Chemotherapy Rechallenge or Reintroduction Compared to Regorafenib or Trifluridine/Tipiracil for Pretreated Metastatic Colorectal Cancer Patients: A Propensity Score Analysis of Treatment Beyond Second Line (Proserpyna Study).

BACKGROUND: The optimal treatment for metastatic colorectal cancer (mCRC) beyond second line is still questioned. Besides the standard of care agents (regorafenib, REG, or trifluridine/tipiracil, FTD/TPI), chemotherapy rechallenge or reintroduction (CTr/r) are commonly considered in clinical practice, despite weak supporting evidence. The prognostic performance of CTr/r, REG and FTD/TPI in this setting are herein evaluated. PATIENTS AND METHODS: PROSERpYNa is a multicenter, observational, retrospective study, in which patients with refractory mCRC, progressing after at least 2 lines of CT, treated with CTr/r, REG or FTD/TPI, are considered eligible and were enrolled in 2 independent data sets (exploratory and validation). Primary endpoint was overall survival (OS); secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (RR) and safety. A propensity score adjustment was accomplished for survival analyses. RESULTS: Data referring to patients treated between Jan-10 and Jan-19 from 3 Italian institutions were gathered (341 and 181 treatments for exploratory and validation data sets respectively). In the exploratory cohort, median OS (18.5 vs. 6.5 months), PFS (6.1 vs. 3.5 months) and RR (28.6% vs. 1.4%) were significantly longer for CTr/r compared to REG/FTD/TPI. Survival benefits were retained at the propensity score analysis, adjusted for independent prognostic factors identified at multivariate analysis. Moreover, these results were confirmed within the validation cohort analyses. CONCLUSIONS: Although the retrospective fashion, CTr/r proved to be a valuable option in this setting in a real-world context, providing superior outcomes compared to standard of care agents at the price of a moderate toxicity.

Treatment of patients with BRAFV600E-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset.

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.

Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience.

BACKGROUND: Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage. PATIENTS AND METHODS: This real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019. RESULTS: Out of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome. CONCLUSIONS: Our real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

Abyssal undular vortices in the Eastern Mediterranean basin.

Abyssal temperature and velocity observations performed within the framework of the Neutrino Mediterranean Observatory, a project devoted to constructing a km(3)-scale underwater telescope for the detection of high-energy cosmic neutrinos, demonstrate cross-fertilization between subnuclear physics and experimental oceanography. Here we use data collected south of Sicily in the Ionian abyssal plain of the Eastern Mediterranean (EM) basin to show for the first time that abyssal vortices exist in the EM, at depths exceeding 2,500 m. The eddies consist of chains of near-inertially pulsating mesoscale cyclones/anticyclones. They are embedded in an abyssal current flowing towards North-Northwest. The paucity of existing data does not allow for an unambiguous determination of the vortex origin. A local generation mechanism seems probable, but a remote genesis cannot be excluded a priori. The presence of such eddies adds further complexity to the discussion of structure and evolution of water masses in the EM.

[Early signs and symptoms before the psychotic onset. A study on the Duration of Untreated Illness (DUI) in a sample of patients with diagnosis of "non-affective psychotic disorders"]. / Segni e sintomi prodromici all'esordio psicotico. Uno studio sulla Duration of Untreated Illness (DUI) in un campione di pazienti con diagnosi di psicosi non affettiva.

AIMS: The aims of the study are to evaluate, in the Italian context, the presence and clinical features of early prodromal symptoms before the psychotic onset and, most of all, the duration of the period between the first onset of any psychiatric symptom and the psychotic onset (Duration of Untreated Illness). MATERIALS AND METHODS: The study was carried out on a sample of 296 inpatients with a diagnosis of "non-affective psychosis" enrolled in "Villa dei Fiori" inpatients Clinic in Rome. The retrospective analysis was developed using clinical records and clinical interview with patients and their parents. The evaluation of the psychotic onset and of DUI was assessed with the PANSS (Positive and Negative Symptoms Scale). RESULTS: The mean DUI is 4.7 ± 4.4 years. We found a connection between DUI and early symptoms of psycosis: depressive symptoms (4.9; DS=5.0) were most frequently observed, followed by anxiety symptoms (5.1; DS=4.8), eating disorders (5.7; DS=3.0); obsessive symptoms (4.5; DS=3.6); social withdrawal (5.9; DS=4.9); psychotic like symptoms (2.6; DS=1.3). DUI resulted lower in psychotic like symptoms than in the depressive ones. CONCLUSION: In Italy DUI turn out to be much longer than in other Country where do exists specialized services for early intervention. For this reason seem to be necessary to explore the opportunity to develop also in Italy specialized services for adolescents and young adults at risk and at their psychotic onset.

[Management of combined psychotherapy and pharmacological treatment. A 'cross sectional' study on a selected sample of psychiatrists]. / Modalità di gestione della terapia integrata in ambito psichiatrico. Uno studio 'cross-sectional' su un campione selezionato di psichiatri.

AIMS: The association between pharmacological treatment and psychotherapy is frequent. However doesn't exist any agreement or guide-line about the management of this combined therapy. Therefore we considered useful to evaluate which were the most frequent way of management of the combined therapy in a sample of 120 psychiatrists. MATERIALS AND METHODS: A 10-items questionnaire finalized to explore the management way of the combined therapy was administered to a sample of 120 psychiatrists. A descriptive analysis of the data was made and the association between different variables was explored. The statistical analysis was performed using SPSS 13.0. RESULTS: 35% of the sample work as a private practitioner, 19.17% is involved in public health (CMHT'S). More than 50% of the sample consider the combined therapy as a effective. In the public field the combined treatment turn out to be the most utilized, opposite than in private practice. 75% of the sample manage alone the combined therapy, while 25% work in team with a colleague. 85% of the pharmacotherapy is utilized in psychosis with positive symptoms, followed by the mood disorder with psychotic symptoms. Neuroleptics are the most frequently prescribed drug. CONCLUSIONS: The combined therapy seems to be useful when coherently with the psychotherapy theory model. The pharmacological treatment should be utilized when strictly necessary and, if is possible, the combined therapy should be managed by one psychiatrist.

Insertion of a loxP site in a size-reduced human accessory chromosome.

The generation in vitro of mammalian artificial chromosomes, in view of the possibility of developing new technologies for gene therapy, is still an ambitious goal. Mammalian artificial chromosomes, to be used as cloning and expression vectors, have been constructed either by de novo synthesis or by reduction of pre-existing chromosomes. In the work here reported, we introduced a loxP sequence into the pericentromeric region of a chromosome 9-derived X-ray-reduced minichromosome, with the purpose of generating a human chromosome vector (HCV). The modified accessory chromosome is linear and mitotically stable, has lost at least 1400 kb of alpha satellite DNA and normally binds CENP-B, CENP-C and CENP-E. The efficiency of gene targeting via loxP mediated homologous recombination was tested using the histone H2B-Green Fluorescent Protein chimaeric gene as a reporter. The frequency of site-specific insertion of the exogenous sequence was found to be about 50% and to occur in a controlled way with regard to the number of copies. The expression level of the fusion protein was stable over prolonged time in culture.

Gene targeting to the centromeric DNA of a human minichromosome.

A human supernumerary minichromosome (MC), previously identified as a derivative of chromosome 9, has been introduced into Chinese hamster ovary (CHO) cells by means of cell fusion. A hybrid clone containing the MC as the only free human chromosome was isolated. A selectable marker gene (neo) inserted into a yeast artificial chromosome (YAC) has been successfully targeted to the MC centromeric DNA via co-transfection with chromosome-9-specific alpha satellite DNA. In situ hybridization and Southern blotting experiments demonstrated that the intact neo gene was integrated into the MC centromeric DNA. Studies on the clonal distribution and on the stability of the MC either in the presence or in the absence of the selective agent have been carried out. The MC is susceptible to further manipulations and may thus represent a model for the construction of a large-capacity vector for somatic gene therapy.

Variation of minisatellites in chemically induced mutagenesis and in gene amplification.

A mutation assay in cultured mammalian cells was developed based on direct analysis of minisatellite DNA. Chinese hamster cells (V79) were mutagenized with nitrosoguanidine and independent colonies were isolated and expanded. DNA fingerprints were then obtained after digestion with HinfI or HaeIII and hybridization with 33.15 and 33.6 probes (Jeffreys et al., 1985). 12 colonies from untreated cells were also analyzed. Digestion with HaeIII and hybridization with 33.15 probe detected the highest frequency of induced variants. The results suggest that minisatellite sequences are hypermutable sites that can be used to monitor the mutagenic effect of chemical agents. We have also analyzed the DNA fingerprints of 17 independent Chinese hamster (CHO) cell lines carrying amplification of the CAD gene. The DNA fingerprint analysis showed a variation in minisatellite regions in 3 lines while no variation was observed in independent colonies from the CHO parental cell line. The results suggest that these sequences may be hot spots for recombination during gene amplification.

Characterization of an X;X translocation by cytological analysis and in situ hybridization.

An X;X chromosomal translocation was ascertained by conventional cytogenetic analysis in a phenotypically normal woman with secondary amenorrhea. In situ hybridization was performed with previously mapped X-specific DNA sequences to study the rearrangement at the molecular level. The results allowed us to demonstrate that the subject is monosomic for the distal region of the short arm of the X and trisomic for the distal region of the long arm.

[Pyloric occlusion caused by calculi in patients with cholecysto-gastric fistula]. / Occlusione pilorica da calcoli in portatrice di fistola colecisto-gastrica.

Personal experience with a case of pyloric occlusion due to calculi in a woman with spontaneous cholecysto-gastric fistula is reported. A general picture of this rare condition is described and the clinical case and the therapy adopted are illustrated. The problems that may be encountered in formulating a precise preoperative diagnosis when the age of the patient and serious general condition do not permit routine investigations are presented.

[Intestinal invagination caused by lipoma of the small intestine]. / Invaginazione intestinale da lipoma del tenue.

A case of ileo-colic invagination caused by lipoma of the last loop of the small intestine is reported. The anatomo-clinical features of this neoformation are illustrated and stress is laid on certain special aspects: the rarity (about 300 cases have been described in the literature), the lack of symptomatology and its insidious development without pathognomonic sign up to the occurrence of occlusive episodes. The surgery carried out and the result obtained are reported.