Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We ...examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial.
Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1–4) were used to assess individual-level surrogacy of NAR for DFS.
After a median follow-up of 50months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS 75.9% (95% confidence interval CI 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P=0.034; PC 1) and resulted in a shift toward lower NAR groups (P=0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P<0.001; PC 3). NAR score remained an independent prognostic factor for DFS low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106–7.020; P<0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303–2.98; P=0.001 in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4.
Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.
One critical step in the therapy of patients with localized pancreatic cancer is the determination of local resectability. The decision between primary surgery versus upfront local or systemic cancer ...therapy seems especially to differ between pancreatic cancer centers. In our cohort study, we analyzed the independent judgement of resectability of five experienced high volume pancreatic surgeons in 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer.
Pretherapeutic CT or MRI scans of 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer were evaluated by 5 independent pancreatic surgeons. Resectability and the degree of abutment of the tumor to the venous and arterial structures adjacent to the pancreas were reported. Interrater reliability and dispersion indices were compared.
One hundred ninety-four CT scans and 6 MRI scans were evaluated and all parameters were evaluated by all surgeons in 133 (66.5%) cases. Low agreement was observed for tumor infiltration of venous structures (κ = 0.265 and κ = 0.285) while good agreement was achieved for the abutment of the tumor to arterial structures (interrater reliability celiac trunk κ = 0.708 P < 0.001). In patients with vascular tumor contact indicating locally advanced disease, surgeons highly agreed on unresectability, but in patients with vascular tumor abutment consistent with borderline resectable disease, the judgement of resectability was less uniform (dispersion index locally advanced vs. borderline resectable p < 0.05).
Excellent agreement between surgeons exists in determining the presence of arterial abutment and locally advanced pancreatic cancer. The determination of resectability in borderline resectable patients is influenced by additional subjective factors.
EudraCT:2009-014476-21 (2013-02-22) and NCT01827553 (2013-04-09).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
The etiology of obsessive–compulsive disorder (OCD) is assumed to involve interactions between genetically determined vulnerability factors and significant environmental features. Here, we ...aim to investigate how the personality trait harm avoidance and the experience of childhood adversities contribute to OCD.
Method
A total of 169 patients with OCD, 157 healthy comparison subjects, and 57 unaffected first‐degree relatives of patients with OCD participated in the study. Harm avoidance was assessed using the Temperament and Character Inventory, and the severity of childhood adversities was measured with the Childhood Trauma Questionnaire.
Results
Both patients with OCD and relatives showed elevated levels of harm avoidance compared to controls. Furthermore, patients exhibited significantly higher scores than relatives. This linear pattern was observed throughout all subscales of harm avoidance, and remained stable after controlling for the severity of depressive and obsessive–compulsive symptoms. With regard to childhood adversities, patients with OCD reported higher levels than relatives and controls.
Conclusion
Our results provide further evidence for a diathesis‐stress model of OCD. While patients and unaffected relatives share elevated levels of harm avoidance, supporting the role of harm avoidance as an endophenotype of OCD, a heightened severity of childhood adversity was only observed in patients. The assumed biological underpinnings of these findings are discussed.
Mixed adenoneuroendocrine carcinomas are highly malignant tumors with both adenocarcinomatous and neuroendocrine components. They can originate in any organ but are more common in the rectum. Due to ...their rarity, current treatment recommendations for mixed adenoneuroendocrine carcinoma are based on limited data and follow general guidelines for the management of adenocarcinomas and neuroendocrine neoplasms. Uncertainty regarding the efficacy of the available local and systemic treatment strategies is a compounding issue. Even those patients with locally limited disease have a relatively short life expectancy. In this report, we describe a case of deep rectal mixed adenoneuroendocrine carcinoma with long survival after chemoradiation.
A 48-year-old Caucasian woman was diagnosed with a grade 3 rectal adenocarcinoma combined with a poorly differentiated large cell neuroendocrine carcinoma component and synchronous metastases (cT3cN1cM1) in both lobes of the liver in 2012. She received concomitant chemoradiotherapy followed by four additional cycles of cisplatin plus irinotecan. Initial treatment induced complete remission of the rectal tumor and liver metastases. Consequently, it was not necessary to surgically resect the primary tumor or any of the metastases. Three months after the end of treatment, one metastasis in the first segment of the liver showed regrowth, and stereotactic body radiotherapy of the metastasis and chemotherapy resulted in a clinical complete response. The patient has been recurrence-free for more than 5 years.
Extended long-term control of a poorly differentiated metastatic (stage IV) mixed adenoneuroendocrine carcinoma is rare. The multimodal first- and second-line regimens of radiotherapy and chemotherapy described in this case report represent a new therapeutic approach. Encouraged by the results in this case, we compiled a review of the literature on mixed adenoneuroendocrine carcinoma.
Objective
Obsessive‐compulsive disorder (OCD) is a complex psychiatric disorder with a substantial genetic contribution. While the specific variants underlying OCD's heritability are still unknown, ...findings from genome‐wide association studies (GWAS) corroborate the importance of common SNPs explaining the phenotypic variance in OCD. Investigating associations between the genetic liability for OCD, as reflected by a polygenic risk score (PRS), and potential endophenotypes of the disorder, such as the personality trait harm avoidance, may aid the understanding of functional pathways from genes to diagnostic phenotypes.
Methods
We derived PRS for OCD at several P‐value thresholds based on the latest Psychiatric Genomics Consortium OCD GWAS (2688 cases, 7037 controls) in an independent sample of OCD patients (n = 180), their unaffected first‐degree relatives (n = 108) and healthy controls (n = 200). Using linear regression, we tested whether these PRS are associated with the personality trait harm avoidance.
Results
Results showed that OCD PRS significantly predicted OCD status, with patients having the highest scores and relatives having intermediate scores. Furthermore, the genetic risk for OCD was associated with harm avoidance across the entire sample, and among OCD patients. As indicated by mediation analyses, harm avoidance mediated the association between the OCD PRS and OCD caseness. These results were observed at multiple P‐value thresholds and persisted after the exclusion of patients with a current comorbid major depressive or anxiety disorder.
Conclusion
Our findings support the polygenic nature of OCD and further validate harm avoidance as a candidate endophenotype and diathesis of OCD.
Purpose
Recurrent prolapse of the posterior pelvic organ compartment presents a management challenge, with the best surgical procedure remaining unclear. We present functional outcome and patient ...satisfaction after laparoscopic and robotic ventral mesh rectopexy (VMR) with biological mesh in patients with recurrence.
Methods
We analyzed data from 30 patients with recurrent posterior pelvic organ prolapse who underwent VMR with biological mesh from August 2012 to January 2018. Data included patient demographics and intra- and postoperative findings; functional outcome as assessed by Cleveland Clinic Constipation Score (CCCS), Obstructed Defecation Score Longo (ODS), and Cleveland Clinic Incontinence Score (CCIS); and patient satisfaction.
Results
CCCS, CCIS, and ODS were significantly improved at 6–12 months postoperatively and at last follow-up. Patient satisfaction (visual analog scale VAS 6.7 0 to 10), subjective symptoms (+ 3.4 scale − 5 to + 5), and quality of life improvement (+ 3.0 scale from − 5 to + 5) were high at last follow-up. The rates of morbidity and major complications were 13% and 3%, respectively. There were no mesh-related complications or deaths. Difference in type of previous surgery (abdominal or transanal/perineal) had no significant effect on results.
Conclusions
VMR with biological mesh is a safe and effective option for patients with recurrent posterior pelvic organ prolapse. It reduces functional symptoms, has a low complication rate, and promotes patient satisfaction.
Purpose
Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 ...multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice.
Methods
One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor.
Results
Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 19.8%; R1/R2/Rx
n
= 11/126; 6.1%). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively;
p
= 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (
p
< 0.001).
Conclusion
Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.
Caveolin-1 (Cav-1) is an integral transmembrane protein and a critical component in interactions of integrin receptors with cytoskeleton-associated and signaling molecules. Since integrin-mediated ...cell adhesion generates signals conferring radiation resistance, we examined the effects of small interfering RNA-mediated knockdown of Cav-1 alone or in combination with beta1-integrin or focal adhesion kinase (FAK) on radiation survival and proliferation of pancreatic carcinoma cell lines. Irradiation induced Cav-1 expression in PATU8902, MiaPaCa2 and Panc1 cell lines. The cell lines showed significant radiosensitization after knockdown of Cav-1, beta1-integrin or FAK and cholesterol depletion by beta-cyclodextrin relative to nonspecific controls. Under knockdown conditions, proliferation of non-irradiated and irradiated cells was significantly attenuated relative to controls. These findings correlated with changes in expression or phosphorylation of Akt, glycogen synthase kinase 3beta, Paxillin, Src, c-Jun N-terminal kinase and mitogen-activated protein kinase. Analysis of DNA microarray data revealed a Cav-1 overexpression in a subset of pancreatic ductal adenocarcinoma samples. The data presented show, for the first time, that disruption of interactions of Cav-1 with beta1-integrin or FAK affects radiation survival and proliferation of pancreatic carcinoma cells and suggest that Cav-1 is critical to these processes. These results indicate that strategies targeting Cav-1 may be useful as an approach to improve conventional therapies, including radiotherapy, for pancreatic cancer.
Purpose
Retroperitoneal (RPS) sarcomas are associated with poor local and abdominal tumor control. However, the benefit of preoperative radio- or chemotherapy alone for these entities is currently ...unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency toward early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation.
Methods
From 2000–2019, 27 patients with intermediate- or high-grade RPS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45–75 Gy) and two cycles of chemotherapy (doxorubicin 50 mg/m
2
BSA/d3 q28 and ifosfamide 1.5 g/m
2
BSA/d1‑5 q28) in neoadjuvant intent. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) additionally received deep regional hyperthermia.
Results
The median follow-up time was 53 months (±56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free survival was 74.6% (±10.1%) and 66.3% (±11.9%), distant metastasis-free survival was 67.2% (±9.7%) and 59.7% (±11.1%), and overall survival was 60.3% (±10.5%) and 60.3% (±10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%), and anemia (11%). There were no treatment-related deaths.
Conclusion
Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal sarcomas is feasible and provided high local control of intermediate- and high-grade sarcoma.
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