Different features of tumor-associated NK cells in patients with low-grade or high-grade peritoneal carcinomatosis

Peritoneal carcinomatosis (PC) is a rare disease defined as diffused implantation of neoplastic cells in the peritoneal cavity. This clinical picture occurs during the evolution of peritoneal tumors, and it is the main cause of morbidity and mortality of patients affected by these pathologies, though cytoreductive surgery with heated intra-peritoneal chemotherapy (CRS/HIPEC) is yielding promising results. In the present study, we evaluated whether the tumor microenvironment of low-grade and high-grade PC could affect the phenotypic and functional features and thus the anti-tumor potential of NK cells. We show that while in the peritoneal fluid (PF) of low-grade PC most CD56dim NK cells show a relatively immature phenotype (NKG2A+KIR\u2013CD57\u2013CD16dim), in the PF of high-grade PC NK cells are, in large majority, mature (CD56dimKIR+CD57+CD16bright). Furthermore, in low-grade PC, PF-NK cells are characterized by a sharp down-regulation of some activating receptors, primarily NKp30 and DNAM-1, while, in high-grade PC, PF-NK cells display a higher expression of the PD-1 inhibitory checkpoint. The compromised phenotype observed in low-grade PC patients corresponds to a functional impairment. On the other hand, in the high-grade PC patients PF-NK cells show much more important defects that only partially reflect the compromised phenotype detected. These data suggest that the PC microenvironment may contribute to tumor escape from immune surveillance by inducing different NK cell impaired features leading to altered anti-tumor activity. Notably, after CRS/HIPEC treatment, the altered NK cell phenotype of a patient with a low-grade disease and favorable prognosis was reverted to a normal one. Our present data offer a clue for the development of new immunotherapeutic strategies capable of restoring the NK-mediated anti-tumor responses in association with the CRS/HIPEC treatment to increase the effectiveness of the current therapy

Achieving temperature-size changes in a unicellular organism.

The temperature-size rule (TSR) is an intraspecific phenomenon describing the phenotypic plastic response of an organism size to the temperature: individuals reared at cooler temperatures mature to be larger adults than those reared at warmer temperatures. The TSR is ubiquitous, affecting >80% species including uni- and multicellular groups. How the TSR is established has received attention in multicellular organisms, but not in unicells. Further, conceptual models suggest the mechanism of size change to be different in these two groups. Here, we test these theories using the protist Cyclidium glaucoma. We measure cell sizes, along with population growth during temperature acclimation, to determine how and when the temperature-size changes are achieved. We show that mother and daughter sizes become temporarily decoupled from the ratio 2:1 during acclimation, but these return to their coupled state (where daughter cells are half the size of the mother cell) once acclimated. Thermal acclimation is rapid, being completed within approximately a single generation. Further, we examine the impact of increased temperatures on carrying capacity and total biomass, to investigate potential adaptive strategies of size change. We demonstrate no temperature effect on carrying capacity, but maximum supported biomass to decrease with increasing temperature

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19

Development of a questionnaire specifically for patients with Ileal Orthotopic Neobladder (IONB)

The ileal orthotopic neobladder (IONB) is often used in patients undergoing radical cystectomy. The IONB allows to void avoiding the disadvantages of the external urinary diversion.In IONB patients the quality of life (QoL) appears compromised by the need to urinate voluntarily. The patients need to wake up at night interrupting the sleep-wake rhythm with consequences on social and emotional life.At present the QoL in IONB patients is evaluated by generic questionnaires. These are useful when IONB patients are compared with patients with different urinary diversions but they are less effective when only IONB patients are evaluated. To address this problem a specific questionnaire-the IONB-PRO-was developed. METHODS: A) Based on a conceptual framework, narrative-based interviews were conducted on 35 IONB patients. A basic pool of 43 items was produced and organized throughout two clinical and four QoL dimensions. An additional 15 IONB patients were interviewed for face validity testing.B) Psychometric testing was conducted on 145 IONB patients. Both classic test strategy and Rasch analysis were applied. Psychometric properties of the resulting scales were comparatively tested against other QoL-validated scales. RESULTS: The IONB-PRO questionnaire includes two sections: one on the QoL and a second section on the capability of the patient to manage the IONB. For evaluation of the QoL, three versions were delivered: 1) a basic 23-item QoL version (3 domains 23-items; alpha 0.86÷ 9.69), 2) a short-form 12-item QoL scale (alpha = 0.947), and 3) a short-form 15-item Rasch QoL scale (alpha = 0.967). Correlations of the long version scales with the corresponding dimensions of the EORTC-QLQ C30 and the EORTC-BLM30 were significant. The short forms exhibited significant correlations with the global health dimension of the EORTC-QLQ and with the urinary subscales of the EORTC-BLM30. The effect size was approximately 1.00 between patients at the 1-year follow-up period and those with 3, 5, and > 5-year follow-up periods for all scales. No relevant differences were observed between the 12-item short-form and the Rasch scale. CONCLUSIONS: The IONB-PRO long and short-forms demonstrated a high level of internal consistency and reliability with an excellent discriminanting validity

HIPEC in the management of metachronous peritoneal carcinomatosis: A single-center retrospective analysis

Cytoreductive surgery (CRS) associated with hyperthermic intra-peritoneal chemotherapy (HIPEC) represents a potentially curative treatment for metachronous peritoneal carcinomatosis (MPC) secondary to colorectal carcinoma (CRC), ovarian cancer (OC), or pseudomixoma peritonei (PMP). However, CRS-HIPEC is still accompanied by a high morbidity. We retrospectively collected data and analysed the outcome of consecutive HIPEC procedures performed in our unit between 2002 and 2014. In the study period 41 patients (Pts) with MPC underwent CRS-HIPEC. Patient age was 57.7 \ub1 10.1 years (range 32\u201377), Female/Male: 34/7. The median follow-up was 22.6 months. The MPC was secondary to OC in 19 Pts (46%), CRC in 14 Pts (34%), and PMP in 8 Pts (20%). Closed HIPEC procedure was performed in the early phase of our experience in 11 Pts (26.8%). Cisplatin (43 mg/m2/l) and Adriamicin (15.25 mg/m2/l) were administered for OC, whereas Cisplatin (25.0 mg/m2/l) and Mitomycin C (3.3 mg/m2/l) for both CRC and PMP. HIPEC was performed for 60 min at 41 \ub0C, and gastrointestinal anastomosis were completed after perfusion. The median operation time was 390 min (95%CI: 366\u2013426). No death occurred in the intraoperative or early postoperative period. The median hospital stay was 15 days (95% CI: 14\u201322). The overall survival at 1, 3 and 5 years were 82%, 53% and 33%, respectively. Although no significant survival difference was observed by stratifying for closed vs. open HIPEC at 1 year (P = 0.0798) and 3 years (P = 0.0867), within these time-points the Kaplan\u2013Meier curves showed a better cumulative survival probability for Pts who underwent the open procedure. In our experience, CRS-HIPEC has revealed to be an effective treatment for MPC from OC, CRC or PMP, with an admissible morbidity and mortality

Espansione tissutale e ricostruzione mammaria: Ruolo di una terapia farmacologica loco-regionale

Aim. The aim of this study was to evaluate the effectiveness of topical 60% dimethyl sulphoxide (DMSO) prior to tissue expansion for breast reconstruction in reducing expander pressure and length of treatment. Methods. Forty patients undergoing immediate breast reconstruction with tissue expanders following modified radical mastectomy were consecutively divided into two groups of 20 subjects each: group A (control) and group B (experimental). Patients from group A underwent traditional tissue expansion, while, to patients of group B, before each filling session, topical 60% DMSO was applied to die skin overlying the expander by soaking-wet surgical sponges left in place for 30 min. The average inflated volume was 395 cc (range 250-580 cc) in group A, and 410 cc (range 240-620 cc) in group B; no statistically significant difference was found between these values. Results. A statistically significant difference was found between the expansion time of group A (mean 6 sessions; range 4-10 sessions with one filling session per week) and group B (mean 4 sessions; range 2-6 sessions with one filling session per week). A statistically significant difference was also found between the average inflated volume per session of group A (90 cc; range 60-130 cc) and group B (120 cc; range 90-160 cc). According to die data obtained by tonometry, a statistically significant difference was found between die average pre-filling and post-filling pressures of group A (28.4 and 66.5 mmHg, respectively) and group B (22.1 and 64.3 mmHg, respectively). Conclusion. Clinical benefits of prefilling topical applications of 60% DMSO observed in our trial were an enhancement of the total volume inflatable per session and a significant shortening of die total expansion period

Espansione tissutale e ricostruzione mammaria: Ruolo di una terapia farmacologica loco-regionale

Aim. The aim of this study was to evaluate the effectiveness of topical 60% dimethyl sulphoxide (DMSO) prior to tissue expansion for breast reconstruction in reducing expander pressure and length of treatment. Methods. Forty patients undergoing immediate breast reconstruction with tissue expanders following modified radical mastectomy were consecutively divided into two groups of 20 subjects each: group A (control) and group B (experimental). Patients from group A underwent traditional tissue expansion, while, to patients of group B, before each filling session, topical 60% DMSO was applied to die skin overlying the expander by soaking-wet surgical sponges left in place for 30 min. The average inflated volume was 395 cc (range 250-580 cc) in group A, and 410 cc (range 240-620 cc) in group B; no statistically significant difference was found between these values. Results. A statistically significant difference was found between the expansion time of group A (mean 6 sessions; range 4-10 sessions with one filling session per week) and group B (mean 4 sessions; range 2-6 sessions with one filling session per week). A statistically significant difference was also found between the average inflated volume per session of group A (90 cc; range 60-130 cc) and group B (120 cc; range 90-160 cc). According to die data obtained by tonometry, a statistically significant difference was found between die average pre-filling and post-filling pressures of group A (28.4 and 66.5 mmHg, respectively) and group B (22.1 and 64.3 mmHg, respectively). Conclusion. Clinical benefits of prefilling topical applications of 60% DMSO observed in our trial were an enhancement of the total volume inflatable per session and a significant shortening of die total expansion period