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Gaetano Pezzicoli,1,2 Elisabetta Filoni,1,2 Angela Gernone,2 Laura Cosmai,3 Mimma Rizzo,4 Camillo Porta2,5 1Department of Biomedical Sciences and Human Oncology, Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘A. Moro’, Bari, Italy; 2Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy; 3Onconephrology Outpatient Clinic, Division of Nephrology and Dialysis, A.S.S.T. Fatebenefratelli-Sacco, Fatebenefratelli Hospital, Milan, Italy; 4Division of Translational Oncology, I.R.C.C.S. Istituti Clinici Scientifici Maugeri, Pavia, Italy; 5Chair of Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, Bari, ItalyCorrespondence: Camillo PortaDivision of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Piazza Giulio Cesare, 11, Bari, 70124, ItalyTel +39-080-5594167Fax +39-080-5593477Email camillo.porta@gmail.com; camillo.porta@uniba.itAbstract: 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.Keywords: everolimus, temsirolimus, Rapa-Link, anti-angiogenics, autophagy

BACKGROUND: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. METHODS: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. RESULTS: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. CONCLUSIONS: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

Canine heartworm disease by Dirofilaria immitis and canine leishmaniosis by Leishmania infantum (CanL) are both vector-borne diseases with frequently overlapping endemicity and able to trigger the acute phase response, being characterized by variations in acute phase proteins (APP). Recently, erythrocyte sedimentation rate (ESR), an indicator of inflammation, has gained attention in veterinary medicine, proving useful in several conditions that include CanL active forms in dogs. This study aims to evaluate ESR in heartworm-infected dogs, compare levels with heartworm-infected and L. infantum seropositive dogs as well as clinically healthy dogs, and assess correlations with other laboratory parameters. From October 2022 to January 2023, a prospective observational study was conducted enrolling heartworm-infected (Dirofilaria group) and heartworm-infected L. infantum seropositive (Dirofilaria/Leishmania group) animals subgrouped according to the CanL clinical form (Dirofilaria/Leishmania active and non-active groups). A group of clinically healthy dogs (control group) was also included. For each dog enrolled physical examination and laboratory tests (complete blood count, biochemical panel including APP, serum protein electrophoresis) were performed. Dirofilaria and Dirofilaria/Leishmania groups presented a significantly higher ESR level compared to healthy dogs. Dirofilaria/Leishmania active group had the highest ESR level among the groups considered. Dirofilaria/Leishmania non-active group had an ESR similar to the Dirofilaria group, but significantly higher and lower compared to the control and the Dirofilaria/Leishmania active group, respectively. A significant positive correlation between ESR and C-Reactive Protein has been found in all groups except for the Dirofilaria/Leishmania non-active group. In Dirofilaria/Leishmania active group a strong positive correlation between ESR and gamma globulins percentage as well as a strong negative correlation between ESR and albumin, albumin/globulins ratio were found. Overall, the ESR was confirmed to be an inflammation marker as well as a helpful disease index, being notably increased in heartworm-infected dogs affected by an active form of CanL.

Abstract We demonstrated the non-inferiority of a dexamethasone (DEX)-sparing (single-dose) regimen with NEPA, a netupitant/palonosetron fixed combination, for preventing chemotherapy-induced nausea and vomiting (CINV) caused by cisplatin. This pre-planned exploratory analysis assessed the effect of the DEX-sparing regimen on a patient’s food intake. Chemotherapy-naïve patients undergoing cisplatin (≥ 70 mg/m2) were given NEPA and DEX (12 mg) on day 1 and randomized to receive either no further DEX (DEX1), or oral DEX (4 mg BID) on days 2–4 (DEX4). Patient-reported endpoint maintenance of usual daily food intake was assessed during the 5-days post-chemotherapy. The relationship between usual daily food intake and CINV control, pre-chemotherapy self-rated food intake and BMI-adjusted weight loss (WL) were evaluated. One-hundred fifty-two patients (76/group) were assessable. The proportion of patients reporting maintenance of usual daily food intake was similar in both groups: 69.7% (95% CI, 58.6–78.9) for DEX1 vs. 72.4% (95% CI, 61.4–81.2) for DEX4. Only CINV control was significantly associated with maintenance of usual daily food intake (P ≤ 0.001) during the overall phase. The DEX-sparing regimen does not adversely affect patient-reported daily food intake post-chemotherapy. The current analysis adds further insights into antiemetic efficacy of DEX sparing beyond day 1 in the challenging setting of cisplatin. Trial registration: The parent study was registered on ClinicalTrials.gov (NCT04201769).

IntroductionAdvanced urothelial carcinoma remains aggressive and very hard to cure, while new treatments will pose a challenge for clinicians and healthcare funding policymakers alike. The U-CHANGE Project aimed to redesign the current model of care for advanced urothelial carcinoma patients to identify limitations (“as is” scenario) and recommend future actions (“to be” scenario).MethodsTwenty-three subject-matter experts, divided into three groups, analyzed the two scenarios as part of a multidimensional consensus process, developing statements for specific domains of the disease, and a simplified Delphi methodology was used to establish consensus among the experts.ResultsRecommended actions included increasing awareness of the disease, increased training of healthcare professionals, improvement of screening strategies and care pathways, increased support for patients and caregivers and relevant recommendations from molecular tumor boards when comprehensive genomic profiling has to be provided for appropriate patient selection to ad hoc targeted therapies.DiscussionWhile the innovative new targeted agents have the potential to significantly alter the clinical approach to this highly aggressive disease, the U-CHANGE Project experience shows that the use of these new agents will require a radical shift in the entire model of care, implementing sustainable changes which anticipate the benefits of future treatments, capable of targeting the right patient with the right agent at different stages of the disease.

Abstract Background The non-inferiority of dexamethasone (DEX) on day 1, with or without low-dose DEX on days 2 and 3, combined with oral NEPA (netupitant/palonosetron), compared with the guideline-consistent use of DEX was demonstrated in cisplatin. Here, we complete the analysis by assessing the impact of emesis on daily lives of patients receiving DEX-sparing regimens using the Functional Living Index-Emesis (FLIE). Methods Chemotherapy-naïve patients undergoing cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized to receive either 1) no further DEX (DEX1), 2) oral DEX (4 mg daily) on days 2–3 (DEX3), or 3) DEX (4 mg twice daily) on days 2–4 (DEX4; control). Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included the FLIE nausea domain, vomiting domain, and overall combined domain scores, as well as the proportion of patients with no impact on daily life (NIDL; overall score > 108). This was a protocol-planned analysis. Results In the DEX1 group, no significant differences were observed in the FLIE nausea score (48.9 [±1.8; SE] vs. 53.7 [±1.5]), vomiting score (56.6 [±1.4] vs. 58.7 [±0.8]) and overall score (105.6 [±2.8] vs.112.4 [±1.9]) versus DEX4 control; similar results were observed in the DEX3 group for nausea score (49.6 [±1.7]), vomiting score (58.2 [±1]) and overall score (107.8 [±2.4]) versus control. There were no significant between-group differences in the proportion of patients reporting NIDL. Conclusion Reducing DEX, when administered with NEPA, does not seem to adversely impact the daily functioning in patients undergoing cisplatin. Trial registration ClinicalTrials.gov NCT04201769 . Registration date: 17/12/2019 - Retrospectively registered.

This prospective study aimed to evaluate inflammatory status in cats affected by chronic kidney disease (CKD) at IRIS stages 2–4, using serum amyloid A (SAA) and the erythrocyte sedimentation rate (ESR) as inflammatory markers. Thirty-two cats with CKD and ten clinically healthy cats (i.e., control group) were enrolled. The recording of signalment data, complete physical examinations, and abdominal ultrasonography were performed for each animal. Additionally, ESR levels, complete blood count, clinical chemistry (including SAA determination), serum protein electrophoresis, and complete urinalysis were executed. This study’s results showed that mean ESR and SAA concentrations in cats with CKD were statistically higher compared to those of the control group (p = 0.0005 and p = 0.007, respectively). The SAA concentration was significantly increased at IRIS stages 2, 3, and 4 compared to the control group. Meanwhile, the ESR was significantly higher in cats at IRIS stages 3 and 4 (p = 0.0003 and p = 0.0007, respectively), but not at IRIS stage 2, compared to the control group. These results provide evidence that feline CKD is associated with a systemic inflammatory status. Moreover, the rise in ESR appears to be more linked to advanced stages of the disease and could, therefore, correlate with the uremic condition.

Background: Peripheral artery disease (PAD) in hemodialysis (HD) patients has a significant social impact due to its prevalence, poor response to standard therapy and dismal prognosis. Rheopheresis is indicated by guidelines for PAD treatment. Materials and Methods: Twenty‐five HD patients affected by PAD stage IV Lerichè‐Fontaine and ischemic ulcer 1C or 2C according to the University of Texas Wound Classification System (UTWCS), without amelioration after traditional medical therapy and/or revascularization, were selected and underwent 12 Rheopheresis sessions in 10 weeks. Improvements in pain symptoms using Numerical Rating Scale (NRS), healing ulcers and laboratory hemorheological parameters have been evaluated. Results: A clinically and statistically significant mean value reduction and of relative percentage differences between estimated marginal means (Δ), calculated at each visits, of NRS was observed, with a maximum value (−48.5%) between the first and last visit. At the end of the treatment period 14.3% of ulcers were completely healed, 46.4% downgraded, 53.6% were stable. Overall, no ulcers upgraded. A statistically significant reduction of the Δ, between the first and last visit, for fibrinogen (−16%) was also observed. Conclusion: Rheopheresis reduced overall painful symptoms; data suggest that it could heal or improve ulcers and hemorheological laboratory parameters in HD patients with PAD and ischemic ulcers resistant to standard therapies. [ABSTRACT FROM AUTHOR]

The trypanosomatid protist Leishmania tarentolae is a saurian-associated parasite vectored by the Sergentomyia minuta sand fly. This study aimed to confirm the circulation of L. infantum and L. tarentolae in sand flies, reptiles and dogs and to isolate new strains of these protists. Reptilian and sheltered dog blood samples were collected, and sand flies were captured. Samples were tested for Leishmania spp. using duplex real-time PCR (dqPCR) and real-time PCR (qPCR); the origin of blood meal was identified in engorged sand flies by conventional PCR. The reptilian blood and intestinal content of sand fly females were cultured. Dog sera were tested by IFAT using both Leishmania species. Four Tarentola mauritanica geckoes were molecularly positive for L. infantum or L. tarentolae, with no co-infections; moreover, amastigote-like forms of L. infantum were observed in the bone marrow. 24/294 sand flies scored positive for Leishmania spp. by dqPCR, 21 S. minuta and two Phlebotomus perniciosus were positive for L. tarentolae, while only a single Ph. perniciosus was positive for L. infantum. Blood meal analysis confirmed reptile and dog in S. minuta, dog and human in Ph. perniciosus and dog in Phlebotomus neglectus. Two axenic strains of L. tarentolae were obtained. Twelve of 19 dogs scored positive for L. infantum and L. tarentolae by IFAT and three of them also for L. infantum by dqPCR, and six by qPCR. These data confirm the sympatric circulation of L. infantum and L. tarentolae in geckoes, sand flies, and dogs, and suggest that geckoes may be infected with L. infantum.

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: This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events. Patients and methods: Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported. Results: Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3–2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5–3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated ( p = 0.009, p