This study´s aim was to analyse clinical outcomes of microvascular reconstructions performed for malignancy-caused midface defects of varying sizes at our department. This retrospective study included 98 patients (38 women; 60 men; age range 16–94 years) who underwent microvascular reconstruction for a malignancy-related midface defect between April 2017 and August 2022. Bony (fibula, scapula) and soft tissue (radial forearm, anterolateral thigh) flap techniques were used depending on defect size. Most defects requiring coverage were classified as class II (n = 70, 71.4

Intraoperative frozen section analysis (IFSA) is a well-established procedure for determining the intraoperative soft tissue resection status in patients with oral squamous cell carcinoma (OSCC). Margin status is a major predictor of the patient´s outcome, histologically free margins of ≥ 5 mm are demanded. This study evaluates the accuracy of IFSA, the impact of margin status and the impact of intraoperative margin revision on disease-free survival (DFS) and overall survival (OS). This retrospective study included 213 patients with OSCC. IFSA results were compared with definitive histopathological reports, Kaplan–Meier analysis was performed. Cut-off values were calculated for resection margins considering known risk factors. IFSA showed positive margins in 8 cases (3.8

Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.

Selective neck dissection (SND) is the treatment of choice in patients with oral squamous cell carcinomas (OSCCs) and clinically node-negative necks (cN0). The treatment of patients with positive-staged necks (cN+) includes SND as well as comprehensive neck dissection (CND). The clear benefit of one or the other remains under debate. We aim to address this lack of clarity by analysing patients with OSCC staged with clinically node-positive necks, treated with either CND or SND using a level-by-level approach. This retrospective study included patients diagnosed with OSCC with clinically (cN+) and pathologically (pN+) positive cervical lymph nodes (LNs) with clear neck level categorization during the years 2010-2019. In total, 74 patients were analysed. Cox regression analysis found no significance for the type of ND being an independent risk factor, neither for overall survival (OS) nor for disease-free survival (DFS). Regional recurrence of CND cases (5.77%) was comparable to SND cases (9.09%). For OS, extracapsular spread (ECS) and male sex were identified as independent risk factors with poorer outcome. pT-stage and ECS were found to be independent risk factors for DFS. The results of this study suggest that both CND and SND may be viable treatment options for certain patients with OSCC pN+.

Importance:Clinicians may be confronted with patients refusing recommended adjuvant therapy (AT) after the primary resection of an advanced oral squamous cell carcinoma (OSCC). However, for this tumor entity, data are lacking regarding the oncological outcomes and associated factors after refusal of AT. Objective:To evaluate the difference in survival and disease recurrence for patients with and without recommended AT after resection of advanced OSCC. Design, Setting, and Participants:In this single-center retrospective matched cohort study, patients with advanced OSCC who refused recommended AT between January 2010 and December 2021 were matched 1:1 according to Union for International Cancer Control tumor staging with patients who completed AT. Exposures:Patients with advanced OSCC who refused or completed recommended AT between 2010 and 2021. Main Outcomes and Measures:The primary outcome of this study was the comparison of overall survival (OS) and recurrence-free survival (RFS) between the 2 study groups. Results:A total of 82 patients (mean [SD] age at time of surgery, 68.0 [11.3] years; 38 [46.3%] female, 44 [53.7%] male) with and without AT (41 per study group) were included in the analysis. Patients refusing AT developed more frequent disease recurrence than patients who completed AT (61.0% vs 26.8%; difference, 34.2%; odds ratio, 4.26; 95% CI, 1.68-10.84). In addition, patients who refused AT presented with lower 2-year OS (72.7% vs 88.6%; difference, 15.9%; 95% CI, 8.6%-40.6%) and much lower 2-year RFS (39.1% vs 74.2%; difference, 35.1%; 95% CI, 0.2%-70.5%). In the patient cohort who rejected AT, a worse OS was associated with female sex (48.6% vs 90.5%; difference, 41.9%; 95% CI, 0.6%-84.4%), pT1-2 category (57.1% vs 92.3%; difference, 35.2%; 95% CI, 3.3%-73.6%), and pN1 or higher category (61.2% vs 82.6%; difference, 21.4%; 95% CI, 14.1%-56.8%). Lower RFS was associated with female sex (37.9% vs 90.9%; difference, 53.0%; 95% CI, 8.0%-97.9%), advanced T category (pT3-4, 35.3% vs 80.0%; difference, 44.7%; 95% CI, 6.4%-95.3%), lymph node yield of 20 or greater (31.4% vs 80.6%; difference, 49.2%; 95% CI, 4.9%-93.4%), and lymph node ratio of less than 4.6% (36.6% vs 84.4%; difference, 47.8%; 95% CI, 1.8%-93.1%). Conclusions and Relevance:In this cohort study of patients with advanced OSCC, refusal of AT was associated with worse oncological outcomes. The prevalence of disease recurrence during follow-up was 34% higher in patients who refused AT than in patients who completed AT. The results from this study may assist clinicians in guiding patients who are considering refusal of or withdrawal from AT.

Synovial sarcoma is a rare and highly aggressive subtype of soft tissue sarcoma. The clinical challenge posed by advanced or metastatic synovial sarcoma, marked by limited treatment options and suboptimal outcomes, necessitates innovative approaches. The topoisomerase II (Topo II) inhibitor doxorubicin has remained the cornerstone systemic treatment for decades, and there is pressing need for improved therapeutic strategies for these patients. This study highlights the potential to enhance the cytotoxic effects of doxorubicin within well-characterized synovial sarcoma cell lines using the potent and selective DNA-PK inhibitor, peposertib. In vitro investigations unveil a p53-mediated synergistic anti-tumor effect when combining doxorubicin with peposertib. The in vitro findings were substantiated by pronounced anti-tumor effects in mice bearing subcutaneously implanted tumors. A well-tolerated regimen for the combined application was established using both pegylated liposomal doxorubicin (PLD) and unmodified doxorubicin. Notably, the combination of PLD and peposertib displayed enhanced anti-tumor efficacy compared to unmodified doxorubicin at equivalent doses, suggesting an improved therapeutic window—a critical consideration for clinical translation. Efficacy studies in two patient-derived xenograft models of synovial sarcoma, accurately reflecting human metastatic disease, further validate the potential of this combined therapy. These findings align with previous evidence showcasing the synergy between DNA-PK inhibition and Topo II inhibitors in diverse tumor models, including breast and ovarian cancers. Our study extends the potential utility of combined therapy to synovial sarcoma.

INTRODUCTION:In lateralized oral squamous cell carcinoma (OSCC) with ipsilateral cervical lymph node metastasis (CLNM), the surgical management of the unsuspicious contralateral neck remains a matter of debate. The aim of this study was to analyze this cohort and to compare the outcomes of patients with and without contralateral elective neck dissection (END).MATERIAL AND METHODS:A retrospective analysis of patients with lateralized OSCC, ipsilateral CLNM (pN+) and contralateral cN0-stage was performed. Patients were divided into two groups according to the surgical management of the contralateral neck: I: END; and II: no END performed. Adjuvant radiotherapy was applied bilaterally in both groups according to individual risk.RESULTS:A total of 65 patients (group I: 16 (24.6%); group II: 49 (75.4%)) with a median follow-up of 28 months were included. Initially, there was no case of contralateral CLNM after surgery. During follow-up, 6 (9.2%) patients presented with recurrent CLNM. In 5 of these cases (7.7%), the contralateral neck (group I: 3/16 (18.8%); group II: 2/49 (4.1%)) was affected. Increased ipsilateral lymph node ratio was associated with contralateral CLNM (p = 0.07). END of the contralateral side showed no significant benefit regarding OS (p = 0.59) and RFS (p = 0.19).CONCLUSIONS:Overall, the risk for occult contralateral CLNM in patients with lateralized OSCC ipsilateral CLNM is low. Our data suggest that END should not be performed routinely in this cohort. Risk-adapted radiotherapy of the contralateral neck alone seems to be sufficient from the oncological point of view.

Metastatic clear cell renal cell carcinomas (ccRCCs) are resistant to DNA-damaging chemotherapies, limiting therapeutic options for patients whose tumors are resistant to tyrosine kinase inhibitors and/or immune checkpoint therapies. Here we show that mouse and human ccRCCs were frequently characterized by high levels of endogenous DNA damage and that cultured ccRCC cells exhibited intact cellular responses to chemotherapy-induced DNA damage. We identify that pharmacological inhibition of the DNA damage-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) with the orally administered, potent, and selective drug M4344 (gartisertib) induced antiproliferative effects in ccRCC cells. This effect was due to replication stress and accumulation of DNA damage in S phase. In some cells, DNA damage persisted into subsequent G2/M and G1 phases, leading to the frequent accumulation of micronuclei. Daily single-agent treatment with M4344 inhibited the growth of ccRCC xenograft tumors. M4344 synergized with chemotherapeutic drugs including cisplatin and carboplatin and the poly(ADP-ribose) polymerase inhibitor olaparib in mouse and human ccRCC cells. Weekly M4344 plus cisplatin treatment showed therapeutic synergy in ccRCC xenografts and was efficacious in an autochthonous mouse ccRCC model. These studies identify ATR inhibition as a potential novel therapeutic option for ccRCC.

Objectives: Oral squamous cell carcinoma (OSCC) arising from the upper oral cavity is rare compared to other localizations. While cervical lymph node metastasis (CLNM) can be predicted to some extent, the probability of occult CLNM remains high. The aim of this study is to determine risk factors affecting clinical decision making. Materials and methods: A retrospective analysis of patients surgically treated between 2012 and 2017 for OSCC of the upper oral cavity was performed. Results: A total of 66 patients were included. Of these, 25 patients (37.9%) presented with CLNM after histopathological examination (pN+/cN0: 10/44 (22.7%); pN+/cN+: 15/22 (68.2%)). Lymph vessel infiltration (p = 0.03) and grade of differentiation (p = 0.03) were associated with an increased probability for CLNM. Patients with positive nodal disease at the time of primary surgery showed higher tumor depth of invasion (DOI) than patients without CLNM (mean 10.3 mm +/- 6.9 versus mean 6.1 mm +/- 4.9; p = 0.02). The optimal DOI cutoff value for the prediction of CLNM was 4.5 mm. The OS was significantly higher in patients with a tumor DOI <= 4.5 mm (p = 0.01). Conclusion: Elective neck dissection should be preferably performed for OSCC of the upper oral cavity. For earlystage and clinically node-negative patients, sentinel-lymph node biopsy can be an alternative, especially in patients with a DOI <= 4.5 mm. Since this group had no occult CLNM below this DOI cutoff value, watch and wait might be an alternative for selected patients.

Different parameters have been identified in patients with oral squamous cell carcinomas (OSCC) that have a serious impact on survival, including residual tumour and extracapsular spread. Moreover, other factors, including the lymph node ratio (LNR) and lymph node yield (LNY), have been suggested as prognostic markers. This retrospective study included patients diagnosed with OSCC and cervical lymph node metastases during the years 2010–2020. Patients’ records were evaluated regarding lymph node status, final therapy regime, tumour recurrence, time to death, tumour association with death, disease-free survival (DSF), and overall survival (OS). In 242 patients with a mean age of 63.57 ± 11.24 years, treated either by selective neck dissection (SND; n = 70) or by modified radical neck dissection (MRND; n = 172), 5772 lymph nodes were detected. The LNR and LNY were identified as independent risk factors in OS and DFS. The optimal cut-off point for the LNY was ≥ 17 lymph nodes in the SND and ≥ 27 lymph nodes in the MRND group. The metastatic lymph node clearance (MLNC) was established as a score to relate the LNR and LNY to the extent of lymph node removal. Survival analysis showed statistically significant differences among score levels. As information about the extent of nodal dissection is excluded from LNR and LNY, we propose the use of a new scoring system comprising individual cut-off values for LNY and LNR with regard to the extent of neck dissection. MLNC might help to identify high-risk OSCC patients with metastatic lymph nodes.

BACKGROUND/AIM:The aim of the present study was to assess the value of panendoscopy of the upper aero-digestive tract in the identification of synchronous tumors in OSCC patients without clinical signs of a second primary tumor.PATIENTS AND METHODS:In this retrospective study, patients diagnosed with a primary OSCC who received surgical therapy between January 1st, 2012 and December 31st, 2017 were included. Participants must have undergone panendoscopy during the staging process. None of these patients showed clinical signs of a second primary tumor.RESULTS:A total of 265 patients (99 females and 166 males; mean age=63.3 years, range=26-96 years) were included. The mean (SD) follow-up was 25.88 (±20.479 SD) months. Five synchronous secondary tumors (1.9%) could be identified within this cohort. Of these, only two (0.8%) were located within the area of panendoscopy and were diagnosed in patients with regular alcohol and/or tobacco abuse. Eighteen metachronous second primary tumors were diagnosed, 10 being located within the upper aero-digestive tract.CONCLUSION:The relevance of routinely performed panendoscopy in patients suffering from an oral squamous cell carcinoma without clinical signs of a secondary tumor should be critically re-evaluated, especially in patients without typical risk factors.

Uphill electron transfers allow reducing inert metabolites and activating low potential metalloenyzmes. One way to overcome the barrier of an uphill electron transfer is coupling to ATP hydrolysis. How the processes are coupled and how they produce a unidirectional transfer preventing the thermodynamically favorable back electron transfer is not understood. Here, we investigated the ATP-dependent electron transfer between the metallo-ATPase reductive activator of CoFeSP (RACo) and its B12-dependent partner protein CoFeSP. We show that electron transfer is triggered by ATP binding, overcoming a Delta E-0' of more than -250 mV. Rapid electron transfer is conformationally gated and requires potassium or ammonium ions. Slow ATP hydrolysis delays the last reaction step to allow rereduction of the oxidized activator, shifting the electron-transfer equilibrium to the products. These insights into the mechanism provide us with a blueprint to efficiently harness the energy of ATP in a coupling scheme with conformational changes to generate a unidirectional uphill electron transfer.