Increased relative biological effectiveness and periventricular radiosensitivity in proton therapy of glioma patients.

PURPOSE: Currently, there is an intense debate on variations in intra-cerebral radiosensitivity and relative biological effectiveness (RBE) in proton therapy of primary brain tumours. Here, both effects were retrospectively investigated using late radiation-induced brain injuries (RIBI) observed in follow-up after proton therapy of patients with diagnosed glioma. METHODS: In total, 42 WHO grade 2-3 glioma patients out of a consecutive patient cohort having received (adjuvant) proton radio(chemo)therapy between 2014 and 2017 were eligible for analysis. RIBI lesions (symptomatic or clinically asymptomatic) were diagnosed and delineated on contrast-enhanced T1-weighted magnetic resonance imaging scans obtained in the first two years of follow-up. Correlation of RIBI location and occurrence with dose (D), proton dose-averaged linear energy transfer (LET) and variable RBE dose parameters were tested in voxel- and in patient-wise logistic regression analyses. Additionally, anatomical and clinical parameters were considered. Model performance was estimated through cross-validated area-under-the-curve (AUC) values. RESULTS: In total, 64 RIBI lesions were diagnosed in 21 patients. The median time between start of proton radio(chemo)therapy and RIBI appearance was 10.2 months. Median distances of the RIBI volume centres to the cerebral ventricles and to the clinical target volume border were 2.1 mm and 1.3 mm, respectively. In voxel-wise regression, the multivariable model with D, D × LET and periventricular region (PVR) revealed the highest AUC of 0.90 (95 % confidence interval: 0.89-0.91) while the corresponding model without D × LET revealed a value of 0.84 (0.83-0.86). In patient-level analysis, the equivalent uniform dose (EUD11, a = 11) in the PVR using a variable RBE was the most prominent predictor for RIBI with an AUC of 0.63 (0.32-0.90). CONCLUSIONS: In this glioma cohort, an increased radiosensitivity within the PVR was observed as well as a spatial correlation of RIBI with an increased RBE. Both need to be considered when delivering radio(chemo)therapy using proton beams.

Is metabolic syndrome a risk factor in hepatectomy? A meta-analysis with subgroup analysis for histologically confirmed hepatic manifestations.

BACKGROUND: Metabolic syndrome (MetS) is a risk factor in surgery. MetS can progress to metabolic (dysfunction)-associated fatty liver disease (MAFLD), a vast-growing etiology of primary liver tumors which are major indications for liver surgery. The aim of this meta-analysis was to investigate the impact of MetS on complications and long-term outcomes after hepatectomy. METHODS: The protocol for this meta-analysis was registered at PROSPERO prior to data extraction. MEDLINE, Web of Science, and Cochrane Library were searched for publications on liver resections and MetS. Comparative studies were included. Outcomes encompassed postoperative complications, mortality, and long-term oncologic status. Data were pooled as odds ratio (OR) with a random-effects model. Risk of bias was assessed using the Quality in Prognostic Studies tool (QUIPS), and the certainty of the evidence was evaluated with GRADE. Subgroup analyses for patients with histopathologically confirmed non-alcoholic fatty liver disease (NAFLD) versus controls were performed. RESULTS: The meta-analyses included fifteen comparative studies. Patients with MetS suffered significantly more overall complications (OR 1.55; 95% CI [1.05; 2.29]; p=0.03), major complications (OR 1.97 95% CI [1.13; 3.43]; p=0.02; I2=62%), postoperative hemorrhages (OR 1.76; 95% CI [1.23; 2.50]; p=0.01) and infections (OR 1.63; 95% CI [1.03; 2.57]; p=0.04). There were no significant differences in mortality, recurrence, 1- or 5-year overall or recurrence-free survivals. Patients with histologically confirmed NAFLD did not have significantly more overall complications; however, PHLF rates were increased (OR 4.87; 95% CI [1.22; 19.47]; p=0.04). Recurrence and survival outcomes did not differ significantly. The certainty of the evidence for each outcome ranged from low to very low. CONCLUSION: Patients with MetS that undergo liver surgery suffer more complications, such as postoperative hemorrhage and infection but not liver-specific complications-PHLF and biliary leakage. Histologically confirmed NAFLD is associated with significantly higher PHLF rates, yet, survivals of these patients are similar to patients without the MetS. Further studies should focus on identifying the tipping point for increased risk in patients with MetS-associated liver disease, as well as reliable markers of MAFLD stages and early markers of PHLF. TRIAL REGISTRATION: PROSPERO Nr: CRD42021253768.

Pushing the limit of liver regeneration - Safety and survival after monosegment-ALPPS: systematic review and individual patient data meta-analysis.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has expanded and spearheaded development in hepatobiliary surgery. Monosegment-ALPPS tests liver regeneration limits and may present as the last feasible curative treatment option. METHODS: Electronic databases (MEDLINE, Web of Science, Google Scholar, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on mono-ALPPS using a predefined strategy without date or language restrictions. Individual patient data was extracted and analyzed. RESULTS: 237 publications were identified. 19 patients were identified to have undergone mono-ALPPS. Primarily, mono-ALPPS has been utilized as curative treatment for CRLM (17 of 19 cases). Successful mono-ALPPS was possible in FLR above 8% SLV. All patients received either chemotherapy alone or in combination with radiotherapy prior to surgery. 8 of 19 patients experienced PHLF grade A or B. There was no in-hospital mortality described. Recurrent disease has occurred in 7 of 19 patients and 3 have died during follow-up. CONCLUSION: Mono-ALPPS is an experimental procedure that provides a reasonably safe opportunity to curatively treat extensive liver malignancies in patients with FLR as low as 8% SLV. PHLF is the most prevalent complication in mono-ALPPS. Mono-ALPPS should be evaluated in a multicentral study setting.

Scirrhous Hepatocellular Carcinoma: Systematic Review and Pooled Data Analysis of Clinical, Radiological, and Histopathological Features.

BACKGROUND: Aberrant subtypes of hepatocellular carcinoma (HCC) account for 20-30% of all HCCs and habitually present a challenge in diagnosis and treatment. Scirrhous hepatocellular carcinoma (s-HCC) is often misdiagnosed as cholangiocarcinoma, fibrolamellar hepatocellular carcinoma, or metastasis. METHODS: Electronic databases (PubMed, Web of Knowledge, Google Scholar, Cochrane Library, and WHO International Clinical Trials Registry Platform) were searched for publications on scirrhous hepatocellular carcinoma without date or language restrictions. Quality assessment was performed using a tool proposed by Murad et al for case reports and series. For observational studies, MINORS quality assessment tool was used. This study was registered at PROSPERO (CRD42020212323). RESULTS: S-HCC arises in patients with chronic hepatitis (hepatitis B in 60% and hepatitis C in 21%). S-HCC primarily affects men with a mean age of 55.8 years. Serum AFP is elevated above 20IU/mL in 66.7% of the patients. On ultrasound, s-HCC presents as hypoechoic or mosaic pattern lesions (47.6% each) and causes a retraction of the liver surface (70%) when near the capsule. Delayed enhancement of the tumor is evident in 87.0%. On MRI, 65.0% of s-HCCs show a target appearance. Histopathologic pattern is mostly irregular (97.6%). Lesions show a bulging appearance (100%), septae (85.6%) and a central scar (63.5%), and usually lack central necrosis (75%). Immunohistochemistry shows HepPar 1 positivity in 64.6%, CK7 in 40.7%, and EMA in 41.9%. The 5-year overall survival rate estimates 45.2% and 45.5% of the patients experience a recurrence after hepatectomy. CONCLUSION: S-HCC is a rare subtype of HCC primarily arising in hepatitis- or cirrhosis-afflicted livers and incorporates atypical radiological and histopathological HCC features. Despite lower recurrence rates, overall survival of patients with s-HCC is poorer than generally for HCC, underlining the need for individualized treatment. Patients with atypical lesions of the liver should be referred to tertiary hospitals for interdisciplinary assessment and treatment.

Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer.

Novel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of-but not all-spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.

Characteristics and Prognostic Factors of Metachronous Second Primary Upper Gastrointestinal Cancer.

BACKGROUND: Patients with metachronous malignancies before carcinomas of the upper gastrointestinal tract were analyzed regarding clinical parameters, oncological outcome, and prognosis. METHODS: We analyzed the data of 1583 patients with gastroesophageal cancer who underwent oncological resections between 2002 and 2018. Of 1583 patients, 172 had a malignant tumor before the upper gastrointestinal cancer (second primary carcinomas) and 1411 without preceding malignancies served as the control group. The analyses were performed between both groups and within the subgroup of second primary carcinomas. RESULTS: Patients with second primary carcinomas were older (P < 0.0001), had more comorbidities (P < 0.0001), and underwent longer surgical resections (P = 0.0024). They had lower (y)pT-categories (P = 0.0427) and had longer stays in intensive care unit (P = 0.0002) and hospital (P = 0.0018). R0-resection was more frequent (P = 0.0275) while having more surgical complications (P = 0.0378). The median survival was 39.5 mo (primary carcinoma) versus 32.9 mo for (second primary carcinoma) and was not significantly different (P = 0.5359).In the subgroup analysis of second primaries, there were no significant survival differences depending on primary tumor entity (P = 0.4989). pT status (P = 0.0062), pN status (P < 0.0001), pM status (P < 0.0001), and R-status (P < 0.0001) were significant prognostic factors. A time period >9 y after the primary cancer could be identified as a novel and beneficial survival factor (P = 0.0496). Most patients with primary colorectal, prostate, hematogenous, or breast cancer had adenocarcinoma, whereas patients with initial otolaryngologic cancers mainly had squamous cell carcinoma. CONCLUSIONS: Second primary carcinomas of the upper gastrointestinal tract show distinct clinical and oncological characteristics. Common prognostic factors are applicable, and oncologic resection is recommended.

Systematic Generation of Patient-Derived Tumor Models in Pancreatic Cancer.

In highly aggressive malignancies like pancreatic cancer (PC), patient-derived tumor models can serve as disease-relevant models to understand disease-related biology as well as to guide clinical decision-making. In this study, we describe a two-step protocol allowing systematic establishment of patient-derived primary cultures from PC patient tumors. Initial xenotransplantation of surgically resected patient tumors (n = 134) into immunodeficient mice allows for efficient in vivo expansion of vital tumor cells and successful tumor expansion in 38% of patient tumors (51/134). Expansion xenografts closely recapitulate the histoarchitecture of their matching patients' primary tumors. Digestion of xenograft tumors and subsequent in vitro cultivation resulted in the successful generation of semi-adherent PC cultures of pure epithelial cell origin in 43.1% of the cases. The established primary cultures include diverse pathological types of PC: Pancreatic ductal adenocarcinoma (86.3%, 19/22), adenosquamous carcinoma (9.1%, 2/22) and ductal adenocarcinoma with oncocytic IPMN (4.5%, 1/22). We here provide a protocol to establish quality-controlled PC patient-derived primary cell cultures from heterogeneous PC patient tumors. In vitro preclinical models provide the basis for the identification and preclinical assessment of novel therapeutic opportunities targeting pancreatic cancer.

Patient-derived xenografts of gastrointestinal cancers are susceptible to rapid and delayed B-lymphoproliferation.

Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B-lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts.