Helene L. Gros

Failure is inevitable in medicine, yet the ideal of the infallible physician contributes to its stigma, leaving students unprepared and vulnerable to self-blame and distress. This study explored medical students’ experiences of failure in clinical settings and how their reflective essays captured changes in perspective. Thirty fourth- to sixth-year medical students at the University of Basel attended a 16 h workshop on failure (August 2021–February 2022) and wrote reflective essays before and after the workshop. Inductive qualitative content analysis examined 60 essays from 18 female and 12 male students, with Transformative Learning Theory serving as a sensitizing lens. Seven themes clustered around three tensions: individual fault versus systemic conditions, silence versus psychological safety, and fear of failure versus learning from failure. Participants described failures amid limited authority, information, or supervision, interpreting them as personal inadequacy. They reported emotional distress, tension between professional ideals and fallibility, and limited opportunities to discuss failure. Illustrative matched essay pairs showed how participants reconsidered their experiences after the workshop, including moving beyond self-blame toward a more systemic understanding of failure. Students valued the supportive environment for sharing experiences, highlighting the importance of addressing failure in medical education, ideally before clinical rotations, and ensuring appropriate supervision.

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest major cancer and has a profoundly immunosuppressive tumor microenvironment (TME). Previous studies have shown that inhibition of the E1 enzyme, which catalyzes the small ubiquitin-like modifiers (SUMO), with the small molecule TAK-981, can reprogram the TME to enhance immune activation and suppress tumor growth. We found that the CD-155/TIGIT pathway, a key regulator of immune evasion in PDAC, is influenced by SUMOylation. We hypothesized that the combination of SUMO E1 and TIGIT inhibition would synergistically induce antitumor immune effects. We used a clinically relevant orthotopic mouse model that consistently develops liver metastases to study this combination therapy alone and in the perioperative setting with surgical resection. The combination of SUMO E1 and TIGIT inhibition significantly prolonged survival. Complete responders exhibited protective immunity and enhanced T-cell reactivity to model-specific alloantigens. Complementary immune analyses of resected tumors demonstrated that combination therapy more significantly reduces the abundance of regulatory FoxP3+CD4+ T cells than either monotherapy alone. Mechanistic studies suggest that SUMO E1 inhibition enhances antibody-mediated elimination of regulatory T cells through innate immune cells, potentially by activation of type I IFN responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy.

Supplementary Table 1. Characteristics of PDAC patients

Gating strategy for analysis of Treg population and TIGIT expression in bone marrow isolated cells

Weights of B6/129 F1J male mice for KPC46 orthotopic pancreatic organoid model data shown in Figure 3B

Flow cytometry gating strategy

Kaplan-Meier survival curves and body weight of FC 1199 and FC 1245 orthotopic pancreatic tumor-bearing C57BL/6 mice treated with SUMOylation and TIGIT inhibitor, alone or in combination

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest major cancer and has a profoundly immunosuppressive tumor microenvironment (TME). Previous studies have shown that inhibition of the E1 enzyme, which catalyzes the small ubiquitin-like modifiers (SUMO), with the small molecule TAK-981, can reprogram the TME to enhance immune activation and suppress tumor growth. We found that the CD-155/TIGIT pathway, a key regulator of immune evasion in PDAC, is influenced by SUMOylation. We hypothesized that the combination of SUMO E1 and TIGIT inhibition would synergistically induce antitumor immune effects. We used a clinically relevant orthotopic mouse model that consistently develops liver metastases to study this combination therapy alone and in the perioperative setting with surgical resection. The combination of SUMO E1 and TIGIT inhibition significantly prolonged survival. Complete responders exhibited protective immunity and enhanced T-cell reactivity to model-specific alloantigens. Complementary immune analyses of resected tumors demonstrated that combination therapy more significantly reduces the abundance of regulatory FoxP3+CD4+ T cells than either monotherapy alone. Mechanistic studies suggest that SUMO E1 inhibition enhances antibody-mediated elimination of regulatory T cells through innate immune cells, potentially by activation of type I IFN responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy.

Aim: Early‐onset colorectal cancer (EOCC), defined as colorectal cancer (CRC) diagnosed in patients under the age of 50, has increased alarmingly in Western countries in recent decades. Although risk factors, diagnostics and treatment approaches have been studied, the subjective experiences of EOCC patients remain underexplored. This study aimed to identify patient‐perceived challenges and their unmet needs in Switzerland, a country with a high‐resource healthcare system with minimal waiting times for investigations and comprehensive healthcare coverage. Method: Nineteen semi‐structured interviews were conducted between 09/2023 and 06/2024 with EOCC patients following a constructivist grounded theory approach. Results: Participants from all cancer stages and aged between 30 and 50 years were recruited. We developed three main themes from the collected data: diagnostic delay, coping mechanisms and stigmatisation. Despite access to a well‐resourced healthcare system, study participants experienced diagnostic delays, indicating the need for increased physician awareness and improved risk‐based screening for high‐risk individuals. Participants' key coping strategies included self‐advocacy and participating in medical decision‐making, like prioritising fertility preservation over rushed treatment. Participants reported fear of stigmatisation and isolation after being diagnosed. Such stigma manifested in concerns over alopecia or living with an ostomy. Finally, participants experienced an internal shift in personal priorities resulting in post‐traumatic growth despite cancer diagnosis Conclusions: EOCC challenges current clinical practices. Better physician awareness, risk‐factor‐based screening policies, integrated discussions about individual treatment such as potential fertility issues and targeting stigma are critical for improving the EOCC patients' journey.