Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial.

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.

Epicure: a European epidemiological study of patients with an advanced or metastatic Urothelial Carcinoma (UC) having progressed to a platinum-based chemotherapy.

BACKGROUND: Platinum-based systemic chemotherapy is considered the backbone for management of advanced urothelial carcinomas. However there is a lack of real world data on the use of such chemotherapy regimens, on patient profiles and on management after treatment failure. METHODS: Fifty-one randomly selected physicians from 4 European countries registered 218 consecutive patients in progression or relapse following a first platinum-based chemotherapy. Patient characteristics, tumor history and treatment regimens, as well as the considerations of physicians on the management of urothelial carcinoma were recorded. RESULTS: A systemic platinum-based regimen had been administered as the initial chemotherapy in 216 patients: 15 in the neoadjuvant setting, 61 in adjuvant therapy conditions, 137 in first-line advanced setting and 3 in other conditions. Of these patients, 76 (35 %) were initially considered as cisplatin-unfit, mainly because of renal impairment (52 patients). After platinum failure, renal impairment was observed in 44 % of patients, ECOG Performance Status ≥ 2 in 17 %, hemoglobinemia < 10 g/dL in 16 %, hepatic metastases in 13 %. 80 % of these patients received further anticancer therapy. Immediately after failure of adjuvant/neoadjuvant chemotherapy, most subsequent anticancer treatments were chemotherapy doublets (35/58), whereas after therapy failure in the advanced setting most patients receiving further anticancer drugs were treated with a single agent (80/114). After first progression to chemotherapy, treatment decisions were mainly driven by Performance Status and prior response to chemotherapy (>30 % patients). The most frequent all-settings second anticancer therapy regimen was vinflunine (70 % of single-agent and 42 % of all subsequent treatments), the main reasons evoked by physicians (>1 out of 4) being survival benefit, safety and phase III evidence. CONCLUSION: In this daily practice experience, a majority of patients with urothelial carcinoma previously treated with a platinum-based therapy received a second chemotherapy regimen, most often a single agent after an initial chemotherapy in the advanced setting and preferably a cytotoxic combination after a neoadjuvant or adjuvant chemotherapy. Performance Status and prior response to chemotherapy were the main drivers of further treatment decisions.

Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis.

BACKGROUND: First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. PATIENTS AND METHODS: Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2 → 2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. RESULTS: In group 4/2 → 2/1, the overall incidence of grade ≥ 3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥ 3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2 → 2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. CONCLUSIONS: mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.

Late onset invasive pneumococcal disease in a liver transplanted patient: beyond the Austrian syndrome.

Invasive disease caused by Streptococcus pneumoniae is a major cause of morbidity and mortality in high-risk individuals with severe comorbidities, including asplenia, chronic alcoholism, and altered immune status. The risk of invasive pneumococcal disease has been significantly higher in transplant patients compared with the general population. Here, we report an unusual case of a disseminated pneumococcal infection with meningitis, endocarditis, spondylodiscitis, and muscle abscess in an asplenic patient on chronic immunosuppressive therapy for liver transplantation performed 17 years before.

A novel multisensory device for the assessment and rehabilitation of perceptual and attentional competencies.

The present study aims to assess a novel technological device suitable for investigating perceptual and attentional competencies in people with or without sensory impairment. The TechPAD is a cabled system including embedded sensors and actuators to enable visual, auditory, and tactile interactions and a capacitive surface receiving inputs from the user. The system is conceived to create multisensory environments, using multiple units controlled separately and simultaneously. We assessed the device by adapting a spatial attention task comparing performances in different cognitive load conditions (high or low) and stimulation (unimodal, bimodal, or trimodal). 28 sighted adults were asked to monitor both the central and peripheral parts of the device and to tap a target stimulus (either visual, auditory, haptic, or multimodal) as fast as they could. Our results suggest that this new device can provide congruent and incongruent multimodal stimuli and quantitatively measure parameters such as reaction time and accuracy, allowing to investigate perceptual mechanisms in multisensory environments.Clinical Relevance-The TechPad is a reliable tool for the assessment of spatial attention during interactive tasks. its application in clinical trials will pave the way to its role in multisensory rehabilitation.

2-¹8fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) for postchemotherapy seminoma residual lesions: a retrospective validation of the SEMPET trial.

BACKGROUND: 2-¹8fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients. PATIENTS AND METHODS: FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome. RESULTS: One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P=0.032). CONCLUSION: Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy.

Low-impact chemical weed control techniques in UNESCO World Heritage Sites of Cuba.

Dichrostachys cinerea is a thorny, acacia-like, fast-growing woody bush which invades fields, wasteland, road sides and other disturbed areas. This gregarious species has become a very aggressive invasive weed in Cuba, where no native predators or pathogens are found. It often encroaches in fallows, overgrazed areas and mismanaged veld. D. cinerea is a very difficult weed to eliminate because of its active suckering, and is liable to produce dense thickets which are quite impenetrable on account of the density and abundance of its long, stiff, sharp thorns. In the Valle de los Ingenios area (Cuba Central), the tree is unchecked and forms veritable forests in areas on which cane growing has been discontinued. Physical management by cutting and burning the plants is not a very efficient control method, since the seeds survive in the soil, and they grow very fast. Therefore, chemical methods via the use of herbicides are often necessary to eradicate this weed. A preliminary study using glyphosate and auxin-like herbicides (2,4-D + picloram, MCPA, and MCPA + 2,4-D) plus adjuvants has been carried out in order to elucidate the best mixtures rendering maximum weed control with minimum herbicide rate and environmental stress. None of the herbicides used except glyphosate and 2,4-D + picloram showed acceptable mortality rates (75-80%) at the recommended doses tested. In the failed herbicide treatments, only the use of double herbicide rates succeeded in controlling marabou. The herbicide mixture of 2,4-D + picloram formulated with either a non-ionic surfactant or a mixture of fatty acid esters was the best option to control D. cinerea in terms of maximum effectiveness and minimum environmental stress, as the reduction in active ingredients applied to the environment was x3 in these two adjuvant-amended formulations compared to 2,4-D + picloram alone.

Early visual deprivation disrupts the mental representation of numbers in visually impaired children.

Several shreds of evidence indicate that visual deprivation does not alter numerical competence neither in adults nor in children. However, studies reporting non-impaired numerical abilities in the visually impaired population present some limitations: (a) they mainly assessed the ability to process numbers (e.g. mathematical competence) rather than represent numbers (e.g. mental number line); (b) they principally focused on positive rather than negative number estimates; (c) they investigated numerical abilities in adult individuals except one focusing on children (Crollen et al. in Cognition 210:104586, 2021). Overall, this could limit a comprehensive explanation of the role exerted by vision on numerical processing when vision is compromised. Here we investigated how congenital visual deprivation affects the ability to represent positive and negative numbers in horizontal and sagittal planes in visually impaired children (thirteen children with low vision, eight children with complete blindness, age range 6-15 years old). We adapted the number-to-position paradigm adopted by Crollen et al. (Cognition 210:104586, 2021), asking children to indicate the spatial position of positive and negative numbers on a graduated rule positioned horizontally or sagittally in the frontal plane. Results suggest that long-term visual deprivation alters the ability to identify the spatial position of numbers independently of the spatial plane and the number polarity. Moreover, results indicate that relying on poor visual acuity is detrimental for low vision children when asked to localize both positive and negative numbers in space, suggesting that visual experience might have a differential role in numerical processing depending on number polarity. Such findings add knowledge related to the impact of visual experience on numerical processing. Since both positive and negative numbers are fundamental aspects of learning mathematical principles, the outcomes of the present study inform about the need to implement early rehabilitation strategies to prevent the risk of numerical difficulties in visually impaired children.

Effects of climate variation on bird escape distances modulate community responses to global change.

Climate and land use are rapidly changing environmental conditions. Behavioral responses to such global perturbations can be used to incorporate interspecific interactions into predictive models of population responses to global change. Flight initiation distance (FID) reflects antipredator behaviour defined as the distance at which an individual takes flight when approached by a human, under standardized conditions. This behavioural trait results from a balance between disturbance, predation risk, food availability and physiological needs, and it is related to geographical range and population trends in European birds. Using 32,145 records of flight initiation distances for 229 bird species during 2006-2019 in 24 European localities, we show that FIDs decreased with increasing temperature and precipitation, as expected if foraging success decreased under warm and humid conditions. Trends were further altered by latitude, urbanisation and body mass, as expected if climate effects on FIDs were mediated by food abundance and need, differing according to position in food webs, supporting foraging models. This provides evidence for a role of behavioural responses within food webs on how bird populations and communities are affected by global change.

Radical metastasectomy followed by sorafenib versus observation in patients withclear cell renal cell carcinoma: extended follow -up of efficacy results from the randomized phase II RESORT trial.

Background: The RESORT trial showed no longer relapse free survival (RFS) with sorafenib following radical metastasectomy in metastatic renal cell carcinoma. We present the updated 42-month follow-up data.Methods: The phase II RESORT trial randomized patients to sorafenib or observation within 12 weeks from surgery. RFS was the primary endpoint.Results: We analyzed 68 patients (32 in sorafenib and 36 in the observation arm), randomized between November 2012 and November 2017. Eighty-one percent in the sorafenib arm and 80% in the observation arm had one metastasis . At a median follow-up of 42 months (interquartile range 31-58), in the observation arm the median RFS was 35 months, RFS probability was 57% (95% CI 42-76%) at 24 and 44% (95% CI 30-65%) at 48 months. In the sorafenib arm, median RFS was 21 months, RFS probability was 50% (95% CI 34-71%) at 24 and 32% (95% CI 18-57%) at 48 months (p = 0.342;HR 1.35;95% CI 0.72-2.54). Forty-seven percent and 37.5% of the patients in the two arms, respectively, are disease free. The site of relapses was independent of the previous metastasectomy site.Expert commentary: Sorafenib after metastasectomy did not improve RFS, but surgery in selected patients should be considered in order to potentially improve survival.Clinical trial registration: www.clinicaltrials.gov identifier is NCT0144480.

Immune-inflammatory biomarkers as prognostic factors for immunotherapy in pretreated advanced urinary tract cancer patients: an analysis of the Italian SAUL cohort.

BACKGROUND: Reliable and affordable prognostic and predictive biomarkers for urothelial carcinoma treated with immunotherapy may allow patients' outcome stratification and drive therapeutic options. The SAUL trial investigated the safety and efficacy of atezolizumab in a real-world setting on 1004 patients with locally advanced or metastatic urothelial carcinoma who progressed to one to three prior systemic therapies. PATIENTS AND METHODS: Using the SAUL Italian cohort of 267 patients, we investigated the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) and the best performing one of these in combination with programmed death-ligand 1 (PD-L1) with or without lactate dehydrogenase (LDH). Previously reported cut-offs (NLR >3 and NLR >5; SII >1375) in addition to study-defined ones derived from receiver operating characteristic (ROC) analysis were used. RESULTS: The cut-off values for NLR and SII by the ROC analysis were 3.65 (sensitivity 60.4; specificity 63.0) and 884 (sensitivity 64.4; specificity 67.5), respectively. The median overall survival (OS) was 14.7 months for NLR <3.65 [95% confidence interval (CI) 9.9-not reached (NR)] versus 6.0 months for NLR ≥3.65 (95% CI 3.9-9.4); 14.7 months for SII <884 (95% CI 10.6-NR) versus 6.0 months for SII ≥884 (95% CI 3.7-8.6). The combination of SII, PD-L1, and LDH stratified OS better than SII plus PD-L1 through better identification of patients with intermediate prognosis (77% versus 48%, respectively). Multivariate analyses confirmed significant correlations with OS and progression-free survival for both the SII + PD-L1 + LDH and SII + PD-L1 combinations. CONCLUSION: The combination of immune-inflammatory biomarkers based on SII, PD-L1, with or without LDH is a potentially useful and easy-to-assess prognostic tool deserving validation to identify patients who may benefit from immunotherapy alone or alternative therapies.

Malignant peritoneal mesothelioma: a multicenter study on 81 cases.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare disease characterized by a difficult diagnosis, different types of presentation, variable course and poor prognosis. MATERIALS AND METHODS: Eighty-one patients with MPM observed in 14 Italian oncology institutions from 1982 to 2007 have been examined with the aim of delineating the history of MPM. RESULTS: Presentation symptoms were ascites, abdominal pain, asthenia, weight loss, anorexia, abdominal mass, fever, diarrhea and vomiting in various associations. Computed tomography scan and echotomography signs were ascites, abdominal mass and peritoneal thickening. Peritoneal fluid cytology (61 cases) was positive for mesothelioma in 31 and for malignancy, not mesothelioma, in 13. Laparoscopy was carried out in 40 cases and laparotomy in 36. Thrombocytosis was present in 59 cases. Associated tumors diagnosed during the lifetime were colorectal cancer in two cases and cheek carcinoma, thyroid carcinoma, tongue carcinoma, bladder carcinoma and testicular seminoma. Thirty patients were treated with surgery and 45 with chemotherapy. The median survival time from diagnosis is 13 months. Ascites, fever and vomiting were significative variables at presentation; only vomiting holds significance in a multivariate analysis. CONCLUSIONS: MPM is a disease with various types of presentation, frequently associated with thrombocytosis, sometimes with other tumors. Survival and diagnosis time can differ in various types of MPM. Prognosis is poor.

The importance of subcapsular anesthesia in the anesthesiological management for thyroid radiofrequency ablation.

Radiofrequency ablation is a minimally invasive procedure alternative to surgery to treat benign thyroid nodules causing compressive symptoms. Tolerability of this procedure, aimed at treatment of benign conditions, is fundamental. In this study, we evaluated if local anesthesia should be enough to reduce both hospital costs and sedation-related risks for the patient, avoiding deep sedation and presence of the anesthesiologist. From July 2017 to August 2018, 14 consecutive patients (mean age 60.1 years) were treated and divided in two groups: Group A (7 patients) underwent systemic sedoanalgesia (intravenous remifentanil/fentanyl ± intravenous midazolam ± intravenous acetaminophen/nonsteroidal anti-inflammatory drugs) + subcutaneous anesthesia (lidocaine), with anesthesiologist. Group B (7 patients) underwent mild systemic sedoanalgesia (oral solution morphine sulfate + intravenous midazolam + intravenous acetaminophen) + both subcutaneous and subcapsular anesthesia (mepivacaine + bupivacaine), without anesthesiologist. Tolerability, sedation grade (Ramsay scale), total opioid dose, complications, and results at 12 months were analyzed and compared. Mean tolerability was 9.4 in group A and 8.9 in group B (p: 0.786). Mean sedation grade was 3.86 in group A and 2.71 in group B (p: 0.016). Mean total opioid dose was 70.9 mg in group A and 10 mg in group B (p:0.00015). No complications were observed. At 12 months, mean volume reduction was 56.1% in the group A and 60% in the group B. In thyroid radiofrequency ablation, subcapsular anesthesia can decrease both total opioid dose and level of patient's sedation without significant differences in tolerability, allowing to perform ablation without the anesthesiologist.

FATAL cryptococcal meningitis in a child with hyper-immunoglobulin M syndrome, with an emphasis on the agent.

Following a fatal case of Cryptococcus neoformans meningitis in a child with X-linked hyper-immunoglobulin M syndrome (XHIGM), we evaluated the fungal isolate in an experimental infection in a mouse model with respect to microbiology, epidemiology, virulence and response to therapy. The minimum inhibitory concentrations for antifungals in the susceptibility test were 0.5mg/L for amphotericin B, 4.0mg/L for fluconazole and 0.12mg/L for voriconazole. Evaluation of pathogenicity by means of an experimental infection in BALB/c mice showed that fungus isolated from the blood and cerebrospinal fluid of the child was able to disseminate, reaching the spleen, lungs and brain, where it caused significant macroscopic alterations in the size and texture of each organ. Treatment of infected mice with amphotericin B reduced the fungal load in the spleen and lungs, but not in the brain.

Prognostic value of human telomerase reverse transcriptase gene expression in oral carcinogenesis.

Human telomerase reverse transcriptase (hTERT) gene expression in resected specimens of oral squamous cell carcinoma (OSCC) and their surrounding tissue, either apparently normal or clearly histologically dysplastic, was evaluated by both real-time RT-PCR and immunohisto-chemical protein analyses. The expression level of hTERT in oral dysplasia and in OSCC was markedly higher than in normal tissues. The correlation between hTERT expression in OSCC and clinico-pathological parameters or survival of OSCC patients was statistically analyzed. Our study demonstrates that there is no significant relationship between hTERT expression and classical clinico-pathological parameters. Interestingly, survival analysis showed both overexpressing cases and lower survival rate in the early stage of OSCC (p=0.03 for immunohistochemistry; p=0.04 for RT real-time PCR). The histological location of hTERT in these tumors has been discussed in the context of the cancer stem cell theory.

Postchemotherapy residual masses in germ cell tumor patients: our experience.

BACKGROUND: The nature of post-chemotherapy tumor residuals can be determined only by excision and histological examination, but at present no consensus has been reached as to whether all patients with residual masses should undergo adjunctive surgery. PATIENTS AND METHODS: Between August 1991 and September 2004, 120 patients with metastatic germ cell tumors were diagnosed at our hospital and 35 of these patients (30%) underwent adjunctive surgery after cisplatin-based chemotherapy. If serum tumor markers were still raised salvage chemotherapy was administered. RESULTS: At the time of surgical intervention 30 patients (86%) had a partial remission with normal markers. Necrosis, differentiated teratoma and undifferentiated tumor were found in nine (30%), 19 (63%) and two (7%) of all patients. Five patients (14%) underwent postchemotherapy resections after second-line cisplatin-based combination chemotherapy. Four of the 35 patients died as a result of their malignant germ cell tumor. The median observation time after the initial diagnosis was 99 months (range 15-172 months). CONCLUSIONS: Secondary resection of residual masses after first or second-line chemotherapy is still an essential part of the treatment of metastatic testicular cancer. Resection of mature teratoma or viable cancer adds to long-term event-free and overall survival in these patients.

Treatment of v-Ki-ras-transformed SVC1 cells with low retinoic acid induces malignancy reversion associated with ras p21 down-regulation.

The effect of nontoxic, low concentrations (10(-8) M) of retinoic acid (RA) for a relatively long time (28 days) on a Kirsten ras-virus transformed cell line (Ki-SVC1), derived from the rat seminal vesicle epithelium, was investigated. In these experimental conditions, the cell treatment with RA induced a decrease of the proliferation rate, apoptosis and a marked reduction of both anchorage-independent growth and tumorigenicity. These biological responses were either preceded or associated with important changes in adenylate cyclase/protein kinase C signaling pathways, the activation of important apoptosis-linked genes and a marked decrease of the v-Ki-ras p21 protein. The significance of these findings is discussed.