Ospedale Villa Scassi

BACKGROUND: Conflicting evidence exists on the efficacy and safety of bivalirudin administered as part of percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome. METHODS: We randomly assigned 7213 patients with an acute coronary syndrome for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin. Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion. Primary outcomes for the comparison between bivalirudin and heparin were the occurrence of major adverse cardiovascular events (a composite of death, myocardial infarction, or stroke) and net adverse clinical events (a composite of major bleeding or a major adverse cardiovascular event). The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events. RESULTS: The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (10.3% and 10.9%, respectively; relative risk, 0.94; 95% confidence interval [CI], 0.81 to 1.09; P=0.44), nor was the rate of net adverse clinical events (11.2% and 12.4%, respectively; relative risk, 0.89; 95% CI, 0.78 to 1.03; P=0.12). Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (11.0% and 11.9%, respectively; relative risk, 0.91; 95% CI, 0.74 to 1.11; P=0.34). CONCLUSIONS: In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin. The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion. (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrials.gov number, NCT01433627.).

BACKGROUND: Through contemporary literature, the optimal strategy to manage coronary chronic total occlusions (CTOs) remains under debate. OBJECTIVES: The aim of the Italian Registry of Chronic Total Occlusions (IRCTO) was to provide data on prevalence, characteristics, and outcome of CTO patients according to the management strategy. METHODS: The IRCTO is a prospective real world multicentre registry enrolling patients showing at least one CTO. Clinical and angiographic data were collected independently from the therapeutic strategy [optimal medical therapy (MT), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG)]; a comparative 1-year clinical follow-up was performed. RESULTS: A total of 1777 patients were enrolled for an overall CTO prevalence of 13.3%. The adopted therapeutic strategies were as follows: MT in 826 patients (46.5%), PCI in 776 patients (43.7%), and CABG in the remaining 175 patients (9.8%). At 1-year follow-up, patients undergoing PCI showed lower rate of major adverse cardiac and cerebrovascular events (MACCE) (2.6% vs. 8.2% and vs. 6.9%; P < 0.001 and P < 0.01) and cardiac death (1.4% vs. 4.7% and vs. 6.3%; P < 0.001 and P < 0.001) in comparison with those treated with MT and CABG, respectively. After propensity score-matching analysis, patients treated with PCI showed lower incidence of cardiac death (1.5 vs. 4.4%; P < 0.001), acute myocardial infarction (1.1 vs. 2.9%; P = 0.03), and re-hospitalization (2.3 vs. 4.4% P = 0.04) in comparison with those managed by MT. CONCLUSIONS: Our data showed how CTO PCI might significantly improve the survival and decrease MACCE occurrence at 1 year follow-up in comparison with MT and/or CABG.

AIM: To evaluate the frequency of complications in bronchoscopy from data compiled between 1/2/2002 to 1/2/2003. MATERIALS AND METHODS: Nineteen Italian centres of thoracic endoscopy participated in the study, for a total of 20,986 bronchoscopies (FBS), including 10,658 explorative bronchoscopies (EB) (50.79%), 5,520 bronchial biopsies (BB) (26.30%), 1,660 transbronchial biopsies (TBB) (7.91%), 1,127 broncho-alveolar lavages (BAL) (5.37%), 930 transbronchial needle-aspirates (TBNA) (4.43%), 1.091 therapeutic bronchoscopies (TB), comprising ND-YAG Laser, argon-plasma, electrocautery knife, stent insertion (5.20%). 82.4% of the procedures involved the use of a flexible bronchoscope, 16.3% were carried out using a rigid bronchoscope and 1.3% using the mixed technique. RESULTS: The total number of complications recorded was 227 (1.08% of the cases examined), including 20 (0.09%) during local anesthesia and pre-medication, 195 (0.92%) during the endoscopic procedures and 12 (0.05%) in the two hours following FBS. The total number of deaths was 4 (0.02%), due to cardiac arrest, pulmonary edema, delayed respiratory failure and shock in pre-medication, respectively. 68.28% of the complications were treated medically, 25.99% by means of endoscopy and 5.72% with surgery. The healing percentage was 98.2%. CONCLUSIONS: This study has shown that bronchoscopy is a safe method with low incidence of mortality and complications. The preparation, experience and continuous training of the operators of the medical and nursing team seem to play a fundamental role in reducing the incidence of complications at least in certain procedures such as BB and TBB.

Biallelic germline mutations in the base excision repair gene MYH have been reported in patients with multiple colorectal adenomas and cancer and in sporadic FAP patients not showing a detectable APC germline mutation. In this study, the prevalence of the common Y165C and G382D germline variants of the MYH gene was examined in 70 FAP/AAPC patients with no detectable APC mutation and a family history compatible with recessive inheritance. In addition, 141 normal-population adenoma patients (mean number of adenomas, 2.8; range, 1-9) and 52 clean colon controls were studied. The entire coding region of the MYH gene was analyzed in Y165C or G382D heterozygous patients. Since the same second mutational event (a 3 bp deletion in exon 14, 1395delGGA) was detected in 3 patients, the prevalence of this variant was also examined in all groups. In all, 14 of 70 patients in the FAP/AAPC group (20%; 95% CI = 11.7-31.6%) had biallelic germline MYH variants and 3 were heterozygotes (4.3%). None of the 141 normal-population adenoma patients carried biallelic germline MYH variants (95% CI = 0.06-4.1%) and 3 were heterozygotes (2.1%). In the control group, no MYH variants were detected. These results indicated that MYH-associated polyposis (MAP) is present in about 20% of Italian FAP/AAPC patients, in whom no germline APC mutation is detectable and showing a family history compatible with recessive inheritance, and in a small fraction of patients with colorectal adenomas in the general population. In addition, our data suggest that mutation 1395delGGA is a subpolymorphic MYH mutational event in some Caucasian populations.

allergy, and for the selection of allergen immunotherapy. Nevertheless, all sIgE tests, including PAMD@, should be evaluated within the framework of a patient's clinical history, because allergen sensitization does not necessarily imply clinical relevant allergies.

Epidemiological data show a higher prevalence of late-onset Alzheimer's disease (AD) in women. The estrogenic deficiency in the post-menopausal period is suspected to be the cause of the gender-related risk of the disease, but studies on the estrogenic therapy and occurrence of AD were not consistent and sometimes contradicting. The aim of this study is to investigate whether a higher exposure to endogenous estrogens is associated with lower risk of dementia or not. Two hundred and four AD patients and 201 control women were considered. By interviews, we evaluated different variables, indirectly correlated to estrogenic natural exposure, as well as educational level and head trauma. These data were correlated in the AD group with the disease progression, as well as with the age at onset. Unexpectedly, we found a significant higher number of pregnancies in the AD than in the control group. Within the AD cases, the number of lifetime pregnancies is related to an earlier onset of the disease. As previously reported, we confirmed that the educational level is a protective factor and that major head trauma represents a risk factor in developing AD. The higher number of pregnancies and a less frequency of nulliparous women, indirectly relate the AD group to a higher estro-progestinic exposure. These findings suggest that it is the increase of progesterone or estrogens level--and not the estrogens decrease, as previously indicated by other authors--that could play a role in the Alzheimer's pathology.

PURPOSE: Crohn's disease is characterized by transmural bowel inflammation and a tendency to form fistulas with adjacent structures. Several different fistulas have been described: enterocutaneous, enteroenteric, enterovesical, enterovaginal, and perineal. Rectovaginal fistulas are difficult to treat despite multimodal therapy. This study was designed to review the current strategic options to best manage this condition. METHODS: We reviewed the English-language literature from 1966 to 2006, using PUBMED, targeting Crohn's disease involving vagina using key words "rectovaginal fistula and CD," "anovaginal fistula and CD," "anovaginal fistula," and "rectovaginal fistula." We excluded the involvement of the vagina from a pouch after a proctectomy. A total of 776 articles were found; 206 articles were identified and judged as being relevant on the basis of title-related articles and links were reviewed. Fifty-three articles were selected after reading the abstract or full manuscript. RESULTS: The management of rectovaginal fistula, representing 9 percent of all fistulas, remains a challenge in the setting of Crohn's disease. Medical treatments are not favorable with low rates of long-term symptomatic control and unacceptable high rates of recurrence. Several novel and new surgical techniques have been described, and rectal advancement flap, in selected patients, seems to have the most successful results. CONCLUSIONS: The management of rectovaginal fistula of Crohn's origin should involve both gastroenterologists and coloproctologists, with the best surgical results being achieved in patients receiving optimum medical therapy. More focused studies targeting these patients with the use of combined medical and surgical therapy are necessary.

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m(-2) and carboplatin AUC 5 mg ml(-1) min(-1) intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those >or=70 years old. A total of 178 patients with an ECOG performance status of or=70 years (27%). Grade 3-4 haematological toxicity was slightly worse in >or=70 vs <70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease control (60.4 vs 66.9%, P=0.47), time to progression (7.2 vs 7.5 months, P=0.42) and survival (10.7 vs 13.9 months, P=0.12). Apart from slightly worse haematological toxicity, there was no significant difference in outcome or toxicity between age groups. The PC regimen is effective and well tolerated in selected elderly patients with MPM.

BACKGROUND: Stapled hemorrhoidopexy has become increasingly popular over the past five years, mainly because of the assumption that it is associated with less pain. However, persistent tags and recurrence might represent a problem, because piles are not excised and severe complications requiring surgery have been occasionally reported. The aim of the present study is to analyze the causes for and the outcome of reintervention following either severely complicated or failed stapled hemorrhoidopexy. METHODS: A total of 232 primary stapled hemorrhoidopexies and 65 reinterventions after stapled hemorrhoidopexy were performed by the authors in five centers devoted to colorectal surgery. Twelve patients of the latter group had the stapled hemorrhoidopexy performed in one of these centers. Thirty-five were males and 30 were females. The mean age was 50 (range, 29-81) years. In all cases the primary indication for stapled hemorrhoidopexy was either third-degree or fourth-degree symptomatic hemorrhoids. In all patients submitted to reoperation the diagnosis of either severely complicated or failed stapled hemorrhoidopexy was made. The clinical history of all of these patients was carefully studied and all underwent inspection, digital exploration, and proctoscopy. After the reintervention, proctoscopy was performed in 61 patients (92 percent) after a median follow-up of 5.5 (range, 1-36) months. RESULTS: Our reoperation rate after stapled hemorrhoidopexy was 11 percent. The most frequent indications for reintervention were persistent, severe anal pain (visual analog pain score higher than 7) in 29 patients (45 percent), severe postoperative bleeding in 20 (31 percent), anal fissure in 16 (21 percent), prolapsing piles in 12 (18 percent), rectal polyp in 11 (16 percent), anorectal sepsis in 11 (16 percent), and fecal incontinence in 7 (11 percent). Thirteen different types of reintervention were needed. Excisional hemorrhoidectomy, removal of staples, and fissurectomy and/or internal sphincterotomy were the most frequent operation (n = 41). A decrease in anal pain, as measured by visual analog pain score, was observed one month after reintervention, compared with that measured preoperatively (from 5.6 +/- 3.6 to 3.0 +/- 2.9) (P < 0.001). Bleeding requiring treatment occurred in six cases (10 percent), anal stricture requiring dilation occurred in three (5 percent), and fecal incontinence in three (5 percent). Proctoscopy showed no recurrences in 52 cases (80 percent) after the reintervention. CONCLUSION: Pain and bleeding mostly caused by piles, fissures, and retained staples were the most frequent causes for reoperation after stapled hemorrhoidopexy. Reintervention was associated with a high bleeding and soiling rate, but was effective in treating pain and other symptoms in the majority of patients. Because of the wide spectrum of different interventions required, a failed or complicated stapled hemorrhoidopexy might be better treated by an experienced colorectal surgeon.

STUDY QUESTION: Is it safe to perform controlled ovarian stimulation (COS) for fertility preservation before starting anticancer therapies or ART after treatments in young breast cancer patients? SUMMARY ANSWER: Performing COS before, or ART following anticancer treatment in young women with breast cancer does not seem to be associated with detrimental prognostic effect in terms of breast cancer recurrence, mortality or event-free survival (EFS). WHAT IS KNOWN ALREADY: COS for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors, even when associated with aromatase inhibitors. Moreover, limited evidence exists on the safety of ART in breast cancer survivors for achieving pregnancy after the completion of anticancer treatments. STUDY DESIGN, SIZE, DURATION: The present systematic review and meta-analysis was carried out by three blinded investigators using the keywords 'breast cancer' and 'fertility preservation'; keywords were combined with Boolean operators. Eligible studies were identified by a systematic literature search of Medline, Web of Science, Embase and Cochrane library with no language or date restriction up to 30 June 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: To be included in this meta-analysis, eligible studies had to be case-control or cohort studies comparing survival outcomes of women who underwent COS or ART before or after breast cancer treatments compared to breast cancer patients not exposed to these strategies. Survival outcomes of interest were cancer recurrence rate, relapse rate, overall survival and number of deaths. Adjusted relative risk (RR) and hazard ratio (HR) with 95% CI were extracted. When the number of events for each group were available but the above measures were not reported, HRs were estimated using the Watkins and Bennett method. We excluded case reports or case series with <10 patients and studies without a control group of breast cancer patients who did not pursue COS or ART. Quality of data and risk of bias were assessed using the Newcastle-Ottawa Assessment Scale. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1835 records were retrieved. After excluding ineligible publications, 15 studies were finally included in the present meta-analysis (n = 4643). Among them, 11 reported the outcomes of breast cancer patients who underwent COS for fertility preservation before starting chemotherapy, and 4 the safety of ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n = 2386), those who underwent COS (n = 1594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) and mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor-positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65). A reduced risk of recurrence was also observed in patients undergoing COS before neoadjuvant chemotherapy (RR 0.22, 95% CI 0.06-0.80). Compared to women not exposed to ART following completion of anticancer treatments (n = 540), those exposed to ART (n = 123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11). LIMITATIONS, REASONS FOR CAUTION: This meta-analysis is based on abstracted data and most of the studies included are retrospective cohort studies. Not all studies had matching criteria between the study population and the controls, and these criteria often differed between the studies. Moreover, rate of recurrence is reported as a punctual event and it is not possible to establish when recurrences occurred and whether follow-up, which was shorter than 5 years in some of the included studies, is adequate to capture late recurrences. WIDER IMPLICATIONS OF THE FINDINGS: Our results demonstrate that performing COS at diagnosis or ART following treatment completion does not seem to be associated with detrimental prognostic effect in young women with breast cancer, including among patients with hormone receptor-positive disease and those receiving neoadjuvant chemotherapy. STUDY FUNDING/COMPETING INTEREST(S): Partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant number MFAG 2020 ID 24698) and the Italian Ministry of Health-5 × 1000 funds 2017 (no grant number). M.L. acted as consultant for Roche, Pfizer, Novartis, Lilly, AstraZeneca, MSD, Exact Sciences, Gilead, Seagen and received speaker honoraria from Roche, Pfizer, Novartis, Lilly, Ipsen, Takeda, Libbs, Knight, Sandoz outside the submitted work. F.S. acted as consultant for Novartis, MSD, Sun Pharma, Philogen and Pierre Fabre and received speaker honoraria from Roche, Novartis, BMS, MSD, Merck, Sun Pharma, Sanofi and Pierre Fabre outside the submitted work. I.D. has acted as a consultant for Roche, has received research grants from Roche and Ferring, has received reagents for academic clinical trial from Roche diagnostics, speaker's fees from Novartis, and support for congresses from Theramex and Ferring outside the submitted work. L.D.M. reported honoraria from Roche, Novartis, Eli Lilly, MSD, Pfizer, Ipsen, Novartis and had an advisory role for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, Seagen, AstraZeneca, Eisai outside the submitted work. The other authors declare no conflict of interest. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. REGISTRATION NUMBER: N/A.

Background: Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions: TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.

Influenza vaccination is generally recommended for non-Hodgkin's lymphoma (NHL) patients, but no data are available about the activity of this vaccine after treatment with rituximab-containing regimens. We evaluated the humoral response to the trivalent seasonal influenza vaccine in a group of NHL patients in complete remission for ≥6 mo (median, 29 mo) after treatment with rituximab-containing regimens (n = 31) compared with age-matched healthy subjects (n = 34). B cell populations and incidence of influenza-like illness were also evaluated. For each viral strain, the response was significantly lower in patients compared with controls and was particularly poor in patients treated with fludarabine-based regimens. In the patient group, the response to vaccination did not fulfill the immunogenic criteria based on the European Committee for Medicinal Products for Human Use requirements. Among the patients, CD27(+) memory B cells were significantly reduced, and their reduction correlated with serum IgM levels and vaccine response. Episodes of influenza-like illness were recorded only in patients. These results showed that NHL patients treated with rituximab-containing regimens have persisting perturbations of B cell compartments and Ig synthesis and may be at particular risk for infection, even in long-standing complete remission.

BACKGROUND: The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM). METHODS: Eligible patients received pemetrexed 500 mg m(-2), carboplatin area under the plasma concentration-time curve (AUC) 5 mg ml(-1) per minute and bevacizumab 15 mg kg(-1), administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated. RESULTS: Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7-46.0%). Forty-four (57.9%, 95% CI 46.0-69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3-4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred. CONCLUSION: The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.

PURPOSE: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. EXPERIMENTAL DESIGN: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. RESULTS: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. CONCLUSIONS: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted.

BACKGROUND: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. METHODS: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. RESULTS: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS - mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. CONCLUSION: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.

Background The co-administration of letrozole during controlled ovarian stimulation (COS) with gonadotropins is used to limit the potentially harmful effects of a supra-physiological rise in estrogen levels on hormone-sensitive cancers. However, the efficacy and safety of adding letrozole to COS remains debated. Methods This is a systematic review and meta-analysis of published studies that compared the efficacy and safety of COS with co-administration of letrozole versus COS without letrozole in all patient populations. A secondary analysis was done including only the studies in breast cancer patients. The primary efficacy endpoint was the number of retrieved mature Metaphase II (MII) oocytes. Secondary efficacy and safety endpoints were total number of oocytes, maturation rate, fertilization rate, number of cryopreserved embryos, peak estradiol levels, progesterone levels, total gonadotropin dose. Data for each endpoint were reported and analyzed thorough mean ratio (MR) with 95% confidence interval (CI). Results A total of 11 records were selected including 2,121 patients (990 patients underwent COS with letrozole and 1,131 COS without letrozole). The addition of letrozole to COS did not have any negative effect on the number of mature oocytes collected (MR=1.00, 95% CI=0.87-1.16; P=0.967) and the other efficacy endpoints. COS with letrozole was associated with significantly decreased peak estradiol levels (MR=0.28, 95% CI=0.24-0.32, P<0.001). Similar results were observed in the secondary analysis including only breast cancer patients. Conclusions These findings are reassuring on the efficacy and safety of COS with gonadotropins and letrozole and are particularly important for fertility preservation in women with hormone-sensitive cancers.

BACKGROUND: It is increasingly recognized that treating pain is crucial for effective care within neurological rehabilitation in the setting of the neurological rehabilitation. The Italian Consensus Conference on Pain in Neurorehabilitation was constituted with the purpose identifying best practices for us in this context. Along with drug therapies and physical interventions, psychological treatments have been proven to be some of the most valuable tools that can be used within a multidisciplinary approach for fostering a reduction in pain intensity. However, there is a need to elucidate what forms of psychotherapy could be effectively matched with the specific pathologies that are typically addressed by neurorehabilitation teams. OBJECTIVES: To extensively assess the available evidence which supports the use of psychological therapies for pain reduction in neurological diseases. METHODS: A systematic review of the studies evaluating the effect of psychotherapies on pain intensity in neurological disorders was performed through an electronic search using PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews. Based on the level of evidence of the included studies, recommendations were outlined separately for the different conditions. RESULTS: The literature search yielded 2352 results and the final database included 400 articles. The overall strength of the recommendations was medium/low. The different forms of psychological interventions, including Cognitive-Behavioral Therapy, cognitive or behavioral techniques, Mindfulness, hypnosis, Acceptance and Commitment Therapy (ACT), Brief Interpersonal Therapy, virtual reality interventions, various forms of biofeedback and mirror therapy were found to be effective for pain reduction in pathologies such as musculoskeletal pain, fibromyalgia, Complex Regional Pain Syndrome, Central Post-Stroke pain, Phantom Limb Pain, pain secondary to Spinal Cord Injury, multiple sclerosis and other debilitating syndromes, diabetic neuropathy, Medically Unexplained Symptoms, migraine and headache. CONCLUSIONS: Psychological interventions and psychotherapies are safe and effective treatments that can be used within an integrated approach for patients undergoing neurological rehabilitation for pain. The different interventions can be specifically selected depending on the disease being treated. A table of evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation is also provided in the final part of the paper.

AIMS: Opinions differ regarding the effectiveness of cardiac pacing in patients affected by reflex syncope. We assessed a standardized guideline-based algorithm in different forms of reflex syncope. METHODS AND RESULTS: In this prospective, multi-centre, observational study, patients aged >40 years, affected by severe unpredictable recurrent reflex syncopes, underwent carotid sinus massage (CSM), followed by tilt testing (TT) if CSM was negative, followed by implantation of an implantable loop recorder (ILR) if TT was negative. Those who had an asystolic response to one of these tests received a dual-chamber pacemaker. POPULATION: 253 patients, mean age 70 ± 12 years, median 4 (3-6) syncopes, 89% without or with short prodromes. Of these patients, 120 (47%) received a pacemaker and 106 were followed up for a mean of 13 ± 7 months: syncope recurred in 10 (9%). The recurrence rate was similar in 61 CSM+ (11%), 30 TT+ (7%), and 15 ILR+ (7%) patients. The actuarial total syncope recurrence rate was 9% (95% confidence interval (CI), 6-12) at 1 year and 15% (95% CI, 10-20) at 2 years and was significantly lower than that observed in the group of 124 patients with non-diagnostic tests who had received an ILR: i.e. 22% (95% CI, 18-26) at 1 year and 37% (95% CI, 30-43) at 2 years (P = 0.004). CONCLUSION: About half of older patients with severe recurrent syncopes without prodromes have an asystolic reflex for which cardiac pacing goes along with a low recurrence rate. The study supports the clinical utility of the algorithm for the selection of candidates to cardiac pacing in everyday clinical practice. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01509534.

We aimed to assess the prevalence of and factors associated with anti- severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positivity in a large population of adult volunteers from five administrative departments of the Liguria and Lombardia regions. A total of 3609 individuals were included in this analysis. Participants were tested for anti-SARS-CoV-2 antibodies [Immunoglobulin G (IgG) and M (IgM) class antibodies] at three private laboratories (Istituto Diganostico Varelli, Medical Center, and Casa della Salute di Genova). Demographic data, occupational or private exposure to SARS-CoV-2-infected patients, and prior medical history consistent with SARS-CoV-2 infection were collected according to a preplanned analysis. The overall seroprevalence of anti-SARS-CoV-2 antibodies (IgG and/or IgM) was 11.0% [398/3609; confidence interval (CI) 10.0%–12.1%]. Seroprevalence was higher in female inmates than in male inmates (12.5% vs. 9.2%, respectively, p = 0.002), with the highest rate observed among adults aged >55 years (13.2%). A generalized estimating equations model showed that the main risk factors associated with SARS-CoV-2 seroprevalence were the following: an occupational exposure to the virus [Odd ratio (OR) = 2.36; 95% CI 1.59–3.50, p = 0.001], being a long-term care facility resident (OR = 4.53; 95% CI 3.19–6.45, p = 0.001), and reporting previous symptoms of influenza-like illness (OR = 4.86; 95% CI 3.75–6.30, p = 0.001) or loss of sense of smell or taste (OR = 41.00; 95% CI 18.94–88.71, p = 0.001). In conclusion, we found a high prevalence (11.0%) of SARS-CoV-2 infection that is significantly associated with residing in long-term care facilities or occupational exposure to the virus. These findings warrant further investigation into SARS-CoV-2 antibody prevalence among the Italian population.

Sir: Lichen sclerosus is a chronic inflammatory disease usually affecting the anogenital area. Tissue sclerosis and atrophy are present. Women are affected more than men. The etiopathogenesis is unknown, and the severe consequences are functional and psychological. Symptoms vary according to the stage of the disease. In the early phase, sclerosis involves the clitoris area; in the advanced phase, it extends to the labia minora, the labia majora, and the fork. The vulva changes shape with subsequent reduction of vulvar introit and painful ulcers appear. Topical corticosteroids are the standard treatment but require continuous administration, and associated complications are evident. Surgical therapy consists of vulvectomy, cryosurgery, and laser ablation.1 However, these procedures add scars to damaged tissues and have high recurrence rates. The aim of this article is to present a new regenerative approach that removes symptoms and reduces atrophy and sclerosis. This method is based on grafting of adipose-derived stem cells and injection of platelet-rich plasma. Fifteen female patients with a histologic diagnosis of lichen sclerosus were treated. Age ranged from 27 to 62 years. All patients had previously undergone steroid therapy, without any significant improvement. A blood sample of 50 ml was drawn from the patient. The blood was centrifuged at 1000 rpm for 6 minutes to obtain platelet-poor plasma. After a second centrifugation (3000 rpm for 12 minutes), a platelet-rich plasma was obtained. Approximately 5 ml of platelet-rich plasma was obtained (centrifuge diameter, 52.5 cm). After sedation and local infiltration by Klein solution, liposuction was carried out from a donor region with a 3-mm cannula and a 10-ml syringe. The lipoaspirate was washed with saline solution, decanted, and injected through a 14-gauge needle in the damaged area (range, 15 ml fat). Finally, 5 ml of platelet-rich plasma was injected into the same areas in the intradermal-intramucosal, subdermal, and submucosal compartments. Before injection, platelet-rich plasma was added with 0.5 ml of calcium chloride for platelet degranulation. All patients left the hospital a few hours after surgery. No adverse events were observed in this series of patients. All patients had moderate pain in the treated areas for 10 days after surgery. Fifteen days after intervention, symptoms improved: itching and burning disappeared within 1 month. Vulvar skin and mucosa appeared more elastic and soft, with a normal color. Four months after surgery, all patients reported total disappearance of pain and symptoms, and the anatomical features of the vulva were quite normal. All patients regained sexual activity. Patients with severe fibrosis and atrophy underwent the procedure one or two times more, after 3 months, with satisfactory and stable results. Follow-up ranged from 6 to 24 months (Fig. 1).Fig. 1.: (Above) Preoperative view of the initial stage of lichen sclerosus in a 52-year-old woman. It is evident by a marked sclerosis of the clitoris area. (Below) Postoperative appearance after two treatments with an interval of 3 months. Complete tissue restoration of the sclerotic area is evident.An innovative approach for patients affected by lichen sclerosus was described, in which the treatment was aimed at repairing tissue dystrophy. Traditional reconstructive surgery (e.g., grafts, flaps) should have had a high risk of complications. Therefore, a regenerative procedure was performed. Examples of skin regeneration after radiotherapy damage by lipofilling have been reported.2 Moreover, other “regenerative” techniques using platelet-rich plasma in dentistry and maxillofacial and orthopedic surgery are described. Growth factors released by platelets have an important role in inflammation reduction, angiogenesis stimulation, and collagen III synthesis.3,4 The procedure can be considered effective as therapy for lichen sclerosus disease. ACKNOWLEDGMENT The authors express their thanks to Barbara Cavazza for invaluable advice and comments regarding the article. Francesco Casabona, M.D. Virginia Priano, M.D. Department of Plastic and Reconstructive Surgery Valerio Vallerino, M.D. Department of Obstetrics and Gynecology Angela Cogliandro, M.D. Department of Transfusion Unit Giorgio Lavagnino, M.D. Department of Plastic and Reconstructive Surgery Villa Scassi Hospital Genoa, Italy