Using Real-world Data to Define a Validated Nomogram for Advanced Bladder Cancer Patients Who Respond to Immunotherapy.

AIMS: Immune checkpoint inhibitors (ICIs) are used in incurable urothelial cancers, both in chemo-naïve and platinum-refractory patients. Efficacy and toxicity data published outside controlled clinical trials are limited. We report overall survival, progression-free survival and toxicities of ICIs in locally advanced (LABC) or metastatic bladder cancer (MBC). We aimed to develop and validate a prognostic model for these patients. MATERIALS AND METHODS: A multicentre real-world individual patient-level data study (n = 272) evaluating ICIs in the first-line platinum-ineligible or platinum-refractory setting for LABC/MBC between March 2017 and February 2020 was undertaken. Cox regression analyses evaluated the association of prognostic factors with overall survival. Data were split to create a training (n = 208) and validation (n = 64) cohort. The backward elimination method with a P-value cut-off of 0.05 was used to develop a reduced prognostic model using the training data set. The concordance index and assessment of observed versus predicted survival probabilities were used to evaluate the final model. RESULTS: The median follow-up was 18.9 (15.8-21.5) months. The median overall survival and progression-free survival in the training cohort were 9.2 (95% confidence interval 7.4-10.5) and 4.5 months (3.5-5.7), respectively. The most common grade 1/2 adverse events recorded were fatigue (47.8%) and infection (19.9%). Five key prognostic factors found in the training set were low haemoglobin, high neutrophil count, choice of immunotherapy favouring pembrolizumab, presence of liver metastasis and steroid use within 30 days of treatment. The concordance index for the training and validation cohorts was 0.66 (standard error = 0.05) and 0.64 (standard error = 0.04), respectively, for the final model. A nomogram was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: Real-world data were used to produce a validated prognostic model for overall survival in LABC/MBC treated with ICIs. This model could assist in patient stratification, interpreting and framing future trials incorporating PD-1/PD-L1 inhibitors in LABC/MBC.

Electrochemotherapy as palliative treatment in patients with recurrent and/or metastatic head and neck tumours: features analysis for an early determination of the partial responsive patients.

OBJECTIVE: The aim of this study was to identify features mainly involved in determining the partial response (PR) to the Electrochemotherapy (ECT) in patients with recurrent and/or metastatic head and neck (H&N) tumor; the identified features were also used in a decision chart in order to provide the clinician with a support tool in deciding further therapies. PATIENTS AND METHODS: 131 patients (186 treatment sessions) with recurrent and/or metastatic H&N neoplasm were subjected to ECT. Treatment response was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 two months after the ECT. The grade of bleeding and pain before, at the end and one week after ECT treatment were evaluated. Univariate and multivariate analysis were performed to identify features involved in determining the patient PR. RESULTS: In the context of the univariate analysis, tumor size significantly influenced the response to ECT, with higher PR rate of 58.3%: 28 among 48 patients with lesion size ≤ 3 centimeters (p-value < 0.001 at Chi-square test). Pain and bleeding pre-treatment were positively correlated to PR (p-value < 0.001 at Chi-square test). A difference in the current flowing in the tissue during treatment was also observed in partially responsive patients, where the median current value (6.6 A) was higher than that achieved in patients that did not show PR (3.3 A). In the context of the multivariate analysis, the best performances are achieved with the BART method (accuracy of 84%). The main clinical factors to predict the partial response, among investigated features, that have shown to be considered were the pain value felt before performing the treatment and the median current delivered during the ECT treatment. A decision-making support tool to predict the patient prognosis in terms of response rate could be represented by the decision tree obtained with CART algorithm, where a pain pre-treatment more than 5 and a median delivered current not less than 2.8 A led to the prediction a partial responsive patient with an accuracy of 75%. CONCLUSIONS: The study confirmed that ECT is an interesting antitumoral therapy in advanced chemo- and radio-refractory H&N neoplasms, able to reduce frequent symptoms and to improve the quality of life. Pain pre-treatment and delivered current are the most important variables when predicting the partial response of patients.

Transoral robotic surgery of parapharyngeal space tumours: a series of four cases.

Tumours arising from the parapharyngeal space (PPS) represent less than 1% of all head and neck tumours. Salivary gland tumours account for 40-50% of PPS lesions and are located in the pre-styloid parapharyngeal space. Pleomorphic adenomas represent 80-90% of salivary tumours in the PPS. Recently, transoral robotic surgery (TORS) has become common in head and neck surgery as a minimally invasive procedure. Four cases of benign PPS tumour treated with TORS are presented here. Preoperative diagnosis was conducted by fine needle aspiration biopsy and magnetic resonance imaging, and the results were used to plan the correct surgical approach. One case required a change of approach to conventional transoral blunt dissection. Patients required pain control and reported dysphagia symptoms for a period of weeks, but no nasogastric tube was needed at any time. This case series indicates that TORS is a safe surgical procedure for the excision of benign tumours of the PPS in selected cases.

Platelet rich plasma in the treatment of bisphosphonate-related osteonecrosis of the jaw: personal experience and review of the literature.

Bisphosphonates (BPs) are a class of synthetic drugs commonly used to treat bone metastasis and various bone diseases that cause osseous fragility (such as osteoporosis). Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a common complication in patients who received BPs, especially intravenously. Recently, osteonecrosis of the jaw (ONJ) caused by chemotherapeutic not belonging to BPs drug class has been reported. For this reason, it has been proposed recently to rename BRONJ in antiresorptive agents related osteonecrosis of the jaw (ARONJ), to include a wider spectrum of drugs that may cause osteonecrosis of the jaw. The most debated topic about ARONJ/BRONJ is therapy. The most adequate procedure is far from being standardized and prevention seems to play a pivotal role. In our study, we considered 72 patients with BRONJ with nonsurgical therapy, surgical therapy, and surgical therapy with platelet rich plasma (PRP) gel to evaluate its therapeutic effect in promoting ONJ wounds healing. Good results showed by PRP in improving wound healing give away to case-control randomized studies that could give definitive evidence of its effectiveness.

Metastatic breast cancer subtypes and central nervous system metastases.

BACKGROUND: Breast cancer (BC) subtypes have different survival and response to therapy. We studied predictors of central nervous system metastases (CNS-M) and outcome after CNS-M diagnosis according to tumor subtype. PATIENTS AND METHODS: 488 patients with diagnosis of metastatic BC were retrospectively evaluated. According to the combination of hormone receptors (HR) and HER2 status, tumors were grouped in: Luminal (Lum), Luminal/HER2+, pure HER2-positive (pHER2+) and triple negative (TN). Time to CNS progression, CNS-M free interval and Overall Survival (OS) after CNS-M occurrence were compared by the log-rank test. Cox-proportional hazard models were used to study predictor factors associated with CNS progression, including tumor subtype and all potentially clinical relevant variables. RESULTS: 115 patients (pts) developed CNS-M with a median time to CNS progression of 31 months. The rate of CNS-M by subtype was: Lum 14%, Lum/HER2+ 35%, pHER2+ 49%, TN 22% (p < 0.001). Compared with Lum tumors, Lum/HER2+ (HR 2.514, p < 0.001), pHER2+ (HR 6.799, p < 0.0001) and TN (HR = 3.179, p < 0.001) subtypes were at higher risk of CNS-M. Median OS in months after CNS-M was: Lum 7.4, Lum/HER2+ 19.2, pHER2+ 7, TN 4.9 (p < 0.002). Belonging to the Lum/HER2+ subtype (HR 0.48, p < 0.037) and having isolated CNS (HR 0.37, p < 0.004) predicted significantly reduced risk of death. CONCLUSIONS: After CNS-M, the Lum/HER2+ subtype appears associated with the longest OS. Prospective clinical trials would be required for evaluating the potential role of screening for asymptomatic CNS lesions and of more aggressive CNS-M treatment in Lum/HER2+ subtype.

Status of level IIb lymph nodes of the neck in squamous cell carcinoma of the oral tongue in patients who underwent modified radical neck dissection and lymph node sentinel biopsy.

Status of lymph nodes of level IIb was examined to identify the incidence of nodal metastasis and the lymphatic drainage in squamous cell carcinoma of the oral tongue in patients undergoing modified radical neck dissection (MRND) and sentinel node biopsy (SNB). Overall, 72 patients were divided into two groups; 38 patients (Group A) of any T and N+ or T3-T4- N0 stage underwent MRND. The surgical specimens were sent to the Pathology Department, divided into specific levels (I, IIa, IIb, III, IV, V) and labelled. The remaining 34 patients (Group B) T1-T2 -N0 stage were submitted to SNB. The histological examination of the specimens of the two groups was performed by staining with haematoxylin and eosin several sections from each node at different levels and then using a molecular marker such as cytokeratin and Epithelial Membrane Antigen (EMA). In Group A: In N0 there were no occult metastases at level IIb; in N+ neck, 8 cases (33.3%) showed metastasis at level IIb (P = 0.04). Metastases at level IIb were observed only in combination with other levels (P = 0.03). In Group B, direct lymphatic drainage was found in 2 patients (5.9%) at level IIb. There were no occult metastases at level IIb. Out of the 54 sentinel nodes harvested, 4 lymph nodes (7.4%) were found to be metastatic; these 4 sentinel nodes were found respectively in 4 patients, 1 at level III, 3 at level II a with an occult metastasis rate of 11.7%. In conclusion, SNB has prospected a new concept of lymphatic drainage that is variable and individual. SNB has demonstrated that direct lymphatic drainage is possible to level II b. In our experience with early cancer of the tongue (T1-T2 NO ), SNB aided with lympho-scintigraphy seems to be a good technique for staging the neck with minimal morbidity.

[Hurthle cell neoplasm: our experience]. / Neoplasia a cellule di Hurthle: nostra esperienza.

Hurthle cell neoplasm is a rare form of thyroid tumors, comprising from 1.5% to 10% of all tumors. Hurthle cell nodules are clinically indistinguishable from other nodular thyroid diseases. The histologic features of Hurthle cell neoplasm don't allow us to exactly distinguish benign nodules from malignant ones. Accurate histologic valutation is possible and necessary for a correct diagnosis and therapy of Hurthle cell tumors. The adenomas usually exhibit a follicular pattern; the carcinomas include a subset of Hurthle cell tumors with different biological behavior, including malignant follicular variants and papillary ones. The authors are in favour of total thyroidectomy for carcinomas and lobectomy plus isthectomy for adenomas; in case of carcinomas, the lymphadenectomy reduces the incidence of local relapse and is necessary in case of lymphnode involvement. Adjuvant radiation therapy is successful in preventing recurrences, in symptomatic metastates as palliative therapy and control recurrence of advanced resected tumors.

[Giant adrenal myelolipoma: a case report and review of the literature]. / Mielolipoma gigante del surrene: case report e review della letteratura.

Adrenal myelolipoma is a rare nonfunctioning tumor consisting histologically of an admixture of adipose tissue and extramedullary hemopoietic elements within the adrenal glands. Most of these lesions are 5 small and asymptomatic, but there are also giant ones, associated with endocrine disorders. These tumors are mostly detected incidentally by imaging. The increasing number of incidentally discovered adrenal myelolipomas arise the question of appropriate treatment modalities. The authors report a case of giant myelolipoma associated with lithiasic cholecystitis and discuss different imaging and terapeutic aspects.

[Our experience with treatment of varicocele in a day-surgery protocol]. / Nostra esperienza nel trattamento del varicocele in regime di day-surgery.

In the last few years the increasing interest for non-invasive operating techniques has allowed to reevaluate the sublinguinal varicocelectomy surgical technique for idiopathic varicocele surgical treatment. During the years 1998-2001, 29 patients have been operated on sub-inguinal varicocelectomy (14 patients were suffering from idiopathic varicocele of third grade, 11 of second grade, 3 of first grade, and 1 subclinical). Out of the 29 patients, only 10 were unable to procreate. All patients were operated under local anesthesia and discharged the same day (day-surgery). Owing to Authors' experience, the sublinguinal varicocelectomy by optical magnifying devices represents the "gold standard" in the idiopathic varicocele treatment because it allows to minimize relapsing rates, to limit post-operation complications, to improve the reproductive faculty of seminal fluid both qualitatively and quantitatively, to cut patient's operating costs significantly, to keep the operation time within acceptable limits, and to be easily learned and carried out.

Hypoxia stimulates human preproendothelin-1 promoter activity in transgenic mice.

Significant elevations in endothelin (ET)-1 levels accompany many diseases, but the underlying regulatory mechanisms are unclear. To investigate the in vivo regulation of human preproendothelin-1 (PPET-1), we examined the activity of the PPET-1 promoter in transgenic mice exposed to hypoxia. Mice expressing one of three PPET-1 promoter-luciferase (PPET-1/LUC) reporter transgenes (approximately 2.5 kb, 138 bp, or none of the 5'-flanking sequences of the PPET-1 gene) were generated. LUC expression was reduced in mice with a truncated 138-bp PPET-1 promoter. Exposure of mice bearing the 2.5-kb PPET-1/LUC transgene to hypoxia (10% O2 for 24 h) increased LUC expression sixfold in pulmonary tissue but only twofold in other tissues. In situ hybridization revealed the strongest transgene expression in the pulmonary vasculature and bronchiolar epithelium. These data are consistent with the hypothesis that hypoxic induction of the PPET-1 gene leads to increased pulmonary production of ET-1 in diseases associated with low O2 tension.

Quantitative analysis of apoptosis and bcl-2 in Sjögren's syndrome.

OBJECTIVE: To determine whether apoptosis plays a significant role in tissue damage of Sjögren's syndrome (SS). METHODS: We performed a quantitative analysis of programmed cell death on salivary glands of 11 patients. Ten age matched women with sicca syndrome served as controls. Morphometric measurement of the fractional volume of acini and ducts showing DNA strand breaks was performed in sections stained by deoxynucleotidyl transferase assay. The extent of bcl-2 expression was determined in sections labeled with monoclonal antibody. The different cell populations infiltrating the glands were examined in tissues stained with anti-leukocyte common antigen and OPD4 monoclonal antibodies. RESULTS: In patients with SS, 68% of the ductal epithelium was occupied by apoptotic structures, whereas only 12% of acini showed DNA strand breaks. Corresponding values in control salivary glands were 3 and 0.13%. bcl-2 labeling was higher in ducts than in acini of both control and pathologic glands. However, in SS a 43% (p < 0.001) and 75% (p < 0.001) reduction in bcl-2 expression was observed in ductal and acinar epithelium, respectively. In comparison with controls, the numerical density of CD4+ cells and plasma cells scattered throughout the interstitium was 323% and 203% higher (p < 0.001) in SS. Moreover, T helper/inducer lymphocytes represented 52% of the inflammatory foci. CONCLUSION: Apoptosis occurs in minor salivary glands of patients with SS with a prevailing localization on the ductal epithelium in association with downregulation of bcl-2 and a large number of infiltrating CD4+ lymphocytes. Thus, the destruction of glandular tissue and the loss of secretory function in SS is dependent on the activation of the suicide program of epithelial cells.

Lipoid pneumonia: a case of cavitary bilateral nodular opacity.

Lipoid pneumonia is a rare disease resulting from the inhalation of fatty or oily materials into the lungs. It can look like acute or chronic pneumonia or a localized granuloma (called paraffinoma). The clinical and radiological features are usually nonspecific and can suggest lung cancer or tuberculosis. As in most cases accidental inhalation of fatty material escapes anamnestic investigation, lipoid pneumonia is rarely diagnosed without invasive intervention. The present study refers to a case of cavitary bilateral nodular opacity due to the accidental inhalation of paraffin oil used as a laxative, whose radiological appearance was quite similar to Wegener's granulomatosis.

Cloning and expression of an endothelin receptor subtype B from human prostate that mediates contraction.

Recent evidence suggests a role for endothelin (ET) in contraction of human prostate [J. Urol. 149:495-499 (1993)]. Although both ETA and ETB receptors have been shown to mediate contraction of smooth muscle, the molecular identity of the contractile ETB receptor is controversial. The aim of this study was to examine the receptor subtype that mediates ET-induced contraction in prostate from patients with benign prostatic hyperplasia. Saturation binding with 125I-ET-1 and 125I-ET-3 in prostate stromal cells (PSC) indicated the presence of receptors with subnanomolar affinity for these radioligands, with equivalent receptor densities. Inhibition of specific 125I-ET-1 or 125I-ET-3 binding in PSC revealed a rank order of potency of ET-1 - ET-3 = sarafotoxin S6c >> BQ-123. These data are consistent with a predominance of ETB receptors in PSC. The functional effects of ET stimulation of PSC were examined in a collagen gel contraction assay. ET-1 and ET-3 caused contraction of underlying collagen gel matrices with EC50 values of 0.4 +/- 0.04 and 0.7 +/- 0.2 nM, respectively. To determine the molecular nature of the contractile ETB receptor in PSC, reverse transcription-polymerase chain reactions were conducted with oligonucleotide primers to the 5' and 3' ends of the coding sequence of the full length human ETB receptor. DNA sequence analysis of the 1.3-kilobase DNA product showed 99% homology to other human ETB receptor cDNAs. The encoded protein has a deduced amino acid sequence identical to that of other human ETB receptors, with the exception of two conservative substitutions. Expression of the PSC ETB cDNA in COS-7 cells resulted in a binding profile similar to that observed in parent cells. Polymerase chain reaction analysis revealed the presence of prepro-ET-1 mRNA in PSC. Collectively, these data indicate that PSC from patients with benign prostatic hyperplasia express ETB receptors that mediate ET-induced contraction.

Expression of the v-Mos oncogene in male meiotic germ cells of transgenic mice results in metaphase arrest.

To explore the role of pp39mos in male germ cell meiosis, we have constructed transgenic mice carrying either the c-Mos or v-Mos genes linked to the human male germ cell-specific phosphoglycerate kinase-2 promoter. All male transgenic mice bearing the v-Mos but not the c-Mos construct were sterile due to arrest of germ cells at metaphase I. Immunocytochemistry performed on sections from control and c-Mos transgenic testes with eight different monoclonal and polyclonal antisera against either alpha-, beta- or gamma-tubulins demonstrated that all could recognize MI spermatocyte spindles from control and c-Mos transgenics, but only one monoclonal anti-microtubule sera decorated the spindles of v-Mos-arrested meiotic figures. Western blot analyses with this one serum revealed a change in proteins in the v-Mos samples. Immunocytochemistry with the MPM-2 monoclonal antibody, which is specific for epitopes phosphorylated during mitosis, demonstrated an increase in cytoplasmic and spindle-associated phosphoproteins in arrested v-Mos spermatocytes. Western analysis with MPM-2 showed an increase in a M(r) 50,000-55,000 and a M(r) 25,000-29,000 protein in Mos transgenic testes when compared to controls. An anti-MAP kinase antibody demonstrated an increase in all four MAP kinases in testes of transgenic mice. Thus, overexpression of pp39v-mos during male germ cell meiosis resulted in an alteration of various cell cycle related kinases and cytostatic factor-like arrest at MI.

Clinical trial of the efficacy and safety of moguisteine in patients with cough associated with chronic respiratory diseases.

This completely randomised, double-blind, placebo-controlled, multicentre trial was carried out to evaluate the antitussive activity and safety of a 200 mg t.i.d. regimen of moguisteine (20 mg/ml ready-to-use suspension) during four days in patients with cough associated to chronic respiratory disorders. A total of 87 patients were enrolled, 42 on moguisteine and 45 on placebo. All had persistent dry or slightly productive coughs associated with chronic respiratory disorders. Seventy three were submitted to per protocol efficacy analyses, and eighty-three to intention-to-treat efficacy analyses. All the patients who were administered the study drug were analysed for safety. The underlying disorders reported as being associated with the target symptom were chronic obstructive pulmonary disease, cough of unknown aetiology, respiratory tract malignant neoplasms and pulmonary fibrosis. The treatment groups appeared to have been homogeneous on admission. The number of coughs in the interval 8-10 a.m. on day four vs day one was reduced by 42% on moguisteine against 14% on placebo; the difference between treatments was statistically significant (p = 0.028). The mean percent reduction of ladder scale scores of cough frequency vs baseline was greater on moguisteine than on placebo both in the day-time (especially on days one and two), and at night. The antitussive activity of moguisteine did not show remarkable variations either by diagnosis or by type of cough (dry/slightly productive). No serious adverse events were reported. No changes/trends were identified in laboratory tests that might indicate functional or toxic effects of moguisteine on specific organs.