Neutrophil-to-Eosinophil Ratio Predicts the Efficacy of Avelumab in Patients With Advanced Urothelial Carcinoma Enrolled in the MALVA Study (Meet-URO 25).

BACKGROUND: Neutrophil-to-eosinophil ratio (NER) has been described to be associated with outcomes to immune checkpoint inhibitors (ICI) in several tumor types, but less is known about its role of in the response to avelumab in advanced urothelial cancer (aUC). Thus, we reported outcomes by NER of aUC patients treated with avelumab as maintenance after initial response to platinum-based chemotherapy and enrolled in the Maintenance with AVeLumAb ([MALVA] in advanced urothelial neoplasms in response to first-line chemotherapy: an observational retrospective study) study (Meet-URO 25). PATIENTS AND METHODS: Median NER at baseline and after 3 cycles of avelumab were calculated. Progression-free survival (PFS) and overall survival (OS) by NER were reported. RESULTS: At the cutoff date (April 15, 2023), a total of 109 patients were included. The median NER was 28.05 at baseline and 24.46 after 3 cycles of avelumab, respectively. Median PFS was not reached for patients with baseline NER less than the median (

Endothelial Migration and Regeneration after Penetrating Trauma Injury in a Deep Anterior Lamellar Keratoplasty Graft: Case Presentation and Literature Overview.

Background: Traumatic injuries in eyes previously treated with Deep Anterior Lamellar Keratoplasty (DALK) can lead to ruptures in the Descemet Membrane (DM) and damage to the corneal endothelium, a crucial layer for maintaining corneal clarity. Due to cell cycle constraints, the human corneal endothelium cannot proliferate; instead, it compensates for injury through cell enlargement and migration from adjacent areas. Methods: This study examines a notable case of corneal endothelial cell migration following a penetrating eye injury in a patient previously treated with DALK for keratoconus, supplemented by a review of relevant literature to contextualize the regenerative response. Results: A 39-year-old male with a history of DALK suffered a traumatic eye injury, resulting in damage to the Descemet Membrane and loss of the crystalline lens. After primary repair and considerations for further surgery, the patient's cornea cleared remarkably, with an improved visual acuity. This demonstrates the DM's potential for self-repair through endothelial cell migration. Conclusions: The outcomes suggest that delaying corneal transplant surgery for up to 3 months following Descemet Membrane injury due to ocular trauma could be advantageous. Allowing time for natural healing processes might eliminate the need for further invasive surgeries, thereby improving patient recovery outcomes.

Combined superficial keratectomy, alcohol delamination and amniotic membrane patch with fibrin glue in Salzmann nodular degeneration.

PURPOSE: To describe the outcomes of five Salzmann's Nodular Degeneration (SND) cases treated with a combination of alcohol delamination, superficial keratectomy and amniotic membrane patch with fibrin glue. METHODS: Five patients affected by SND with significant discomfort and decreased visual acuity were evaluated with refraction, best corrected visual acuity, Break-up time test, corneal topography, Anterior Segment of Optical Coherence Tomography and images of anterior segment with a full slit lamp examination. All the patients underwent alcohol delamination of the corneal epithelium followed by superficial keratectomy to remove the subepithelial nodules. A patch of amniotic membrane was applied to all of them with a ring shape and a banana shape in two patients due to the location of the disease. A bandage contact lens was inserted. The patch was kept in place for 14 days. Another bandage contact lens was inserted for 21 days until the corneal epithelium had completely healed. RESULTS: The surgical procedure was successful in removing the nodules in all patients. Vision was restored in all cases with a significant regularization of the corneal surface and reduction of ocular discomfort. After a 12-month follow-up, none of the patients showed recurrence of the disease. CONCLUSIONS: Combining alcohol delamination with superficial keratectomy and amniotic membrane patch with fibrin glue is an effective procedure for the management of SND to regularize the corneal surface and avoid the recurrence of subsequent nodules. This report is the first description of the outcomes of SND cases treated with a combination of the aforementioned techniques.

Increasing incidence of contact-lens-related Acanthamoeba keratitis in a tertiary ophthalmology department in an Italian population.

PURPOSE: The purpose of this paper is to report the increasing incidence of contact-lens related Acanthamoeba keratitis (AK) in a tertiary ophthalmology department in Umbria, central Italy. METHODS: Observational and retrospective case series were carried out. A total of nine eyes with a diagnosis of AK were examined. All patients underwent a full slit lamp examination, in vivo confocal microscopy (IVCM) and corneal scraping. The IVCM was repeated at one and two-week and at one, three and six-month intervals. Samples of domestic tap water were also examined for PCR analysis. Patients were treated with levofloxacin0,5%, Polyhexamethylene biguanide 0.02%, and Propamidine Isetionate0,1%. RESULTS: All patients were contact lens wearers. The average patient age was 27.75 (range 18-45), with three men and five women. The main clinical features were ciliary congestion, diffuse epitheliopathy with punctuated keratitis, multiple, small sub-epithelial, greyish, corneal infiltrates with epithelial defect, pseudodendritic corneal lesions, perineural infiltrates, corneal stromal cellularity, and stromal infiltrates. IVCM was indicative of Acanthamoeba in seven out of the nine eyes. All the positive IVCM images were section images showing double walled, bright-spot cysts with a clear chain-like arrangement of five or more cysts identified in three of the patients. PCR analysis of the water was negative in all cases. CONCLUSION: Although PCR is the most common method used, the increased incidence of AK could mainly be related to a proper IVCM interpretation. A broad-spectrum antibiotic, such as levofloxacin might play a role in the early treatment of AK reducing the virulence of the amoeba.

Interface of biomolecular condensates modulates redox reactions.

Biomolecular condensates mediate diverse cellular processes. The density transition process of condensate formation results in selective partitioning of molecules, which define a distinct chemical environment within the condensates. However, the fundamental features of the chemical environment and the mechanisms by which such environment can contribute to condensate functions have not been revealed. Here, we report that an electric potential gradient, thereby an electric field, is established at the liquid-liquid interface between the condensate and the bulk environment due to the density transition of ions and molecules brought about by phase separation. We find that the interface of condensates can drive spontaneous redox reactions in vitro and in living cells. Our results uncover a fundamental physicochemical property of the interface of condensates and the mechanism by which the interface can modulate biochemical activities.

Irinotecan- vs. Oxaliplatin-Based Doublets in KRASG12C-Mutated Metastatic Colorectal Cancer-A Multicentre Propensity-Score-Matched Retrospective Analysis.

BACKGROUND: KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. METHODS: A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/- bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment-effect interactions. KRASG12D-mutated patients were analysed as control. RESULTS: One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). CONCLUSIONS: First-line irinotecan-based regimens provided better survival results in KRASG12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations.

Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the "CARACAS" study.

BACKGROUND: Molecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking. PATIENTS AND METHODS: In the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. On pre-treatment tumour tissue samples, we assessed Human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by FoundationOne CDx. Tumour-infiltrating lymphocytes were characterised on haematoxylin-eosine-stained samples. Primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers. RESULTS: High PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01-0.68; p = 0.019) and PFS (HR = 0.44; 95%CI = 0.15-1.27; p = 0.129). High expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19-1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20-0.92; p = 0.03). Neither OS (HR = 1.30; 95%CI = 0.72-2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74-2.31; p = 0.357) was affected by high (>1.2) Tumour-infiltrating lymphocytes count. High TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13-0.81; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23-1.00; p = 0.015). CONCLUSIONS: To our knowledge, TranslaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors.

A Prospective Observational Study on the Structuring Process and Implementation of a Large Regional, Inter-hospital, Virtual Multidisciplinary Tumor Board on Prostate Cancer.

BACKGROUND/AIM: At present, multidisciplinary tumor boards (MDTB) are considered best practice in oncology. However, web-based virtualization of MDTB may increase participation in meetings, the number of cases discussed, and adherence to guidelines, deliver better treatment, and eventually improve outcomes for patients with prostate cancer. PATIENTS AND METHODS: This is an observational study focused on exploring the structuring process and implementing a multi-institutional virtual MDTB in Sicily, Italy. Other endpoints included the analysis of cooperation between participants, adherence to guidelines, patient outcomes, and patient satisfaction. RESULTS: Overall, 126 patients were referred to the virtual MDTB for a total of 302 cases discussed in an 18-month period. Nearly 45% of cases were referred from general hospitals or tertiary centers, 38% from comprehensive cancer centers, and only 17% from academic ones. Most health professional participants (95%) reported eliminating geographical barriers and consequently reducing costs and saving time as key advantages of virtual meetings over face-to-face ones. Using a specifically designed platform for virtual MDTBs was another excellent point, especially to geolocate clinical trials and time-lapse data storage. The majority of referred patients had stage T 3-4 prostate cancer (79%). Overall, 71% of proposals discussed were approved unchanged, while 19% changed after the virtual MDTB discussion. Debated points were mostly radiologic, surgical, medical, or radiation treatment-related issues. In particular, the prescriptive appropriateness of positron emission tomography with 68Ga-prostatic specific membrane antigen, newer drugs, radiation versus surgical approach, stage T3-4 cases, and adjuvant therapy represented the most debated issues. The proposed diagnostic and/or therapeutic options were controlled for adherence to the guidelines and/or updated scientific evidence. Overall, 98% of approved proposals and changes were in line with the guidelines. Overall, most participants felt virtual MDTB was very useful and case discussions led to a major change of strategy in 19% of cases. CONCLUSION: Virtual MDTBs are a very useful way to achieve best management of prostate cancer while saving time and fostering cooperation.

Activity-Based Sensing for Chemistry-Enabled Biology: Illuminating Principles, Probes, and Prospects for Boronate Reagents for Studying Hydrogen Peroxide.

Activity-based sensing (ABS) offers a general approach that exploits chemical reactivity as a method for selective detection and manipulation of biological analytes. Here, we illustrate the value of this chemical platform to enable new biological discovery through a case study in the design and application of ABS reagents for studying hydrogen peroxide (H2O2), a major type of reactive oxygen species (ROS) that regulates a diverse array of vital cellular signaling processes to sustain life. Specifically, we summarize advances in the use of activity-based boronate probes for the detection of H2O2 featuring high molecular selectivity over other ROS, with an emphasis on tailoring designs in chemical structure to promote new biological principles of redox signaling.

Evaluation of warm compresses and topical cyclosporine treatment in meibomian gland dysfunction by confocal scanning laser microscopy.

PURPOSE: The aim of our study is to confirm the utility of warm compresses (WC) and artificial tears (AT) in meibomian gland dysfunction (MGD) management and to understand if its association with topical cyclosporine A (CsA) improves outcomes. METHODS: Patients with diagnosis of MGD-related dry eye were evaluated. In this prospective, randomized, double-masked study, patients were randomized in two treatments: AT plus WC (group A), and AT plus WC plus CsA 0.05% ophthalmic emulsion (group B). At baseline and at 1, 3, and 6 months, Ocular Surface Disease Index (OSDI) questionnaire was completed, and tear evaluation (BUT, Schirmer and osmolarity test), ocular surface evaluation (fluorescein and lissamine green staining), clinical (Shimazaki grading) and in vivo confocal microscopy (IVCM) evaluation of rete ridges (RRs) were performed. RESULTS: A total of 40 eyes, 20 in each group, completed the study. Analysis of OSDI, tear test, ocular surface evaluation and clinical grading of MG showed significant improvement at 6 months, whereas no difference was found between the two groups at 6 months. The analysis of IVCM showed significant improvement in both groups, but significantly better results in group B were found compared to group A at 6 months. CONCLUSION: WC performed 3 times daily during the 1st month and once daily afterwards, in addition to AT, were useful to manage the obstruction of MG and related signs and symptoms. Additional effects of CsA were visible in IVCM only at 6 months. IVCM is an effective tool to monitor treatments in MGD.

The prognostic value of baseline and early variations of peripheral blood inflammatory ratios and their cellular components in patients with metastatic renal cell carcinoma treated with nivolumab: The Δ-Meet-URO analysis.

Background: Treatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors. Methods: By a pre-specified analysis of the Meet-URO 15 multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs. Results: The analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction <0.001), higher baseline IR values (NLR: p = 0.012, SII: p = 0.003, PLR: p = 0.003), increasing NLR and systemic immune-inflammatory index (SII) (i.e., NLR x platelets) Δ (p for interaction time-group = 0.0053 and 0.0435, respectively) were associated with disease progression. OS and PFS were significantly shorter in patients with baseline lower lymphocytes (p < 0.001 for both) and higher platelets (p = 0.004 and p < 0.001, respectively) alongside early neutrophils Δ (p = 0.046 and p = 0.033, respectively). Early neutrophils and NLR Δ were independent prognostic factors for both OS (p = 0.014 and p = 0.011, respectively) and PFS (p = 0.023 and p = 0.001, respectively), alongside baseline NLR (p < 0.001 for both) and other known prognostic variables. Conclusions: Early neutrophils and NLR Δ may represent new dynamic prognostic factors with clinical utility for on-treatment decisions.

Primary small gauge pars plana vitrectomy and silicone oil endotamponade for endophthalmitis after cataract surgery: Clinical and OCT findings.

BACKGROUND: Retrospective analysis of morphological and functional outcomes after pars-plana vitrectomy and Silicone-Oil (SO) endotamponade in acute postoperative endophthalmitis (APOE). METHODS: Minimum follow-up was 6 months. Every included patient received best-corrected visual acuity (BCVA) assessment, pre-operatively and at last follow-up. Spectralis OCT was used to investigate disorganization of inner (DRIL) and outer (DROL) retinal layers at 1, 3, 6 months and at last follow-up. OCT-A was performed to assess foveal avascular zone (FAZ) and vascular perfusion density (VPD) at 6 months and at last follow-up. RESULTS: Seventeen eyes were recruited. Postoperative findings: BCVA ≥ 20/40 (in 14 eyes); epiretinal membranes (13); hyperreflective epiretinal material soon after surgery in (6) SO-filled eyes; inner retinal layers atrophy (5); macular edema (2); DROL (4) with persistent EZ disruption at final visit (2); no significant difference between study and fellow eyes in central macular thickness, FAZ and VPD; VPD decreased in all cases with prominent disorganization of retinal architecture. CONCLUSION: OCT changes after APOE can be persistent or completely/partially self-resolving and seems related to the outward progression path of the infection/inflammation from the vitreous cavity to the inner and outer retina, rather than to the surgery.

The prognostic value of the previous nephrectomy in pretreated metastatic renal cell carcinoma receiving immunotherapy: a sub-analysis of the Meet-URO 15 study.

BACKGROUND: Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. METHODS: We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. RESULTS: Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32-0.60, p < 0.001) with a longer median overall survival (OS) (35.9 months vs 12.1 months), 1-year OS of 71.6% vs 50.5% and 2-years OS of 56.5% vs 22.0% compared to those who did not. No significant interaction between nephrectomy and the overall five Meet-URO score risk groups was observed (p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p < 0.001), but not for groups 4 and 5 (p = 0.54). CONCLUSIONS: Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.

Organometallic S-arylation Reagents for Rapid PEGylation of Biomolecules.

Bioconjugation techniques for biomolecule-polymer conjugation are numerous; however, slow kinetics and steric challenges generally necessitate excess reagents or long reaction times. Organometallic transformations are known to circumvent these issues; yet, harsh reaction conditions, incompatibility in aqueous media, and substrate promiscuity often limit their use in a biological context. The work reported herein demonstrates a facile and benign organometallic Au(III) S-arylation approach that enables the synthesis of poly(ethylene glycol) monomethyl ether (mPEG)-protein conjugates with high efficiency. Isolable and bench-stable 2, 5, and 10 kDa mPEG-Au(III) reagents were synthesized via oxidative addition into terminal aryl iodide substituents installed on mPEG substrates with a (Me-DalPhos)Au(I)Cl precursor. Reaction of the isolable mPEG-Au(III) oxidative addition complexes with a cysteine thiol on a biomolecule resulted in facile and selective cysteine arylation chemistry, forging covalent S-aryl linkages and affording the mPEG-biomolecule conjugates. Notably, low polymer reagent loadings were used to achieve near quantitative conversion at room temperature in 1 min due to the rapid kinetics and high chemoselectivity of this Au-based bioconjugation approach. Therefore, this work represents an important addition to the protein-polymer conjugation chemical toolbox.

ToxR is a c-di-GMP binding protein that modulates surface-associated behaviour in Pseudomonas aeruginosa.

Pseudomonas aeruginosa uses multiple protein regulators that work in tandem to control the production of a wide range of virulence factors and facilitate rapid adaptation to diverse environmental conditions. In this opportunistic pathogen, ToxR was known to positively regulate the production of the major virulence factor exotoxin A and now, through analysis of genetic changes between two sublines of P. aeruginosa PAO1 and functional complementation of swarming, we have identified a previously unknown role of ToxR in surface-associated motility in P. aeruginosa. Further analysis revealed that ToxR had an impact on swarming motility by regulating the Rhl quorum sensing system and subsequent production of rhamnolipid surfactants. Additionally, ToxR was found to tightly bind cyclic diguanylate (c-di-GMP) and negatively affect traits controlled by this second messenger including reducing biofilm formation and the expression of Psl and Pel exopolysaccharides, necessary for attachment and sessile communities matrix scaffolding, in P. aeruginosa. Moreover, a link between the post-transcriptional regulator RsmA and toxR expression via the alternative sigma factor PvdS, induced under iron-limiting conditions, is established. This study reveals the importance of ToxR in a sophisticated regulation of free-living and biofilm-associated lifestyles, appropriate for establishing acute or chronic P. aeruginosa infections.

A puromycin-dependent activity-based sensing probe for histochemical staining of hydrogen peroxide in cells and animal tissues.

Hydrogen peroxide (H2O2) is a key member of the reactive oxygen species family of transient small molecules that has broad contributions to oxidative stress and redox signaling. The development of selective and sensitive chemical probes can enable the study of H2O2 biology in cell, tissue and animal models. Peroxymycin-1 is a histochemical activity-based sensing probe that responds to H2O2 via chemoselective boronate oxidation to release puromycin, which is then covalently incorporated into nascent proteins by the ribosome and can be detected by antibody staining. Here, we describe an optimized two-step, one-pot protocol for synthesizing Peroxymycin-1 with improved yields over our originally reported procedure. We also present detailed procedures for applying Peroxymycin-1 to a broad range of biological samples spanning cells to animal tissues for profiling H2O2 levels through histochemical detection by using commercially available anti-puromycin antibodies. The preparation of Peroxymycin-1 takes 9 h, the confocal imaging experiments of endogenous H2O2 levels across different cancer cell lines take 1 d, the dot blot analysis of mouse liver tissues takes 1 d and the confocal imaging of mouse liver tissues takes 3-4 d.

New dosimetric parameters to predict ano-rectal toxicity during radiotherapy treatment.

PURPOSE: Radiotherapy is essential in the treatment of locally advanced rectal cancer. Side effects of radiotherapy in the treatment of rectal cancer have a great effect on quality of life. The aim of this retrospective study is to evaluate the correlation between dosimetric parameters and acute toxicity in rectal cancer patients. METHODS: We analyzed the Dose Volume Histogram parameters for both the target structures and the Organs at risk of 89 patients. A dedicated statistical analysis was performed for all the acute toxicities showing a frequency rate higher than 20%. A linear logistic regression model was elaborated using the variable showing the highest level of significance at the univariate analysis. RESULTS: The occurrence of proctitis was significantly correlated with three dosimetric parameters: D98% of low ano-rectum, D98% and Dmean of low ano-rectum wall. A predictive linear logistic regression model reports that the D98% of the wall of the low ano-rectum must be < 38.5 Gy to decrease the rate of proctitis. A general analysis on grade 2 acute toxicity occurrence reported that it was correlated with D98% of low ano rectum. CONCLUSIONS: Two dose constraints were elaborated: D98%<33.5 Gy for low ano rectum to prevent grade 2 acute toxicity and D98%<25 Gy for low ano-rectum wall to prevent proctitis (grade 1 or superior).

Development and Multicentre Validation of the Modena Score to Predict Survival in Advanced Biliary Cancers Undergoing Second-Line Chemotherapy.

Background: The role of second-line chemotherapy in advanced biliary cancers (ABCs) has only recently been established in phase III randomized trial and the optimal selection of patients most likely to benefit from it remains challenging. Methods: A cohort of 98 ABC treated second-line chemotherapy was used as a developmental dataset to identify covariates independently associated with overall survival (OS). Kaplan-Meier analysis was used to investigate the association between variables and OS and those retaining statistically significance were combined in a multiplexed score. Results: The following pretreatment variables were independently associated with OS: ECOG PS > 0, peritoneal disease, LDH > 430 UI/L, albumin <3.5 gr/dL, gamma-GT >100 UI/L, sodium <140 mEq/L, absolute lymphocyte count <1000/mmc, and PFS to first-line <6 months. Based on these results, a scoring system was developed that identified three subgroups with statistically different OS: low-risk (mOS 18 months), intermediate-risk (mOS 9.4 months) and high-risk (mOS 2.9 months) (p < 0.001). The prognostic model was both internally and externally validated in a multicentre cohort of 120 ABCs. Conclusion: The Modena score is a multiplexed scoring system capable of accurately risk-stratified ABCs treated with second-line chemotherapy. Based on its reproducibility, usability and generalizability, it has the potential for assisting therapeutic decision-making in the clinic and risk-stratification in future trials.

Five-Fraction Stereotactic Radiotherapy for Brain Metastases: A Single-Institution Experience on Different Dose Schedules.

INTRODUCTION: The most common intracranial neoplasm diagnosed in adults are brain metastases (BrM). The benefit in terms of clinical control and toxicity for stereotactic radiotherapy (SRT) has been investigated for patients with low load of BrM. AIM: The aim of this single-institution experience was to investigate the best dose schedule for five-fraction SRT (FFSRT). METHODS: A retrospective analysis of patients treated for BrM with different dose schedules of FFSRT was performed. Local control (LC) and clinical outcomes were evaluated with magnetic resonance imaging at 3, 6, and 9 months. Toxicity data were also collected. RESULTS: A total of 41 patients treated from November 2016 to September 2020 were enrolled in the analysis. Non-small cell lung cancer (51.2%) and breast cancer (24.3%) represented the most frequent primitive tumors. Treatment was performed on 5 consecutive days with prescribed dose ranging from 30 to 40 Gy, prescribed to the 95% isodose line that covered at least 98% of the gross tumor volume. Statistically significant differences (p = 0.025) with higher LC rates for dose schedules >6 Gy for fractions. Toxicity rates were not found to be higher than G1. CONCLUSION: The results of this retrospective analysis suggest that FFSRT for BrM seems to be safe and feasible. Our results also underline that a total dose lower than 30 Gy in 5 fractions should not be used due to the expected minor LC.