Pembrolizumab and nab-paclitaxel as salvage therapy for platinum-treated, locally advanced or metastatic urothelial carcinoma: interim results of the open-label, single-arm, phase II PEANUT study.

BACKGROUND: Pembrolizumab is a new standard of care for patients with platinum-treated, metastatic urothelial carcinoma (UC). Nab-paclitaxel is active in advanced UC. In the PEANUT study (NCT03464734) we investigated their combination in advanced UC. PATIENTS AND METHODS: PEANUT was an open-label, single-arm, phase II trial that included patients who had failed one or two chemotherapy regimens, including platinum chemotherapy. Biomarker analyses focused on programmed cell-death ligand-1 combined positive score (CPS) and comprehensive genomic profiling on tumor samples and circulating tumor DNA. Patients received 200 mg pembrolizumab on day 1 (D1), and 125 mg/m2 nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) according to RECIST (v1.1). The assumption was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). RESULTS: Between January 2019 and January 2020, the PEANUT study enrolled 70 patients: 24% had failed two prior systemic therapies; 31% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1; and 28.6% had liver metastases. After a median follow-up of 9.8 months, 40 patients have relapsed (57.1%). The median PFS was 5.9 months [95% confidence interval (CI) 3.1-11.5]. The confirmed objective response rate (ORR) was 38.6% (95% CI 27-51) with 17 partial responses and 10 complete responses (14.3%). The median duration of response was not reached. Five patients (7.1%) had ongoing responses lasting >12 months. The most common any-grade treatment-related adverse events included alopecia (71.4%), neutropenia (32.9%), and peripheral neuropathy (34.3%). Neither tumor mutational burden nor CPS was significantly associated with PFS at univariable analyses. The single-arm design of the trial was the major limitation. CONCLUSIONS: Pembrolizumab combined with nab-paclitaxel, as second- and third-line chemoimmunotherapy for metastatic UC, showed a favorable safety profile, durable PFS, and a clinically meaningful ORR in these preliminary analyses. This combination warrants additional randomized studies in earlier disease stages. CLINICALTRIALS. GOV NUMBER: ClinicalTrials.govNCT03464734; https://clinicaltrials.gov/ct2/show/NCT03464734.

Photoactivated processes in optical fibers: generation and conversion mechanisms of twofold coordinated Si and Ge atoms.

In this work we present an extensive investigation of nanoscale physical phenomena related to oxygen-deficient centers (ODCs) in silica and Ge-doped silica by means of first-principles calculations, including nudged-elastic band, electron paramagnetic resonance parameters calculations, and many-body perturbation theory (GW and Bethe-Salpeter equation) techniques. We show that by neutralizing positively charged oxygen monovacancies we can obtain model structures of twofold Si and Ge defects of which the calculated absorption spectra and singlet-to-triplet transitions are in excellent agreement with the experimental optical absorption and photo-luminescence data. In particular we provide an exhaustive analysis of the main exciton peaks related to the presence of twofold defects including long-range correlation effects. By calculating the reaction pathways and energy barriers necessary for the interconversion, we advance a double precursory origin of the [Formula: see text] and Ge(2) centers as due to the ionization of neutral oxygen monovacancies (Si-Si and Ge-Si dimers) and as due to the ionization of twofold Si and Ge defects. Furthermore two distinct structural conversion mechanisms are found to occur between the neutral oxygen monovacancy and the twofold Si (and Ge) atom configurations. Such conversion mechanisms allow to explain the radiation induced generation of the ODC(II) centers, their photobleaching, and also their generation during the drawing of optical fibers.

Isolation of the CH3˙ rotor in a thermally stable inert matrix: first characterization of the gradual transition from classical to quantum behaviour at low temperatures.

Matrix isolation is a method which plays a key role in isolating and characterizing highly reactive molecular radicals. However, the isolation matrices, usually composed of noble gases or small diamagnetic molecules, are stable only at very low temperatures, as they begin to desegregate even above a few tens of Kelvin. Here we report on the successful isolation of CH3˙ radicals in the cages of a nearly inert clathrate-SiO2 matrix. This host is found to exhibit a comparable inertness with respect to that of most conventional noble gas matrices but it is characterized by a peculiar thermal stability. The latter property is related to the covalent nature of the host material and gives the opportunity to study the confined radicals from a few degrees of Kelvin up to at least room temperature. Thanks to this advantage we were able to explore with continuity for the first time the CH3˙ rotor properties by electron paramagnetic resonance spectroscopy, starting from the quantum rotations which are observable only at the lowest temperatures (T ≈ 4 K), going through the gradual transition to the classical motion (4 K < T < 30 K), and ending with the properties of the fully classical rotor (T > 30 K). The method of isolation presented here is found to be very effective and promising, as it is expected to be applicable to a large variety of different molecular radicals.

Identification of paramagnetic centers in irradiated Sn-doped silicon dioxide by first-principles.

We present a first-principles investigation of Sn paramagnetic centers in Sn-doped vitreous silica based on calculations of the electron paramagnetic resonance (EPR) parameters. The present investigation provides evidence of an extended analogy between the family of Ge paramagnetic centers in Ge-doped silica and the family of Sn paramagnetic centers in Sn-doped silica for SnO2concentrations below phase separation. We infer, also keeping into account the larger spin-orbit coupling of Sn atoms with respect to Ge atoms, that a peculiar and highly distorted three-fold coordinated Sn center (i.e. the Sn forward-oriented configuration) should give rise to an orthorhombic EPR signal of which we suggest a fingerprint in the EPR spectra recorded by Chiodiniet al(2001Phys. Rev.B64073102). Given its structural analogy with theEα'and Ge(2) centers, we here name it as the 'Sn(2) center'. Moreover, we show that the single trapped electron at a SnO4tetrahedron constitutes a paramagnetic center responsible for the orthorhombic EPR signal reported in Chiodiniet al(1998Phys. Rev.B589615), confuting the early assignment to a distorted variant of the Sn-E' center. We hence relabel the latter orthorhombic EPR signal as the 'Sn(1) center' due to its analogy to the Ge(1) center in Ge-doped silica.

Probing densified silica glass structure by molecular oxygen and E' center formation under electron irradiation.

This study aims to learn more about the structure of densified silica with focus on the metamict-like silica phase (density = 2.26 g/cm3) by examining the formation of E' point defects and interstitial molecular oxygen O2 by 2.5 MeV electron irradiation. High-dose (11 GGy) irradiation creates a metamict-like phase and a large amount of interstitial O2, which is destroyed upon subsequent additional lower-dose electron irradiation. The O2 cathodoluminescence (CL) data indicate that the formation of O2 from peroxy linkages Si-O-O-Si in silica network is strongly dependent on the intertetrahedral void sizes. The position and shape of the O2 emission line support the idea that the configuration of these voids in metamict phase is close to that of non-densified silica. Moreover, data support the strong correlation between the formation of 3-membered rings of Si-O bonds and E'-centers when silica density increases from 2.20 to 2.26 g/cm3.

Evolution of photo-induced defects in Ge-doped fiber/preform: influence of the drawing.

We have studied the generation mechanisms of two different radiation-induced point defects, the Ge(1) and Ge(2) centers, in a germanosilicate fiber and in its original preform. The samples have been investigated before and after X-ray irradiation using the confocal microscopy luminescence and the electron paramagnetic resonance techniques. Our experimental results show the higher radiation sensitivity of the fiber as compared to the perform and suggest a relation between Ge(1) and Ge(2) generation. To explain our data we have used different models, finding that the destruction probability of the Ge(1) and Ge(2) defects is larger in fiber than in preform, whereas the generation one is similar. Finally we found that the higher radiation sensitivity of the fiber at low doses is essentially related to the presence of germanium lone pair center generated by the drawing.

Dependence of the emission properties of the germanium lone pair center on Ge doping of silica.

We present an experimental investigation regarding the changes induced by the Ge doping level on the emission profile of the germanium lone pair center (GLPC) in Ge doped silica. The investigated samples have been produced by the sol-gel method and by plasma-activated chemical vapor deposition and have doping levels up to 20% by weight. The recorded photoluminescence spectra show that the GLPC emission profile is the same when the Ge content is lower than ∼ 1% by weight, whereas it changes for higher doping levels. We have also performed Raman scattering measurements that show the decrease of the D1 Raman band at 490 cm( - 1) when the Ge content is higher than 1% by weight. The data suggest that both changes can be related to matrix modifications. These findings improve our knowledge of the matrix effects on the physical properties of the point defects and, in particular, for the GLPC they show that variations in their emission properties are induced by the presence of a second Ge atom close to the defect within a sphere with a radius of about 2 nm.

Cabozantinib Plus Durvalumab in Patients With Advanced Urothelial Carcinoma After Platinum Chemotherapy: Safety and Preliminary Activity of the Open-Label, Single-Arm, Phase 2 ARCADIA Trial.

BACKGROUND: Durvalumab and cabozantinib have shown single-agent activity in patients with metastatic urothelial carcinoma (UC). ARCADIA is a phase 2 study evaluating their combination in patients with platinum-treated, advanced UC (NCT03824691). Herein, we report the results of the planned interim safety analysis and the preliminary activity. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1, UC and non-UC histology, and failure of a maximum of two regimens received cabozantinib 40 mg daily, orally, in combination with durvalumab 1500 mg, intravenously, every 28 days. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 every two cycles and by fluorodeoxyglucose positron emission tomography (FDG-PET) scans. RESULTS: As of August 20, 2020, 16 patients were enrolled with a median follow-up of 6.7 months (range, 2-11). Four patients (25%) had ECOG PS 1 and had received two prior regimens. No grades 3 or 4 treatment-related adverse events (TRAEs) occurred within the first two cycles. The most common grades 1 and 2 TRAEs were fatigue (7, 43.8%), diarrhea (5, 31.3%), and dysphonia (5, 31.3%). Objective responses were seen in six patients (37.5%; 95% confidence interval, 15.2-64.6), including two complete responses (12.5%). One additional patient with bone-only disease obtained a decrease in FDG uptake and in circulating tumor DNA consistent with response. Angiogenesis-related gene alterations were found in 57% responders versus 0% nonresponders. CONCLUSION: The durvalumab and cabozantinib combination was safe and endowed with preliminary clinical activity in patients with advanced UC. Mature results will clarify the role of cabozantinib and that of tumor biomarkers in this tumor type.

v-P2O5 micro-clustering in P-doped silica studied by a first-principles Raman investigation.

Synthetic vitreous silica is currently the preferred material for the production of optical fibres because of the several excellent properties of this glass, e.g. high transmission in the visible and IR domains, high mechanical strength, chemical durability, and ease of doping with various materials. For instance, fiber lasers and amplifiers exploit the light amplification properties provided by rare-earth ions employed as dopants in the core of silica-based optical fibers. The structure and composition of the nearest neighbor shell surrounding rare-earth ions in silica-based optical fibers and amplifiers have been intensively debated in the last decade. To reduce aggregation effects between rare-earth ions, co-dopants such as phosphorus and aluminium are added as structural modifiers; phosphorus-doping, in particular, has proved to be very efficient in dissolving rare-earth ions. In this work, we provide further insights concerning the embedding of P atoms into the silica network, which may be relevant for explaining the ease of formation of a phosphorus pentoxide nearest-neighbor shell around a rare-earth dopant. In particular, by means of first-principles calculations, we discuss alternative models for an irradiation (UV, x-, γ-rays) induced paramagnetic center, i.e. the so called room-temperature phosphorus-oxygen-hole center, and its precursors. We report that the most likely precursor of a room-temperature phosphorus-oxygen-hole center comprises of a micro-cluster of a few (at least two) neighboring phosphate tetrahedra, and correspondingly that the occurrence of isolated [(O-)2P(=O)2]- units is unlikely even at low P-doping concentrations. In fact, this work predicts that the symmetric stretching of P=O bonds in isolated [(O-)2P(=O)2]- units appears as a Raman band at a frequency of ~1110 cm-1, and only by including at least another corner-sharing phosphate tetrahedron, it is shown to shift to higher frequencies (up to ~40 cm-1) due to the shortening of P=O bonds, thereby leading to an improved agreement with the observed Raman band located at ~1145 cm-1.

Anti-PSMA 124I-scFvD2B as a new immuno-PET tool for prostate cancer: preclinical proof of principle.

BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer-related death in the Western population. The use in oncology of positron emission tomography/computed tomography (PET/CT) with emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease and detection of metastatic lesions. Prostate-specific membrane antigen (PSMA) expression, directly related to androgen-independence, metastasis and progression, renders this tumour associate antigen a good target for the development of new radiopharmaceuticals for PET. Aim of this study was to demonstrate in a preclinical in vivo model (PSMA-positive versus PSMA-negative tumours) the targeting specificity and sensitivity of the anti-PSMA single-chain variable fragment (scFv) labelled with 124I. METHODS: The 124I-labeling conditions of the antibody fragment scFvD2B were optimized and assessed for purity and immunoreactivity. The specificity of 124I-scFvD2B was tested in mice bearing PSMA-positive and PSMA-negative tumours to assess both ex-vivo biodistribution and immune-PET. RESULTS: The uptake fraction of 124I-scFvD2B was very high on PSMA positive cells (range 75-91%) and highly specific and immuno-PET at the optimal time point, defined between 15 h and 24 h, provides a specific localization of lesions bearing the target antigen of interest (PSMA positive vs PSMA negative tumors %ID/g: p = 0.0198 and p = 0.0176 respectively) yielding a median target/background ratio around 30-40. CONCLUSIONS: Preclinical in vivo results of our immuno-PET reagent are highly promising. The target to background ratio is improved notably using PET compared to SPECT previously performed. These data suggest that, upon clinical confirmation of sensitivity and specificity, our anti-PSMA 124I-scFvD2B may be superior to other diagnostic modalities for PCa. The possibility to combine in patients our 124I-scFvD2B in multi-modal systems, such as PET/CT, PET/MR and PET/SPECT/CT, will provide quantitative 3D tomographic images improving the knowledge of cancer biology and treatment.

Twofold co-ordinated Ge defects induced by gamma-ray irradiation in Ge-doped SiO2.

We report an experimental study by photoluminescence, optical absorption and Electron Paramagnetic Resonance measurements on the effects of exposure of Ge-doped amorphous SiO2 to gamma ray radiation at room temperature. We have evidenced that irradiation at doses of the order of 1 MGy is able to generate Ge-related defects, recognizable from their optical properties as twofold coordinated Ge centers. Until now, such centers, responsible for photosensitivity of Ge-doped SiO2, have been induced only in synthesis procedures of materials. The found result evidences a role played by gamma radiation in generating photosensitive defects and could furnish a novel basis for photosensitive pattern writing through ionizing radiation.

Prognostic relevance of cell proliferation in major salivary gland carcinomas.

Several proliferation markers, such as DNA ploidy, Ki67, MiB1 and proliferating cell nuclear antigen have been shown to correlate with clinical course and prognosis in several epithelial tumours and lymphomas. In the present study, the prognostic relevance of these markers was evaluated in major salivary gland carcinomas. A sample of 36 cases out of 85 patients submitted to surgery for major salivary gland carcinomas at our institution between 1987 and 1997 were studied. The sample comprised 8 adenoid-cystic carcinomas, 6 ductal carcinomas, 11 mucoepidermoid carcinomas and 11 acinic cell carcinomas. Follow-up ranged from 1 to 12 years (mean 6.2). In some patients, DNA ploidy (euploid or aneuploid) was studied by flow cytometry. In others, proliferation activity was studied by means of monoclonal antibody MiB1, identifying cells in the proliferative cycle. In some patients, both techniques were used. Follow-up was related to these indices, TNM and stage. Even if ploidy suggested a favourable outcome in diploid cancer (13 favourable vs. 2 unfavourable) and poor outcome in aneuploid cancer (4 favourable vs. 5 unfavourable), the difference was not statistically significant with p = 0.06 in Fisher's exact test. Instead, the proliferative tumour cell fraction, evaluated by MiB1, was statistically correlated with prognosis. Comparing survival curves by Log rank Test it yielded p = 0.007 using an MiB1 cut-off of 5. Applying a cut-off of 20 yielded p = 0.001. Of particular interest were MiB1 values in acinic cell carcinomas for which grading is challenging and lacks consensus. In our group of acinic cell carcinomas, survival correlated with values of MiB1 > or < 15 with p = 0.009 in Log rank test. In conclusion, despite a trend towards correlation between ploidy and prognosis, the present study yielded p = 0.06, whereas the proliferative fraction assessed by MiB1 was significantly correlated with outcomes. Indeed, "growth fraction" in acinic cell carcinomas may stratify different classes of risk.

Clinical variability in adult-onset acid maltase deficiency: report of affected sibs and review of the literature.

Acid maltase deficiency (AMD) is a rare cause of muscle disease in adult patients. The present report of 2 sibs and review of 36 previously reported cases illustrates the vast clinical variability in adult-onset AMD. This is 1 of only 3 reports to document tongue weakness and enlargement in an adult with AMD. The presenting signs and symptoms usually include progressive limb weakness, restrictive lung disease, or both. Consistent supportive abnormalities include a modest elevation in serum CK, a reduction in the forced vital capacity, and abnormal spontaneous activity (that is, myotonic discharges or fibrillations) in resting muscles during needle electromyography. The clinical spectrum is also extended to include distal limb weakness, scapular winging, asymmetric muscle weakness, and tongue involvement.

Psychogenic respiratory distress.

Five patients developed recurrent episodes of psychogenic respiratory difficulty that were superimposed on psychogenic neurologic symptoms. Misdiagnosis resulted in long hospital stays, code blue alerts, intubation, mechanical ventilation, and, in one case, tracheostomy. Patients "learned" psychogenic respiratory distress because their breathing symptoms evoked distinct evidence of anxiety in physicians and staff. In these patients, gain was not incidental but exerted primary control over symptom selection. The behavioral mechanisms involved in the pathogenesis of psychogenic respiratory distress have significant implications for its diagnosis, treatment, and prevention.

Acute sensory neuropathy-neuronopathy from pyridoxine overdose.

We report two patients who developed an acute, profound, and permanent sensory deficit after treatment with massive doses of parenteral pyridoxine. Aside from rapid onset, their clinical picture resembles that described in chronic pyridoxine neurotoxicity. It also is consonant with experimental models of acute pyridoxine intoxication and is probably secondary to a sensory ganglion neuronopathy. These patients also had transient autonomic dysfunction, mild weakness, nystagmus, lethargy, and respiratory depression. These previously undocumented features may be attributable to either the preservative used in the parenteral pyridoxine preparation or to the exceptionally high doses of pyridoxine these patients received.

Human pulmonary dirofilariasis: report of a new European case.

We report a new European case of pulmonary dirofilariasis occurring in an Italian patient. The paper emphasizes the peculiar pathological features of Pulmonary Dirofilariasis, that, on clinical and radiological grounds, closely imitates primary or secondary neoplasms. The disease characteristically presents itself as a solitary subpleural coin-like lesion, histologically corresponding to a well demarcated, roughly spherical infarct, centered by a medium-sized thrombosed artery whose lumen contains the parasite, i.e. a Dirofilaria nematode.

Experimental Trypanosoma evansi infection in South American coati (Nasua nasua): hematological, biochemical and histopathological changes.

The course of an experimental Trypanosoma evansi infection in coatis (Nasua nasua, carnivora, Procyonidae) was followed for 262 days. Hematological analysis of the infected coatis revealed a marked decline in hemoglobin, packed-cell volume, and total erythrocyte count. An intense anemia followed the first wave of parasitemia and persisted until the end of the experimental period. Biochemical analysis showed increased serum levels of alanine aminotransferase and aspartate aminotransferase and decreased albumin. The main histopathological features consisted of myocarditis with the presence of degenerate cardiac fibers and meningoencephalitis. This study has shown that coatis infected with T. evansi develop a chronic disease.

Post-stress end-systolic left ventricular dilation: a marker of endocardial post-ischemic stunning.

Several studies have shown the accuracy of gated single photon emission computed tomography (SPECT) using thallium-201 and technetium tracers in the assessment of myocardial perfusion and function. Gated SPECT has been successfully utilized to detect post-stress left ventricular ejection fraction (LVEF) reduction resulting from post-ischemic stunning in patients with coronary obstruction. The aim of this study was to evaluate whether the post-stress LVEF impairment could be related to the post-stress end-systolic ventricular dilation resulting from post-ischemic endocardial stunning. Two hundred and eighty-two consecutive patients were studied by conventional diagnostic 2 day stress/rest gated SPECT following injection of 925 MBq of 99mTc-tetrofosmin using a dual-headed SPECT camera. One hundred and forty-seven of these patients (52%) showed reversible perfusion defects, 69 (24%) permanent defects and the remaining 66 (24%) had normal perfusion. One hundred and thirty-eight of these patients had a history of myocardial infarction (MI) and 19% underwent coronary angiography without an intervening cardiac event. Perfusion was analysed on ungated images using 20 segments scored on a five-point scale (0, normal; 4, no uptake), while wall thickening (WT) was assessed visually on stress/rest end-systolic images using a four-point score (0, normal; 3, absence of WT). LVEF and volumes were calculated using an automatic algorithm. The post-stress and rest ratios were determined for both end-diastolic (EDV) and end-systolic (ESV) volume. Normal values for all these parameters were obtained using data from 149 patients with a low likelihood (<5%) of coronary artery disease (CAD). In 50 of the 147 (34%) of patients with reversible perfusion defects, post-stress LVEF was >5% lower than rest values (stunned group), while the remaining 97 patients did not show a significant LVEF change (group 2A). The percentage of patients who developed exercise-induced angina, the percentage of patients who underwent coronary angiography and the segmental summed perfusion and WT scores were significantly higher in the stunned group compared with group 2A. Only ESV increased significantly post-stress, and this increase occurred only in stunned patients. Both EDV and ESV ratios were significantly higher in the stunned group compared with normal controls (P=0.008 and P<0.000001, respectively) and with the subgroup 2A (P=0.011 and P<10(-12), respectively). The ESV stress/rest ratio correlated significantly with the summed WT difference score by univariate analysis in stunned patients. It can be concluded that the post-stress ESV dilation, obtained by stress/rest gated SPECT, seems to be due to endocardial post-ischemic stunning. The stunned patients showed more severe clinical, angiographic, perfusion and function parameters.

Immunosuppression by peritoneal BCG-induced granulomas in mice.

1. Intraperitoneal injection of viable BCG resulted in the formation of peritoneal granulomas in mice. Granuloma-bearing animals presented a specific immunosuppression of delayed-type hypersensitivity (DTH) to BCG. 2. The transplantation of peritoneal granulomas induced by BCG to animals previously sensitized with BCG suppressed the DTH response to this antigen in the recipient animals to the same extent as observed in animals with granulomas induced by the injection of BCG. No suppression was observed in animals transplanted with granulomas induced by either Cytodex or talc. 3. The hypersensitivity reaction to Brucella abortus and the acute inflammatory reaction produced by carrageenin were not affected by granuloma transplantation. 4. Granulomas collected from animals treated with a lethal does of irradiation maintained the capacity to suppress DTH in recipient animals. 5. These results suggest that the response observed in granuloma recipients is modulated by cells within the granuloma.