Klara Dorman

Pancreatic cancer (PC) is a highly aggressive malignancy characterized by limited opportunities for early diagnosis and poor clinical outcomes, underscoring the need for minimally invasive biomarkers to improve detection and patient stratification. Given emerging evidence that mitochondrial DNA (mtDNA) alterations reflect cancer-related biological processes, this study investigated whether blood-derived mtDNA profiles could provide clinically relevant information in PC. In this exploratory study, whole-blood mtDNA from 33 PC patients and 10 healthy individuals were analyzed using next-generation sequencing to assess single-nucleotide variants (SNVs), allele frequencies, and mtDNA copy number. A total of 252 unique mtDNA SNVs were identified, including variants exclusive to PC patients, variants unique to controls, and variants shared between groups. While the overall SNV burden did not differ significantly between groups, PC patients showed distinct mutation distributions and allele frequency patterns, with cancer-exclusive variants occurring predominantly at low allele frequencies. Mutation hotspots were observed in the ND5, COI, and D-loop regions, implicating genes involved in oxidative phosphorylation and mtDNA maintenance. Although mtDNA copy number did not differ significantly between groups, greater variability was observed among PC patients and was associated with differences in survival outcomes. Overall, these findings indicate that blood-based mtDNA profiling captures biologically relevant variation associated with PC and supports further development of integrated mtDNA-based approaches for improved risk assessment and patient stratification.

Prediction of response to checkpoint inhibition (ICI) and immune related adverse events (irAEs) remain a challenge in the immunotherapy of solid tumors. To better understand the real-world clinical courses under ICI and identify possible predictive markers for response and irAEs, we retrospectively collected and analysed data from our interdisciplinary CCCMunich ^LMU outpatient clinic. We analysed the clinical course, standard laboratory parameters and staging results of 342 patients who received ICI therapy in the interdisciplinary outpatient clinic of the CCCMunich ^LMU between January 2015 and November 2020. Initial response to ICI was defined as complete response, partial response, stable disease or mixed response with treatment continuation in the second radiologic staging after start of therapy. Median age of the included patients was 67 years (25–89). More male patients received ICI on our outpatient ward than female patients (67.8% vs. 32.2%). The most common entities were urothelial carcinoma (21.3%) and bronchial carcinoma (19.6%), followed by renal cell carcinoma (18.7%), and head and neck tumors (10.8%). 24.6% of patients were initial responders. Patients who did not respond to ICI therapy had lower leukocyte, lymphocyte, monocyte, and neutrophil counts before treatment start compared to initial responders. The consolidation of these laboratory parameters into a score could not accurately predict initial response or progression-free survival (PFS). IrAEs occurred in approximately one-third of all included patients. The main side effects in patients expierencing irAEs were thyroiditis (20.5%), pneumonitis (16.4%), hepatitis (15.8%), and dermatological side effects (11.0%). Patients experiencing irAEs had a significantly longer PFS than patients without irAEs. Side effects were more frequent and severe in patients treated with combined ICI. Autoimmune disorders were not associated with more frequent occurrence of irAEs. This retrospective analysis illustrates the real-world use of ICI in clinical practice. With only 24.6% of patients responding to ICI, the clinical need for predictive markers is obvious and standard laboratory parameters such as white blood cell counts may become part of a comprehensive score to predict response and adverse events.

Relapse and regimen-related toxicities remain major challenges in achieving long-term survival, particularly among older patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have demonstrated the feasibility of treosulfan-based conditioning, noting stable engraftment and low non-relapse mortality (NRM) in patients undergoing HLA-matched allo-HSCT. However, data on treosulfan-based conditioning in the HLA-haploidentical transplantation (HaploT) setting are limited. We retrospectively compared conditioning with fludarabine–cyclophosphamide (FC)–melphalan (110 mg/m²) and FC-treosulfan (30 g/m²) prior to HaploT using post-transplantation cyclophosphamide (PTCy) in patients with high-risk MDS/AML patients ≥ 50 years, transplanted from 2009–2021 at our institution (n = 80). After balancing patient characteristics by a matched-pair analysis, we identified twenty-one matched pairs. Two-year OS and LFS were similar among the groups (OS 66% and LFS 66%, p = 0.8 and p = 0.57). However, FC-melphalan was associated with a significantly lower probability of relapse compared to FC-treosulfan (0% vs. 24%, p = 0.006), counterbalanced by a higher NRM (33% vs. 10%, p = 0.05). Time to engraftment and incidences of acute and chronic graft-versus-host disease (GvHD) did not differ significantly. In conclusion, HaploT using FC-treosulfan in combination with PTCy in patients aged ≥50 years with MDS/AML appears safe and effective, particularly in advanced disease stages. We confirm the favorable extramedullary toxicity profile, allowing for potential dose intensification to enhance antileukemic activity.

This analysis of the RASH trial (NCT01729481) aimed at gaining a better understanding of the “Burden of Therapy” (BOTh^®TM) in pancreatic ductal adenocarcinoma (PDAC). In the RASH study, 150 patients with newly diagnosed metastatic PDAC were treated with gemcitabine plus erlotinib (gem/erlotinib) for four weeks. Patients who developed a skin rash during this four-week run-in phase continued with the gem/erlotinib treatment, while rash-negative patients were switched to FOLFIRINOX. The study demonstrated a 1-year survival rate of rash-positive patients who received gem/erlotinib as first-line treatment that was comparable to previous reports of patients receiving FOLFIRINOX. To understand whether these comparable survival rates may be accompanied by better tolerability of the gem/erlotinib treatment compared to FOLFIRINOX, the BOTh^®TM methodology was used to continuously quantify and depict the burden of therapy generated by treatment emergent events (TEAEs). Sensory neuropathy was significantly more common in the FOLFIRINOX arm, and prevalence as well as severity increased over time. In both arms, the BOTh^®TM associated with diarrhea decreased over the course of treatment. The BOTh^®TM caused by neutropenia was comparable in both arms but decreased in the FOLFIRINOX arm over time, possibly due to chemotherapy dose reductions. Overall, gem/erlotinib was associated with a slightly higher overall BOTh^®TM, but the difference was not statistically significant (p = 0.6735). In summary, the BOTh^®TM analysis facilitates the evaluation of TEAEs. In patients fit for intense chemotherapeutic regimens, FOLFIRINOX is associated with a lower BOTh^®TM than gem/erlotinib.

Background/Aim: Endometriosis is a common disorder in reproductive-age women leading to a broad range of symptoms and is associated with a higher risk for endometrioid ovarian carcinoma. Case Report: We report the case of a 55 year-old woman with previously undiagnosed endometriosis presenting with a large mediastinal cancer of unknown primary (CUP) and synchronous Union Internationale Contre le Cancer (UICC) stage II rectal adenocarcinoma. Histopathologically the mediastinal tumor resembled endometrial carcinoma and laparoscopically endometriotic lesions on the patient’s peritoneum were detected. The patient was treated with neoadjuvant carboplatin and paclitaxel, followed by resection of the mediastinal tumor. After recovery, the patient received neoadjuvant short-course radiation to the rectal adenocarcinoma, which was resected afterwards. No primary endometrial carcinoma was found in the uterus, leading to the most likely conclusion that the mediastinal tumor derived from an extragenital endometriotic lesion. Conclusion: Although rare, cases of degeneration of endometriosis have been described. In this case not only the localization of endometriosis was uncommon, but also its malignant transformation and synchronous diagnosis of a rectal adenocarcinoma, complicating diagnosis, and treatment of the patient. This rare case highlights the importance of diagnosing and treating patients with CUP or multiple malignancies at large interdisciplinary centers to reach the best possible outcome.

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (T_reg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). T_reg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8⁺ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.