS: We conducted a retrospective analysis of health records of patients with CRC who had at least one tumor-informed ctDNA assay from May 2019 through July 1, 2022. Recurrence was defined as radiographic evidence of disease. Descriptive characteristics of the cohort, ctDNA results, and subsequent interventions were recorded. RESULTS: Of the 120 patients included, the median age at diagnosis was 67 years, 46% were female, and 94% were White. At diagnosis, 10 patients had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. Of 476 ctDNA assays performed, 70% were performed in patients who had recurrent disease most commonly to monitor the effectiveness of therapeutic interventions and 16% resulted in a change in clinical decision making. There were 110 recurrences identified in 62 patients, as some patients experienced more than one recurrence over time. Compared with serum carcinoembryonic antigen levels, ctDNA results correlated better with radiologic imaging. CONCLUSION: Routine ctDNA monitoring for MRD detection has been adopted in clinical practice; however, 84% of ctDNA assays performed did not result in a change in clinical management. This suggests the need for further clinical research data to guide routine clinical use of ctDNA MRD testing in CRC.

Targeted Therapies in Advanced Cholangiocarcinoma.

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.

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study.

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.

Prevotella bivia Septic Arthritis in an Immunocompetent Adult: A Case Report and Review of Literature.

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.

Completion of Genetic Testing and Incidence of Pathogenic Germline Mutation among Patients with Early-Onset Colorectal Cancer: A Single Institution Analysis.

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.

Tumor Mutational Burden in Real-World Patients With Pancreatic Cancer: Genomic Alterations and Predictive Value for Immune Checkpoint Inhibitor Effectiveness.

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.

Gastrointestinal perforation after bevacizumab: a multi-site, single-institution study with a focus on survival.

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.

Utilization of Circulating Tumor Cells in the Management of Solid Tumors.

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.

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden.

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.

Financial hardship in breast cancer survivors: a prospective analysis of change in financial concerns over time.

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.

Systemic Therapy in Advanced Hepatocellular Carcinoma: Patient Selection and Key Considerations.

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.

A randomized, double-blinded feasibility trial of educational materials for hiccups in chemotherapy-treated patients with cancer.

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.

Cabozantinib Following Immunotherapy in Patients with Advanced Hepatocellular Carcinoma.

(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.

Pemigatinib in cholangiocarcinoma with a FGFR2 rearrangement or fusion.

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.

Trends and risk factors in the antibiotic management of skin and soft tissue infections in the United States.

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.

Guilt and Burnout in Medical Students.

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.

Intravascular large B-cell lymphoma presenting with fever and refractory acidosis.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse large B-cell lymphoma, characterized by malignant B-cells primarily localized to the lumina of small- and medium-sized blood vessels without lymphadenopathy. Two patients initially presented with fever of unknown origin and persistent lactic acidosis without evidence of tissue hypoxia. Neither patient had an identifiable source of infection and both underwent peripheral blood smear demonstrating leukocytosis with a neutrophilic predominance and thrombocytopenia without evidence of hematologic malignancy. One had previously had a bone marrow biopsy which was unremarkable. Both patients' condition deteriorated rapidly, progressing to multiorgan failure requiring pressors and mechanical ventilation, which ultimately resulted in cardiopulmonary arrest. At autopsy, each patient demonstrated malignant lymphocytoid cells, staining positive for CD20, localized to the lumina of small- and medium-sized vessels in multiple organs, including the lungs, liver, spleen, and kidneys, among others, allowing for the diagnosis of IVLBCL. IVLBCL is exceedingly rare, which in combination with significant variability in presentation, can make identification and diagnosis challenging. Diagnosis requires biopsy, therefore a high index of suspicion is needed to obtain an adequate tissue sample, whether pre- or postmortem. In the presented cases, both patients exhibited type B lactic acidosis with an unknown etiology that was ultimately determined at autopsy.

Iatrogenic Iron Overload Causing Porphyria Cutanea Tarda in a Patient With a Rare Nonsense Heterozygous UROD Gene Mutation.

Porphyria cutanea tarda (PCT) is a rare dermatologic condition characterized by blistering of sun-exposed surfaces and elevated hepatic enzymes. It may infrequently occur as the primary presentation of underlying hemochromatosis. A 61-year-old female with anemia caused by chronic kidney disease and end-stage renal disease on hemodialysis presented with a bullous rash on her hands with associated pruritus. The rash worsened despite conservative treatment. An initial biopsy demonstrated a pauci-inflammatory cell-poor subepidermal cleft. Subsequent workup revealed elevated serum and urine porphyrins, confirming a diagnosis of PCT. Additionally, her skin was darkened and ferritin was elevated. MRI of the liver demonstrated iron overload with genetic testing negative for C282Y or H63D mutations, supporting a diagnosis of secondary hemochromatosis. Further genetic testing revealed that the patient had a rare heterozygous nonsense mutation of the uroporphyrinogen decarboxylase (UROD) gene, for a sequence variant designated c.616C>T, which is predicted to result in premature protein termination (p.Gln206*). PCT occurs due to decreased function of UROD, leading to accumulation of porphyrins causing dermatologic manifestations and liver injury. UROD is inactivated in an iron-dependent process, explaining the mechanistic link between hemochromatosis and PCT.