Cytoreduction plus hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis in colorectal cancer patients: a single-center cohort study

BACKGROUND: In this study, we report our experience of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC), focusing on the factors affecting survival. METHODS: All patients with surgically treated PC from colorectal cancer and with no involvement of other organs referred to our institute from March 2005 to December 2017 were included in the analysis. RESULTS: Thirty-eight patients underwent CRS-HIPEC, and all had a completeness of cytoreduction score of 0 (CC0). The median operating time was 645 min (interquartile range [IQR] 565-710). Five patients (13.1%) had Clavien-Dindo grade >\u20092 postoperative complications. Median overall survival (OS) was 60 months. In the Cox regression for OS, calculated on the CRS-HIPEC group, the peritoneal cancer index (PCI) >\u20096 (hazard ratio [HR] 4.48, IQR 1.68-11.9, P = 0.003) and significant nodal involvement (N2) (HR 3.89, IQR 1.50-10.1, P = 0.005) were independent prognostic factors. Median disease-free survival (DFS) was 16 months. Only N2 (HR 2.44, IQR 1.11-5.36, P = 0.027) was a significantly negative prognostic factor for DFS in multivariate analysis. CONCLUSIONS: CRS-HIPEC can substantially improve survival. However, patients with high PCI (PCI >\u20096) and significant nodal involvement (N2) may not benefit from the procedure

Geodetic model of the 2016 Central Italy earthquake sequence inferred from InSAR and GPS data

We investigate a large geodetic data set of interferometric synthetic aperture radar (InSAR)and GPS measurements to determine the source parameters for the three main shocks of the 2016Central Italy earthquake sequence on 24 August and 26 and 30 October (Mw6.1, 5.9, and 6.5,respectively). Our preferred model is consistent with the activation of four main coseismic asperitiesbelonging to the SW dipping normal fault system associated with the Mount Gorzano-Mount Vettore-Mount Bove alignment. Additional slip, equivalent to aMw~ 6.1–6.2 earthquake, on a secondary (1) NEdipping antithetic fault and/or (2) on a WNW dipping low-angle fault in the hanging wall of the mainsystem is required to better reproduce the complex deformation pattern associated with the greatestseismic event (theMw6.5 earthquake). The recognition of ancillary faults involved in the sequencesuggests a complex interaction in the activated crustal volume between the main normal faults and thesecondary structures and a partitioning of strain releas

TRIBE-2: A phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Background: Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. Methods/design: TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. Discussion: The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. Trial registration: TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014

TRIPLETE: A randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer

FOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective of RAS and BRAF molecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity in RAS and BRAF wild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients with RAS and BRAF wild-type metastatic colorectal cancer. Methods This is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreated RAS and BRAF wild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m 2, oxaliplatin 85 mg/m 2, L-leucovorin 200 mg/m 2, 5-fluoruracil 2400 mg/m 2 48-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5-fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria. Discussion The relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres. Clinical trial information NCT03231722

Optimized EGFR blockade strategies in <i>EGFR</i> addicted gastroesophageal adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Tissutal and Fluidic Aspects in Osteopathic Manual Therapy: A Narrative Review

Over the years, several authors have discussed the possibility of considering somatic dysfunction (SD) as a “nosological element” detectable on palpation. There are many aspects to consider regarding the etiology and diagnosis of SD, and the literature on osteopathic issues provides details on physiological signs that characterize it, including tissue texture changes. Recent knowledge suggests that how tissue and, in particular, connective tissue, responds to osteopathic treatment may depend on the modulation of the inflammation degree. Low-grade inflammation (LGI) may act on the extracellular matrix (ECM) and on cellular elements; and these mechanisms may be mediated by biological water. With its molecules organized in structures called exclusion zones (EZ), water could explain the functioning of both healthy and injured tissues, and how they can respond to osteopathic treatment with possible EZ normalization as a result. The relationship between inflammation and DS and the mechanisms involved are described by several authors; however, this review suggests a new model relating to the characteristics of DS and to its clinical implications by linking to LGI. Tissue alterations detectable by osteopathic palpation would be mediated by body fluids and in particular by biological water which has well-defined biophysical characteristics. Research in this area is certainly still to be explored, but our suggestion seems plausible to explain many dynamics related to osteopathic treatment. We believe that this could open up a fascinating scenario of therapeutic possibilities and knowledge in the future

3D CT-Inclusive Deep-Learning Model to Predict Mortality, ICU Admittance, and Intubation in COVID-19 Patients

Chest CT is a useful initial exam in patients with coronavirus disease 2019 (COVID-19) for assessing lung damage. AI-powered predictive models could be useful to better allocate resources in the midst of the pandemic. Our aim was to build a deep-learning (DL) model for COVID-19 outcome prediction inclusive of 3D chest CT images acquired at hospital admission. This retrospective multicentric study included 1051 patients (mean age 69, SD = 15) who presented to the emergency department of three different institutions between 20th March 2020 and 20th January 2021 with COVID-19 confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Chest CT at hospital admission were evaluated by a 3D residual neural network algorithm. Training, internal validation, and external validation groups included 608, 153, and 290 patients, respectively. Images, clinical, and laboratory data were fed into different customizations of a dense neural network to choose the best performing architecture for the prediction of mortality, intubation, and intensive care unit (ICU) admission. The AI model tested on CT and clinical features displayed accuracy, sensitivity, specificity, and ROC-AUC, respectively, of 91.7%, 90.5%, 92.4%, and 95% for the prediction of patient's mortality; 91.3%, 91.5%, 89.8%, and 95% for intubation; and 89.6%, 90.2%, 86.5%, and 94% for ICU admission (internal validation) in the testing cohort. The performance was lower in the validation cohort for mortality (71.7%, 55.6%, 74.8%, 72%), intubation (72.6%, 74.7%, 45.7%, 64%), and ICU admission (74.7%, 77%, 46%, 70%) prediction. The addition of the available laboratory data led to an increase in sensitivity for patient's mortality (66%) and specificity for intubation and ICU admission (50%, 52%, respectively), while the other metrics maintained similar performance results. We present a deep-learning model to predict mortality, ICU admittance, and intubation in COVID-19 patients