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Simple Summary: We provide an extensive review of the fundamental principles of statistical science that are needed to accurately interpret randomized controlled trials (RCTs). We use these principles to explain how RCTs are motivated by the powerful but strange idea that flipping a coin to choose each patient's treatment is the most statistically reliable way to compare treatments. Random treatment assignment ensures fair comparisons between treatments because it does away with bias and confounding from variables other than treatment. If the goal is to estimate treatment effects in a patient population, rather than compare two or more treatments, then random sampling, not random treatment assignment, is required. However, random sampling is virtually impossible to carry out in a clinical trial because patients are accrued over time as they arrive in the clinic, subject to a trial's entry criteria. Consequently, in practice, a trial provides a nonrepresentative convenience sample. Valid treatment comparisons provided by RCT data subsequently require additional causal assumptions of transportability of between-treatment effects from the sample to the patient population of interest. This may be used as a basis for choosing treatments for future patients. The present paper discusses what this means for practicing physicians who encounter RCT data in the literature. This article describes rationales and limitations for making inferences based on data from randomized controlled trials (RCTs). We argue that obtaining a representative random sample from a patient population is impossible for a clinical trial because patients are accrued sequentially over time and thus comprise a convenience sample, subject only to protocol entry criteria. Consequently, the trial's sample is unlikely to represent a definable patient population. We use causal diagrams to illustrate the difference between random allocation of interventions within a clinical trial sample and true simple or stratified random sampling, as executed in surveys. We argue that group-specific statistics, such as a median survival time estimate for a treatment arm in an RCT, have limited meaning as estimates of larger patient population parameters. In contrast, random allocation between interventions facilitates comparative causal inferences about between-treatment effects, such as hazard ratios or differences between probabilities of response. Comparative inferences also require the assumption of transportability from a clinical trial's convenience sample to a targeted patient population. We focus on the consequences and limitations of randomization procedures in order to clarify the distinctions between pairs of complementary concepts of fundamental importance to data science and RCT interpretation. These include internal and external validity, generalizability and transportability, uncertainty and variability, representativeness and inclusiveness, blocking and stratification, relevance and robustness, forward and reverse causal inference, intention to treat and per protocol analyses, and potential outcomes and counterfactuals. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the deep inferior epigastric perforator flap (DIEP) has become the most frequent autologous flap in breast reconstruction, it remains unclear whether reconstruction should be performed at the same time as the mastectomy or delayed. Therefore, we conducted a meta-analysis to offer an overview of recipient site postoperative complications and help guide practicians toward the ideal timing for breast reconstruction. A pooled analysis using the Mantel and Haenszel methods with a fixed effect model provided results as an odd ratio with a 95% confidence interval. Among most complications including hematoma, infection, fat necrosis, and flap loss, no significant differences were observed. However, delayed wound healing was significantly higher for patients who underwent delayed breast reconstruction. This paper offers evidence that both surgical timings offer similar outcomes and are, therefore, valid surgical strategies. Purpose: The setting regarding the ideal timing for deep inferior epigastric perforator flap (DIEP) reconstruction remains unclear. Immediate breast reconstruction (IBR) is performed at the same time as mastectomy, while delayed breast reconstruction (DBR) is performed at any time after mastectomy except immediately. We compared both strategies to assess whether IBR or DBR should be performed to reduce postoperative adverse events. Methods: A systematic review of PubMed, Embase, Medline, Cochrane, and Web of Science was conducted, aiming at articles comparing the recipient site outcomes of IBR versus DBR with DIEP. We used the Mantel–Haenszel method with a fixed effects model. Results were expressed as the OR with a 95% CI. Results: Two retrospective and two prospective studies were identified involving 5784 DIEPs (1744 immediate and 4040 delayed). We showed a significant difference in favor of IBR for wound healing issues (OR = 0.57, 95% CI 0.41, 0.77; p = 0.0003). However, no significant differences for hematoma, infection, fat necrosis, partial flap loss, and total flap loss rate were seen. Conclusions: Despite variability in the choice of the ideal time for breast reconstruction and outcomes reported among studies, immediate DIEP surgery appears to be a reliable setting with less delayed healing issues. [ABSTRACT FROM AUTHOR]

Simple Summary: Our findings confirm the role of developmental aspects in extracranial germ cell tumors (eGCTs). Strong associations between syndromes or congenital anomalies and eGCTs may hint at the need for research to identify potential causes and mechanisms. Strong effects were observed for Swyer and Currarino syndrome. The strengths of the associations emphasize the need for further elaboration on presently discussed pathophysiological mechanisms. For other suggested risk factors such as Klinefelter, Turner, and Down syndrome, the strength of risk appears to be substantially low and may be missed because of diagnostic bias for the first two or lack of power for the latter. A number of further syndromes were identified in single cases. Most of these pertain to girls. GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum's holistic concept, malignant and benign teratomas were registered. We used a case–control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher's exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7–2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2–88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgery to prevent breast and ovarian cancer is very effective, but there is limited research into the quality of life afterwards, particularly with reference to quality-of-life scores known as utility scores. These are important for patients at increased cancer risk who are considering surgery and are essential for health-economic evaluations. This article used data from a systematic review of different quality-of-life questionnaires given to patients following these surgeries. We converted these data into utility scores, as recommended by the national guidelines. This shows that surgery to prevent breast cancer is associated with a long-term utility score of 0.92 and surgery to prevent ovarian cancer has a score of 0.97, indicating a mild–moderate impact. These are the first utility scores sourced from patients who have undergone these procedures, and they are important to doctors counselling patients about cancer prevention options and to researchers. Higher-quality studies are still needed, using the recommended quality-of-life questionnaire (EQ-5D). Background: Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are the most effective breast and ovarian cancer preventive interventions. EQ-5D is the recommended tool to assess the quality of life and determine health-related utility scores (HRUSs), yet there are no published EQ-5D HRUSs after these procedures. These are essential for clinicians counselling patients and for health-economic evaluations. Methods: We used aggregate data from our published systematic review and converted SF-36/SF-12 summary scores to EQ-5D HRUSs using a published mapping algorithm. Study control arm or age-matched country-specific reference values provided comparison. Random-effects meta-analysis provided adjusted disutilities and utility scores. Subgroup analyses included long-term vs. short-term follow-up. Results: Four studies (209 patients) reported RRM outcomes using SF-36, and five studies (742 patients) reported RRSO outcomes using SF-12/SF-36. RRM is associated with a long-term (>2 years) disutility of −0.08 (95% CI −0.11, −0.04) (I2 31.4%) and a utility of 0.92 (95% CI 0.88, 0.95) (I2 31.4%). RRSO is associated with a long-term (>1 year) disutility of −0.03 (95% CI −0.05, 0.00) (I2 17.2%) and a utility of 0.97 (95% CI 0.94, 0.99) (I2 34.0%). Conclusions: We present the first HRUSs sourced from patients following RRM and RRSO. There is a need for high-quality prospective studies to characterise quality of life at different timepoints. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this review was to evaluate the feasibility and the effectiveness of radiation therapy combined with local tumor ablation therapy in the treatment of primary and recurrent lung cancer in terms of toxicity profile and local control rate. Six studies featuring a total of 115 patients and 119 lesions were selected, showing encouraging outcomes that appear to be promising in terms of toxicity profile. Further prospective studies are need to better delineate combining LTA-RT treatment benefits in this setting. In patients with early-stage or recurrent NSCLC who are unable to tolerate surgery, a benefit could derive only from a systemic therapy or another few forms of local therapy. A systematic review was performed to evaluate the feasibility and the effectiveness of radiotherapy combined with local ablative therapies in the treatment of primary and recurrent lung cancer in terms of toxicity profile and local control rate. Six studies featuring a total of 115 patients who met eligibility criteria and 119 lesions were included. Three studies evaluated lung cancer patients with a medically inoperable condition treated with image-guided local ablative therapies followed by radiotherapy: their local control rate (LC) ranged from 75% to 91.7% with only 15 patients (19.4%) reporting local recurrence after combined modality treatment. The other three studies provided a salvage option for patients with locally recurrent NSCLC after RT: the median follow-up period varied from 8.3 to 69.3 months with an LC rate ranging from 50% to 100%. The most common complications were radiation pneumonitis (9.5%) and pneumothorax (29.8%). The proposed intervention appears to be promising in terms of toxicity profile and local control rate. Further prospective studies are need to better delineate combining LTA-RT treatment benefits in this setting. [ABSTRACT FROM AUTHOR]

Simple Summary: This study group has previously published and documented that multimodal prehabilitation (enhanced optimization of physical function and adjustment of modifiable medical issues) before major bladder surgery is feasible and leads to a positive change in patients' fitness and functional status from a short-term perspective after surgery. However, long-term follow-ups after prehabilitation have not yet been published. Thus, this study aims to evaluate 1-year results on the efficacy of physical prehabilitation on functional capacity and nutritional recovery to inform the bladder cancer community of the potential of prehabilitation. The results show that prehabilitation in major bladder cancer surgery can significantly improve physical function and support the maintenance of nutritional status one year after major bladder cancer surgery. The results promote the gradual recognition that early restoration of physical function is vital to a full recovery. Multimodal prehabilitation is the process of enhancing physiological, nutritional, and psychological resilience to increase patients' functional capacity before major cancer surgery and aims to empower the patient to withstand the pending stress of major surgery and ultimately to improve long-term outcomes. The effect of physical prehabilitation to counteract the physical decline in surgical cancer patients has been documented; however, long-term results have not yet been published. This follow-up study aims to evaluate 1-year results on the efficacy of physical prehabilitation after bladder cancer surgery. The efficacy of prehabilitation was measured over the course of 1 year in 107 patients randomized to (1) pre- and rehabilitation or (2) standard care divided by n = 50 in the intervention (I) and n = 57 in the standard group (S). Physical function was measured by muscle leg power, and nutritional status was expressed with handgrip strength. Prehabilitation in major bladder cancer surgery can significantly improve physical function with 19.8 Watt/kg (p = 0.04), lean body mass (p = 0.047) and body cell mass (p = 0.03), and regained nutritional status one year after surgery. The results demonstrate that the restoration of physical function is vital to a full recovery. [ABSTRACT FROM AUTHOR]

Simple Summary: Two-dimensional shear wave elastography (2D-SWE) has demonstrated predictive value for symptomatic post-hepatectomy liver failure (PHLF) in hepatocellular carcinoma (HCC). Our aim was to develop and validate an interpretable radiomics model based on 2D-SWE for predicting symptomatic PHLF in patients undergoing liver resection for HCC. We proposed an interpretable clinical–radiomics model based on both multi-patch radiomics and clinical features, which showed an AUC of 0.822 in the test cohort, higher than the clinical model (AUC: 0.684, p = 0.007), radiomics model (AUC: 0.784, p = 0.415), end-stage liver disease (MELD) score (AUC: 0.529, p < 0.001), and albumin–bilirubin (ALBI) score (AUC: 0.644, p = 0.016). The SHAP analysis showed that first-order radiomics features were the most important features for PHLF prediction. The clinical–radiomics model is useful for predicting symptomatic PHLF in HCC with high model interpretability, which may serve as a useful tool for therapeutic decision making to improve perioperative management. Objective: The aim of this study was to develop and validate an interpretable radiomics model based on two-dimensional shear wave elastography (2D-SWE) for symptomatic post-hepatectomy liver failure (PHLF) prediction in patients undergoing liver resection for hepatocellular carcinoma (HCC). Methods: A total of 345 consecutive patients were enrolled. A five-fold cross-validation was performed during training, and the models were evaluated in the independent test cohort. A multi-patch radiomics model was established based on the 2D-SWE images for predicting symptomatic PHLF. Clinical features were incorporated into the models to train the clinical–radiomics model. The radiomics model and the clinical–radiomics model were compared with the clinical model comprising clinical variables and other clinical predictive indices, including the model for end-stage liver disease (MELD) score and albumin–bilirubin (ALBI) score. Shapley Additive exPlanations (SHAP) was used for post hoc interpretability of the radiomics model. Results: The clinical–radiomics model achieved an AUC of 0.867 (95% CI 0.787–0.947) in the five-fold cross-validation, and this score was higher than that of the clinical model (AUC: 0.809; 95% CI: 0.715–0.902) and the radiomics model (AUC: 0.746; 95% CI: 0.681–0.811). The clinical–radiomics model showed an AUC of 0.822 in the test cohort, higher than that of the clinical model (AUC: 0.684, p = 0.007), radiomics model (AUC: 0.784, p = 0.415), MELD score (AUC: 0.529, p < 0.001), and ALBI score (AUC: 0.644, p = 0.016). The SHAP analysis showed that the first-order radiomics features, including first-order maximum 64 × 64, first-order 90th percentile 64 × 64, and first-order 10th percentile 32 × 32, were the most important features for PHLF prediction. Conclusion: An interpretable clinical–radiomics model based on 2D-SWE and clinical variables can help in predicting symptomatic PHLF in HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Anti-EGFR-related skin toxicity has been described as a predictive biomarker of response in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). With the CAVE mCRC trial we previously provided the first evidence of the activity of cetuximab plus avelumab as rechallenge treatment in pretreated chemo-refractory RAS WT mCRC. Nowadays, skin toxicity remains the only confirmed clinical biomarker of response to anti-EGFR treatment in mCRC. The role of skin toxicity has not yet been explored in a rechallenge setting. In this paper we provide a post-hoc analysis of the CAVE mCRC trial that investigated the role of skin toxicity as a predictive biomarker of activity of cetuximab plus avelumab treatment and its correlation with different clinico-molecular variables on survival at the univariate and multivariate levels. High-grade skin toxicity, together to the circulating tumor DNA RAS/BRAF/EGFR wild-type status were the only variables with an impact on PFS and OS. The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2–3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9–20.6); whereas 44/77 (57.1%) patients with grade 0–1 ST exhibited mOS of 8.2 months (CI 95%, 5.5–10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29–0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4–5.7) in patients with grade 2–3 ST, compared to patients with grade 0–1 ST with mPFS of 3.4 months (CI 95%, 2.7–4.1; HR, 0.49; CI 95%, 0.3–0.8; p = 0.004). Grade 2–3 ST (HR, 0.51; CI 95%, 0.29–0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27–0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27–0.9; p = 0.023), whereas there was a trend towards ST grade 2–3 (HR, 0.54; CI 95%, 0.29–1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge. [ABSTRACT FROM AUTHOR]

Simple Summary: Poly ADP-ribose polymerase inhibitors (PARPis) can be used in men with advanced prostate cancer. Unfortunately, this class of therapeutics has demonstrated the risk of developing hematological adverse events. We conducted a systematic review and meta-analysis of several PARPi clinical trials to further evaluate the incidence of anemia, thrombocytopenia, and neutropenia adverse events in prostate cancer patients. We found that this treatment is significantly associated with hematologic suppression. Further stratification suggests differences may exist between PARPis within this class of therapy. Background: Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events. Objective: To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer. Study Methodology: A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews—Cochrane were queried from inception to 9 June 2023. The Mantel–Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities. Results: The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37–4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97–10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60–6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06–11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80–10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77–17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities. Conclusion: PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient–physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs. [ABSTRACT FROM AUTHOR]

Simple Summary: CTHRC1 is a protein with pro-tumoral effects that is highly expressed in tumors. We found that cancer stroma is the major source of CTHRC1 secretion in pancreatic cancer, and CTHRC1 regulates cancer extracellular matrix (ECM) remodeling by activating pancreatic stellate cells (PSCs), a main component of pancreatic cancer stroma. Our results show that CTHRC1-activated PSCs differentiated into myofibroblast-like CAFs (myCAFs). Moreover, the pro-tumoral effects manifested by CTHRC1 were more potent through PSC activation than via autocrine action. Periostin, a stroma-specific molecule, demonstrated an essential role in the CTHRC1–PSCs–cancer metastasis axis. Blocking CTHRC1 reversed PSC activation in vitro and showed significant anti-tumoral effects in animal models. However, long-term CTHRC1 treatment likely caused a shift from myCAFs into inflammatory CAFs. This study elucidates PSC activation as the central mechanism underlying the pro-tumoral effects of CTHRC1 and suggests that future studies on CTHRC1 as a potential therapeutic target for pancreatic cancer are warranted. [BACKGROUND] Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that contributes to the progression of various cancers, including pancreatic cancer. The higher expression of CTHRC1 in tumor tissues is associated with poorer survival outcomes. However, its specific roles in tumor extracellular matrix (ECM) remodeling remain unclear. Our study aims to investigate the influences of CTHRC1 on pancreatic stellate cells (PSCs), a main source of ECM production in pancreatic cancer. [METHODS AND RESULTS] The analyses of the publicly available pancreatic cancer patient data revealed that CTHRC1 is mainly expressed in cancer stroma and highly correlated with ECM-related genes. An in vitro study showed that more than 40% of these genes can be upregulated by CTHRC1. CTHRC1 specifically activated PSC into myofibroblast-like cancer-associated fibroblasts (myCAFs), which are characterized by a significantly upregulated POSTN gene expression. Periostin (coded by the POSTN gene) has a central role in the CTHRC1–PSCs–cancer metastasis axis. Furthermore, CTHRC1 promoted pancreatic cancer cell proliferation through PSC activation to a greater extent than via direct stimulation. Proof-of-concept experiments showed that the long-term (4-week) inhibition of CTHRC1 led to significant tumor suppression and ECM reduction, and also resulted in an unexpected shift in the CAF subtype from myCAFs to inflammatory CAFs (iCAFs). [CONCLUSION] PSC activation was demonstrated to be the key molecular mechanism responsible for the tumor-promoting effects of CTHRC1, and CTHRC1 has a critical role in CAF subtype differentiation and tumor microenvironment (TME) remodeling. The inhibition of CTHRC1 as a therapeutic strategy for the treatment of pancreatic cancer warrants further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: The need for prognostic and predictive biomarkers in pancreatic neuroendocrine neoplasms (PNENs) is great. Overexpression of somatostatin receptors (SSTRs) provides a molecular basis for imaging these tumors with 68Ga-labeled somatostatin (SST) PET/CT and for treatment with somatostatin analogs. We evaluated all 5 somatostatin receptors (SSTR1-5) with immunohistochemistry and prospectively compared the results with both [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT in a cohort of 21 non-functional (NF) PNENs. SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. High SSTR5 expression correlated with a low Ki-67 proliferation index, suggesting a better prognosis for these patients. Thus, our results confirm that SSTR2 has the highest impact on SSTR PET signaling of PNENs. Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [68Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [68Ga]Ga-DOTANOC and [18F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [68Ga]Ga-DOTANOC finding (Spearman's rho 0.382, p = 0.043). All [68Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal. [ABSTRACT FROM AUTHOR]