Does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? First survival outcomes from the PURE-01 study☆.

BACKGROUND: Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in the PURE-01 study (NCT02736266). PATIENTS AND METHODS: We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out. RESULTS: After a median [interquartile range (IQR)] follow-up of 23 (15-29) months, 12- and 24-month EFS were 84.5% [95% confidence interval (CI): 78.5-90.9] and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypN+ (N = 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P = 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months (IQR: 11-15). The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes. CONCLUSIONS: The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.

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.

Nickel-Catalyzed Synthesis of Stereochemically Defined Enamides via Bi- and Tricomponent Coupling Reaction.

The stereoselective synthesis of (E)-trisubstituted tertiary enamides is documented via site-selective Ni-catalyzed ß-arylation of allenamides with boronic acids in high yields (up to 89%). The nucleophilic character of the "organo-Ni" intermediates is further exploited to implement a one-pot tricomponent procedure involving the final allylation of aldehydes (yields up to 93%). Mechanistic insights and efficiency on a gram scale process were also documented.

The effect of post-sintering treatments on the fatigue and biological behavior of Ti-6Al-4V ELI parts made by selective laser melting.

Fatigue resistance and biocompatibility are key parameters for the successful implantation of hard-tissue prostheses, which nowadays are more and more frequently manufactured by selective laser melting (SLM). For this purpose, the present paper is aimed at investigating the effect of post-sintering treatments on the fatigue behavior and biological properties of Ti samples produced by SLM. After the building process, all samples are heat treated to achieve a complete stress relief. The remaining ones are tribofinished with the aim of reducing the surface roughness of the as-sintered condition. Part of the tribofinished samples are then subjected to one of the following post-sintering treatments: (i) shot peening, (ii) hot isostatic pressing (HIP), and (iii) electropolishing. It is found that shot peening and HIP are the most effective treatments to improve the high and the very-high cycle fatigue resistance, respectively. At the same time, they preserve the good biocompatibility ensured by the biomedical Titanium Grade 23.

[A rare cause of oral pain: The pterygoid hamulus syndrome]. / Une cause rare de douleur orofaciale: le syndrome de l'hamulus ptérygoïdien.

INTRODUCTION: Pterygoid hamulus syndrome (PHS) is a rare cause of orofacial and oropharyngeal pain. PHS can be associated with a hamulus hypertrophy or with a bursitis of the palatosalpingeus but it has not always an anatomic cause. OBSERVATION: A 36-year-old woman was seen for a constant posterior palatal pain spreading towards oropharynx, increasing during swallowing and lasting for more than 6 months. Physical examination showed an erythema of the soft palate, medially to the hamulus. Hamulus palpation was painful and revealed hamulus hypertrophia on both sides. A bilateral PHS was evocated. DISCUSSION: This observation is typical of a PHS. We propose a review of the literature of this little-known syndrome. Treatment is initially conservative (corticosteroids) but surgery can be proposed in case of morphological anomalies of the hamulus.

Orbital soft tissue surgery for patients with Treacher-Collins or Nager syndrome. A new surgical approach with early correction of soft tissue: prospective study.

Orbitopalpebral anomalies in mandibulofacial dysostosis (Treacher-Collins syndrome) can be difficult to correct surgically and most authors recommend correction of the malar bone after the age of 8 years. We propose a new, early surgical approach for periorbital defects that involves initial implantation of autologous fat and subperiosteal malar lift with a pedicled upper eyelid flap. We prospectively studied 5 children, 3 of whom had previously had orbital reconstruction. Initial fat graft into the periorbital area was followed by a subperiosteal malar lift with lateral canthopexy, and a pedicled upper eyelid flap if needed. Two surgeons independently assessed the patients' characteristics including scleral show before and after operation, antimongoloid palpebral fissures, canthal dystopia, number 6 cleft (Tessier classification), skin quality, and surgical and ophthalmic complications. Before operation 3 patients had had ophthalmic problems. Postoperative evaluation showed improvements in scleral show, canthal dystopia, and skin quality, and correction of antimongoloid palpebral fissures and subcutaneous number 6 clefts. There were no postoperative complications. The proposed protocol gave satisfactory aesthetic and functional results in children with Treacher-Collins syndrome. We recommend that it is considered for periorbital reconstruction in all patients with a mandibulofacial deformity.

Propriospinal myoclonus following intrathecal bupivacaine in hip surgery: a case report.

Propriospinal myoclonus is a rare disorder characterized by sudden, shock-like, involuntary jerks that arise from the axial muscles and spread both rostrally and caudally to other myotomes through slow polysynaptic pathways. It can be idiopathic or secondary to intrinsic and extrinsic spinal cord lesions; additionally, it can develop as an adverse effect to the administration of several drugs, including neuraxial local anesthetics. This article describes a case of transient propriospinal myoclonus in a 77-year-old woman undergoing surgery for hip replacement who received 12 mg of 0.5% normobaric bupivacaine administered by a 25-G spinal needle. On postoperative day 1, the patient presented with spinal myoclonus, defined by clinical and electrophysiologic studies. Valproate and clonazepam controlled the symptoms, and on day 4 the myoclonus completely disappeared. Few cases of myoclonus induced by intrathecal bupivacaine administration have been reported in the literature, but systematic reviews written to clarify the global incidence and the physiopathology of this complication are still lacking.

Cr(Salen)-catalyzed addition of 1,3-dichloropropene to aromatic aldehydes. A simple access to optically active vinyl epoxides.

[reaction: see text]. Chiral Cr(Salen) complex (1) prepared in situ from CrCl3 promotes the enantioselective addition of 1,3-dichloropropene to aromatic aldehydes in the presence of Mn as the stoichiometric reductant and Me3SiCl as a scavenger. The resulting 1,2-chlorohydrins obtained in good enantiomeric and diastereoisomeric excesses can be easily transformed into the corresponding chiral vinyl epoxides.

The First Catalytic Enantioselective Nozaki-Hiyama Reaction.

The Nozaki-Hiyama reaction can be performed in an enantioselective catalytic way! The catalytic system utilizes 10 mol % of an inexpensive chiral [Cr(salen)] complex. The [Cr(salen)]/Mn/Me(3)SiCl system effectively promotes the enantioselective addition of allyl chloride to aliphatic and aromatic aldehydes at room temperature (65-89 % ee, 40-60 % yield).

Multiresidue determination of 19 fungicides in processed fruits and vegetables by capillary gas chromatography after gel permeation chromatography.

A gas chromatographic (GC) method was developed for simultaneous determination of 19 fungicides (chlorothalonil, vinclozolin, dichlofuanid, triadimefon, penconazole, chlozolinate, captan, procymidone, triadimenol, folpet, hexaconazole, myclobutanil, cyproconazole, propiconazole, nuarimol, captafol, iprodione, fenarimol, and bitertanol) and the acaricide tetradifon in tomato puree, peach nectar, orange juice, and canned peas. Samples were extracted with acetone, partitioned with ethyl acetate-cyclohexane (50 + 50, v/v), and cleaned using gel permeation chromatography with ethyl acetate-cyclohexane (50 + 50, v/v) as eluant. The final extract was analyzed by GC with ion trap mass spectrometry (ITMS) using a DB5 capillary column. Recoveries from fortified samples ranged from 74.6 to 99.3%, except for triadimenol and bitertanol. Quantitation limits for most analytes were between 0.005 and 0.050 mg/kg. The purified extracts were analyzed further by GC with electron capture and nitrogen phosphorus detection, and the results were compared with those obtained by ITMS.

Multiresidue method for determination of organochlorine insecticides and polychlorinated biphenyl congeners in fatty processed foods.

A previously published gel permeation chromatographic (GPC) procedure for determination of organophosphorus insecticides is used to determine 24 organochlorine (OC) pesticide and 9 polychlorinated biphenyl (PCB) residues in 8 fatty preserved foods of vegetable and animal origin. Samples are extracted with methylene chloride and cleaned up by automated GPC with a Biobeads SX3 column and a methylene chloride-cyclohexane (15 + 85) eluant. Compounds are quantitated by gas chromatography/ mass spectrometry (GC/MS) with selected ion monitoring using a DB-5 column. Average recoveries of OC pesticides from samples fortified at 0.010-0.080 mg/kg ranged from 73 to 98%. Average recoveries of 9 PCB congeners spiked at 2 levels (0.0025 and 0.020 mg/kg) were between 85 and 104%. Quantitation limits were between 0.002 and 0.025 mg/kg, depending on the compound. The purified extracts were analyzed further by GC with electron capture detection (ECD), and the results were compared with those obtained by MS. Determination of some OC pesticides and PCB congeners was not possible by ECD because of matrix interference.

Multiresidue method for determination of organophosphorus insecticide residues in fatty processed foods by gel permeation chromatography.

A multiresidue method for quantitative determination of 39 organophosphorus compounds (parent pesticides and their major metabolites) in 7 fatty processed foods is described. Samples are extracted with methylene chloride and cleaned up by automated gel permeation chromatography with a Biobeads SX3 column and a methylene chloride-cyclohexane (15 + 85) eluant. Organophosphorus compounds are quantitated by capillary gas-liquid chromatography with flame photometric detection using OV-1701 and DB-5 columns. Average recoveries from samples fortified at 0.025-1 mg/kg ranged from 50.6% for dichlorvos to 185% for malaoxon. Determination limits were between 0.005 and 0.040 micrograms/mL. Results were confirmed by gas chromatography/mass spectrometry with selected-ion monitoring.

[The echographic and computed tomographic diagnosis of polysplenia]. / Diagnosi ecografica e con Tomografia Computerizzata della polisplenia.

Polysplenia syndrome is a malformation with impaired visceral lateralization; it consists in the incomplete development of the spleen which is replaced by two or more splenules (1-3 cm phi). This malformation is often associated with other anomalies and is more frequently seen in situs inversus and situs ambiguus. On the basis of their findings in 3 cases, the authors describe the main US and radiographic patterns of polysplenia syndrome, that is: polysplenia syndrome associated with situs solitus (several splenules where the spleen should be, without other anomalies); polysplenia syndrome associated with situs ambiguus (splenules in the right hypochondrium with such anomalies as "umbrella-like" liver and the absence of the hepatic segment of the inferior vena cava and enlargement of both azygos and hemiazygos veins); polysplenia syndrome associated with situs viscerum inversus (right-sided splenules, with transposition of abdominal and thoracic organs). The splenules exhibit the same echogenicity as the liver; when situs viscerum ambiguus is present. US patterns of splenuli are equivocal and may mimic liver metastases. On the contrary, CT allows better demonstration of both the anomaly and the associated malformations.

[Therapeutic problems in euthyroid multinodular goiter]. / Problematiche terapeutiche nel gozzo multinodulare eutiroideo.

Now therapeutic different possibilities of goitre pathology seem well defined, in front of limit of suppressive therapeutic range in initial stages, prevalently diffuse, that interest young people and arise in jodic want lands; it's possible that medic theraphy ends can't be obtained because of not responders patient, or even for possibilities of controindications. Local presence of suspicious nodules and the need of goitre volumetric reduction for aesthetical and compressory ends, with the possibility in course of time of functional changes are sure reasons to surgery. Certainly main problems exist about surgery definition of multinodular disease with bilobar involvement where there is comparing between total and subtotal thyroid exeresis. Now by literature analysis and our School experience we think that surgery choice, considered before operation, must find absolute assurance after preoperative morphotopographic careful exploration of thyroid. We think that total thyroidectomy must be done when it's certain a total gland involvement, reserving subtotal thyroidectomy in the other cases; always employing a careful surgery technique, keeping operative field interely bloodless to identify important structures and dissection plan narrowly close by capsule.