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Background: First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear. Methods: This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Results: 31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension. Conclusions: The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable. Trial registration number: NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681

This article discusses the current knowledge on the role of the neurological structures, especially the cerebellum and the hypothalamus, and compares the information with human medicine. Micturition is a complex voluntary and involuntarily mechanism. Its physiological completion strictly depends on the hierarchical organisation of the central nervous system pathways in the peripheral nervous system. Although the role of the peripheral nervous system and subcortical areas, such as brainstem centres, are well established in veterinary medicine, the role of the cerebellum and hypothalamus have been poorly investigated and understood. Lower urinary tract dysfunction is often associated with neurological diseases that cause neurogenic bladder (NB). The neuroplasticity of the nervous system in the developmental changes of the mechanism of micturition during the prenatal and postnatal periods is also analysed.

In the last decade, the inhibition of the mechanistic target of Rapamycin (mTOR) in renal clear cell carcinoma (RCC) has disappointed the clinician’s expectations. Many clinical trials highlighted the low efficacy and unmanageable safety profile of first-generation mTOR inhibitors (Rapalogs), thus limiting their use in the clinical practice only to those patients who already failed several therapy lines. In this review, we analyze the major resistance mechanisms that undermine the efficacy of this class of drugs. Moreover, we describe some of the possible strategies to overcome the mechanisms of resistance and their clinical experimentation, with particular focus on novel mTOR inhibitors and the combinations of mTOR inhibitors and other anti-cancer drugs.

Background Immunotherapeutic drugs, such as domperidone, have been shown to be promising treatments against canine leishmaniosis (CanL), but limited data are available. The aim of this pilot study (therapeutic, prospective and non-controlled) was to evaluate the effect of domperidone on serum antibody titers of Leishmania infantum, globulins, gamma globulins, acute-phase proteins (e.g. C-reactive protein [CRP]), big endothelin-1 (big ET-1), serum creatinine (SC) and proteinuria in dogs with leishmaniosis affected by chronic kidney disease (CKD). Methods Dogs were recruited if “exposed” to or “infected” with L. infantum and affected by CKD (IRIS stage 1 [proteinuric] or IRIS stage 2–3a [SC Results Of the 14 recruited dogs, nine showed a statistically significant reduction in SC (χ2 = 9.1, df = 3, P = 0.028), but not in the urine protein/creatinine ratio (χ2 = 6.43, df = 3, P = 0.092). All dogs showed a significant reduction in antibody titers for L. infantum (χ2 = 9.56, df = 2, P = 0.008), globulins (χ2 = 11.08, df = 3, P = 0.011) and gamma globulins (χ2 = 12.38, df = 3, P = 0.006) during the study period. There was also a statistically significant reduction in CRP (χ2 = 16.7, df = 3, P = 0.001), but not in big ET-1 (χ2 = 2.04, df = 3, P = 0.563). Conclusions This study provides preliminary results on the ability of domperidone to improve SC and reduce anti-L. infantum antibody titers, globulins, gamma globulins and CRP in dogs with leishmaniosis and CKD. Graphical abstract

Collecting duct carcinomas (CDCs) are a particularly rare subtype of kidney cancer, endowed by a particularly poor prognosis. Since no active treatments have been established for CDCs, due to similarities with upper tract urothelial carcinomas, the use of the cisplatin-gemcitabine doublet is usually recommended. Here we report a retrospective analysis of 36 metastatic CDCs treated, as everyday clinical practice, with either cisplatin-gemcitabine or cisplatin-gemcitabine-paclitaxel from 2005 to 2021. Thirty-three patients received gemcitabine (1000 mg/m2, days 1 and 8) and cisplatin (70 mg/m2, day 1), while 3 were treated with paclitaxel (80 mg/m2, days 1 and 8), gemcitabine (1000 mg/m2, days 1 and 8) and cisplatin (70 mg/m2, day 1), every 21 days for a maximum of 6 cycles. Eight out of 36 patients (22.2%) experienced a partial response, while 9 others (25%) had a disease stabilization. No benefit was observed in the only 3 patients treated with the triplet. Median PFS was just 6 months, while median OS was 8 months. The commonest grade ≥3 treatment-related adverse events were: neutropenia (75%, 11.1% of febrile neutropenia), anemia (50%), thrombocytopenia (38.8%), and vomiting (8.3%). Dose omissions and dose reductions were common, and few frail patients started the treatment with a 25% dose reduction. In conclusion, our real-world experience confirmed the modest activity and relevant toxicity of cisplatin-based chemotherapy for the treatment of CDCs. More translational studies and novel study designs are thus badly needed in these still orphan tumors.

Lower urinary tract disease (LUTD) includes abnormalities in the structure and function of the bladder and the urethra. LUTD caused by neurological disease is defined neurogenic bladder (NB). The integrity of the central nervous system (CNS) and peripheral nervous system (PNS) is required to explicate normal micturition, maintaining the proper function of bladder and urethra. The location and type of neurological lesions influence the pattern of clinical manifestations, potential treatment, and prognosis. Though, in dogs and cats, spinal cord injury is considered mainly responsible for bladder and/or urethra incompetence, other disorders, congenital or acquired, involving CNS or PNS, could play a role in NB. In veterinary medicine, the information about the epidemiology, prevalence, etiopathogenesis, diagnosis and treatment of NB are scattered. The aim of this study is to provide an overview of the epidemiology, prevalence, clinical findings, diagnosis and prognosis for NB in dogs and cats compared with humans.

Background Chronic kidney disease (CKD) represents the main cause of mortality in dogs with leishmaniosis. Domperidone has recently been reported to improve kidney function in leishmaniotic dogs affected by CKD. Serum symmetric dimethylarginine (sSDMA) has also been shown to be a useful biomarker for earlier detection of decreased kidney function when compared to serum creatinine (sCr). This study aimed to assess the efficacy of domperidone plus renal diet in slowing the progression of nephropathy in leishmaniotic dogs with CKD, evaluating sSDMA and sCr as markers of kidney function. Methods This study was a therapeutic, prospective, randomized, controlled, 11-month-long field trial. Dogs were recruited if classified as “exposed” to or “infected” with Leishmania infantum and affected by CKD at early stages. After enrolment (T0), dogs were randomized into groups T (treatment) and C (control). All dogs were fed a renal diet and then followed up at 90 (T1), 210 (T2), and 330 (T3) days after inclusion in the study. At T1 and T2, dogs in group T received an oral suspension of domperidone (1 ml/10 kg once a day for up to 28 days). Results Twenty-two dogs (i.e., n = 12 in group T and n = 10 in group C) completed the study. At T0, the entire population of enrolled dogs presented a mean sSDMA value of 16.5 ± 3.4 μg/dl. At T1 (i.e., after 3 months of renal diet), sSDMA was significantly decreased in both groups, with an sSDMA of 13.1 ± 4.4 μg/dl for the entire population involved. From T1 to T3, sSDMA gradually increased in group C, while remaining stable in group T, which continued to show a significantly lower value of sSDMA at T3 than at T0. Regarding sCr, at T0 and T1, the mean values of the entire population of dogs were 1.1 ± 0.3 and 1.0 ± 0.4 mg/dl, respectively, with no statistical differences between groups T and C. In group T, sCr decreased significantly from T0 to T1, while returning at T3 to values similar to T0. Conclusions In this study, domperidone plus renal diet reduced the progression of kidney disease in leishmaniotic dogs affected by CKD. Graphical Abstract

Canine idiopathic epilepsy is a common neurological disease characterized by the enduring predisposition of the cerebral cortex to generate seizures. An etiological explanation has not been fully identified in humans and dogs, and, among the presumed causes, several studies support the possible involvement of gut microbiota. In this review, the authors summarize the evidence of the reasonable role of gut microbiota in epilepsy through the so-called gut–brain axis. The authors provide an overview of recent clinical and preclinical studies in humans and dogs in which the modulation of intestinal permeability, the alteration of local immune response, and the alteration in production of essential metabolites and neurotransmitters associated with dysbiosis could be responsible for the pathogenesis of canine epilepsy. A systematic review of the literature, following the PRISMA guidelines, was performed in two databases (PubMed and Web of Science). Eleven studies were included and reviewed supporting the connection between gut microbiota and epilepsy via the gut–brain axis.

Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, in this study we delineated a lipidomic profile of human ccRCC and integrated it with transcriptomic data to connect the variations in cancer lipid metabolism with gene expression changes. Untargeted lipidomic analysis was performed on 20 ccRCC and 20 paired normal tissues, using LC-MS and GC-MS. Different lipid classes were altered in cancer compared to normal tissue. Among the long chain fatty acids (LCFAs), significant accumulations of polyunsaturated fatty acids (PUFAs) were found. Integrated lipidomic and transcriptomic analysis showed that fatty acid desaturation and elongation pathways were enriched in neoplastic tissue. Consistent with these findings, we observed increased expression of stearoyl-CoA desaturase (SCD1) and FA elongase 2 and 5 in ccRCC. Primary renal cancer cells treated with a small molecule SCD1 inhibitor (A939572) proliferated at a slower rate than untreated cancer cells. In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells. In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.

Background: Considering the growing genitourinary (GU) cancer population undergoing systemic treatment with immune checkpoint inhibitors (ICIs) in the context of the COVID-19 pandemic, we planned a clinical audit in 24 Italian institutions treating GU malignancies. Objective: The primary objective was investigating the clinical impact of COVID-19 in GU cancer patients undergoing ICI-based therapy during the first outbreak of SARS-CoV-2 contagion in Italy. Design, setting, and participants: The included centers were 24 Oncology Departments. Two online forms were completed by the responsible Oncology Consultants, respectively, for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) patients receiving at least one administration of ICIs between 31 January 2020 and 30 June 2020. Results and limitation: In total, 287 mRCC patients and 130 mUC patients were included. The COVID-19 incidence was, respectively, 3.5%, with mortality 1%, in mRCC patients and 7.7%, with mortality 3.1%, in mUC patients. In both groups, 40% of patients developing COVID-19 permanently discontinued anticancer treatment. The pre-test SARS-CoV-2 probability in the subgroup of patients who underwent nasal/pharyngeal swab ranged from 14% in mRCC to 26% in mUC. The main limitation of the work was its nature of audit: data were not recorded at the single-patient level. Conclusion: GU cancer patients undergoing active treatment with ICIs have meaningful risk factors for developing severe events from COVID-19 and permanent discontinuation of therapy after the infection. Treatment delays due to organizational issues during the pandemic were unlikely to affect the treatment outcome in this population.

This study aims to evaluate the erythrocyte sedimentation rate (ESR) in Leishmania infantum-seropositive dogs compared with healthy dogs and to assess the existence of a correlation between ESR and clinical form of Canine leishmaniosis (CanL) as well as acute phase proteins (APPs). From October 2021 to January 2022, dogs were recruited in this study if L. infantum-seropositive by enzyme-linked immunoassay and classified as exposed or affected by a CanL active form based on physical examination, clinical score, and laboratory results [i.e., complete blood count, biochemical panel such as C-reactive protein (CRP) and serum ferritin, serum protein electrophoresis, and fibrinogen concentration measurement]. To evaluate the ESR of the dogs, a point-of-care device was used with a reference interval of 0–10 mm/h. Moreover, the ESR evaluation has been also performed in clinically healthy dogs, as control group. Thirty-six L. infantum-seropositive dogs [i.e., exposed (n = 10) and affected by CanL active form (n = 26)] were included in the study. Twenty-two healthy dogs were also enrolled. The mean value of ESR in dogs affected by a CanL active form was significantly higher than in exposed and healthy dogs (p < 0.0001). The ESR level was increased in 92% of dogs with CanL active form while positive APPs such as CRP, fibrinogen, and serum ferritin were increased only in 46, 48, and 58% of the animals, respectively. In exposed dogs, the ESR level was increased in 40% of cases. In dogs with active form, a significant positive correlation between ESR and total proteins, globulins, CRP, and fibrinogen, as well as a significant negative correlation between ESR and hematocrit, hemoglobin, and albumin/globulin ratio were detected. This study provides for the first-time data on ESR in L. infantum-seropositive dogs demonstrating dogs affected by a CanL active form have the highest ESR level and the majority of these dogs presented an increased ESR compared with exposed and healthy dogs. The evaluation of ESR by a point-of-care device proved to be a simple, inexpensive, and ready-to-use benchtop tool and ESR can be considered a helpful and timely inflammatory biomarker for the diagnosis of a CanL active form.

According to the main Guidelines on canine heartworm disease (HWD) by the American and European Societies (i.e., AHS, ESDA, and ESCCAP), a correct diagnosis of Dirofilaria immitis infection should include the detection of circulating microfilariae in the whole blood and the adult antigens in serum or plasma sample. So far, scant data are available on laboratory abnormalities in dogs affected by HWD, although techniques including serum protein electrophoresis (SPEP) have proved to be useful for the diagnosis and monitoring of other vector-borne diseases, such as the canine leishmaniosis. Therefore, this study aims to evaluate the SPEP pattern in dogs naturally infected by D. immitis. Furthermore, a systematic review of the literature on this topic was carried out. Medical records from heartworm-positive dogs, of any sex, age, and breed and with available clinical examination and laboratory test results (i.e., complete blood count, serum biochemical profile, and SPEP) were retrospectively collected. If available, laboratory results obtained from dogs after treatment for HWD were also evaluated. When compared with the reference intervals, out of 30 dogs infected by D. immitis and enrolled, 63.3% (n = 19) had a lower percentage of albumin, and 80.0% (n = 24) had higher percentages of beta globulins, with beta-2, and especially beta-3 globulins the most frequently altered fractions. In terms of absolute values (g/dL), the proportion of dogs with hypoalbuminemia, and increased total globulin, alpha, beta- and gamma globulins were 4/30 (13.3%), 6/30 (20.0%), 2/30 (6.7%), 16/30 (53.3%) and 8/30 (26.7%), respectively. For 7 dogs, SPEP results evaluated three and six months after treatment with doxycycline (10 mg/kg BID for 4 weeks) were available. In these dogs a significant post-treatment increase in the percentage of albumin, alpha-2 globulin, and albumin/globulins ratio was observed, as well as a significant decrease both in the percentage and in the absolute value of total-, beta-, and beta-3 globulins. The systematic review of literature databases yielded a total of three studies that were considered eligible and included in the qualitative synthesis. This study provides novel information on SPEP alterations in dogs naturally infected by D. immitis. The evaluation of serum proteins and their electrophoretic pattern may represent an important diagnostic tool for a prompt and accurate diagnosis (e.g., differentiating infections in dogs sharing similar clinical signs and endemic in the same geographical area) and monitoring of HWD.

Conjunctival swabs (CS) are the most promising non-invasive samples for the diagnosis and the regular screening of

Background To reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin‐based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low‐dose DEX on days 2 and 3, combined with an oral fixed‐dose combination of netupitant and palonosetron (NEPA), compared with the guideline‐consistent use of 4‐day DEX. Patients and Methods In this open‐label, multicenter study, chemotherapy‐naïve patients undergoing high‐dose cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2–3 (DEX3), or (c) DEX (4 mg twice daily) on days 2–4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5‐day overall phase. The noninferiority margin was set at −15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea). Results Two‐hundred twenty‐eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX‐sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, −12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups. Conclusion A simplified regimen of NEPA plus single‐dose DEX offers comparable chemotherapy‐induced nausea and vomiting prevention throughout 5 days post‐chemotherapy with the advantage of sparing patients additional doses of DEX in the high–emetic‐risk setting of cisplatin‐based chemotherapy. Implications for Practice Dexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy‐induced emesis. Although generally considered safe, even short‐term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post‐chemotherapy with a simplified regimen of netupitant/palonosetron plus single‐dose DEX versus the standard 4‐day DEX reference treatment in high‐dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised., This study was designed to test whether two different dexamethasone‐sparing regimens, when administered with NEPA, might provide the opportunity to reduce the total corticosteroid dose while maintaining the same degree of chemotherapy‐induced nausea and vomiting control in patients undergoing cisplatin‐based chemotherapy.

Background and aim: Over 80% (365/454) of the nation’s centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, 2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment. Methods: We investigated fixed factors and contextual effects by multilevel modeling. Classification and Regression Tree (CART) analysis was used to develop decision rules. Results: Increased positivity among hemodialysis patients was predicted by center location [incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 1.20–1.51], positive healthcare workers (IRR 1.09, 95% CI 1.02–1.17), test-all policy (IRR 5.94, 95% CI 3.36–10.45), and infected proportion in the general population (IRR 1.002, 95% CI 1.001–1.003) (all p < 0.01). Conversely, lockdown duration exerted a protective effect (IRR 0.95, 95% CI 0.94–0.98) (p < 0.01). The province-contextual effects accounted for 10% of the total variability. Predictive factors for peritoneal dialysis and transplant cases were center location and infected proportion in the general population. Using recursive partitioning, we identified decision thresholds at general population incidence ≥ 229 per 100,000 and at ≥ 3 positive healthcare workers. Conclusions: Beyond fixed risk factors, shared with the general population, the increased and heterogeneous proportion of positive patients is related to the center’s testing policy, the number of positive patients and healthcare workers, and to contextual effects at the province level. Nephrology centers may adopt simple decision rules to strengthen containment measures timely.