TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma.

Introduction: The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC. Aims: In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways. Results: Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC. Conclusion: Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

Artificial intelligence-based algorithms for the diagnosis of prostate cancer: A systematic review.

OBJECTIVES: The high incidence of prostate cancer causes prostatic samples to significantly affect pathology laboratories workflow and turnaround times (TATs). Whole-slide imaging (WSI) and artificial intelligence (AI) have both gained approval for primary diagnosis in prostate pathology, providing physicians with novel tools for their daily routine. METHODS: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was carried out in electronic databases to gather the available evidence on the application of AI-based algorithms to prostate cancer. RESULTS: Of 6290 articles, 80 were included, mostly (59%) dealing with biopsy specimens. Glass slides were digitized to WSI in most studies (89%), roughly two-thirds of which (66%) exploited convolutional neural networks for computational analysis. The algorithms achieved good to excellent results about cancer detection and grading, along with significantly reduced TATs. Furthermore, several studies showed a relevant correlation between AI-identified histologic features and prognostic predictive variables such as biochemical recurrence, extraprostatic extension, perineural invasion, and disease-free survival. CONCLUSIONS: The published evidence suggests that AI can be reliably used for prostate cancer detection and grading, assisting pathologists in the time-consuming screening of slides. Further technologic improvement would help widening AI's adoption in prostate pathology, as well as expanding its prognostic predictive potential.

Characterization of two transcriptomic subtypes of marker-null large cell carcinoma of the lung suggests different origin and potential new therapeutic perspectives.

Pulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes.

A rare case of jejunal Vanek's tumor causing intussusception in an adult: a case report and comprehensive literature overview.

Inflammatory fibroid polyp, or Vanek's tumor, is an uncommon benign small bowel tumor and a rare cause of intussusception in adults. This case involves a 62-year-old man with persistent abdominal pain, diagnosed with jejunoileal intussusception. A 4 cm inflammatory fibroid polyp was discovered during surgery, leading to distal jejunal resection. Despite the rarity of adult intussusceptions, they should be considered in abdominal pain diagnoses. The optimal management approach, whether en bloc resection or initial reduction with limited resection, remains debated.

Effect of Supervised and Unsupervised Exercise Training in Outdoor Gym on the Lifestyle of Elderly People.

The aim of this study was to investigate the effectiveness of supervised and unsupervised physical training programs using outdoor gym equipment on the lifestyles of elderly people. METHODS: physically independent elderly people were randomly distributed into three groups: supervised training (n: 20; ST), unsupervised training (n: 20; UT) and control (n: 20; C). The ST and UT groups completed a 12-week program, with exercises performed three times a week. The ST group underwent weekly 30 min sessions consisting of a 5 min warm-up (walking at 60% of HRmax), followed by 20 sets of 30, "monitored by a metronome with 30" of passive recovery between sets and a five-minute cool-down. The following equipment was used: elliptical, rowing, surfing and leg press. The UT group was instructed to freely attend the gym and train spontaneously using the same equipment used by ST. Lifestyle changes were evaluated using a questionnaire containing specific domains. RESULTS: no significant differences were identified in the domains for family, physical activity, nutrition, smoking, sleep, behavior, introspection, work and overall score; however, the values corresponding to the alcohol domain for the ST and UT groups were lower (p < 0.05) than the C group, remaining even lower after the 12 weeks of intervention. Time effect (p < 0.05) was found only in the ST group for the physical domains, sleep, behavior and overall score. CONCLUSION: elderly people submitted to supervised and unsupervised physical exercise programs using outdoor gym equipment present positive changes in lifestyle parameters compared to physical inactive elderly people.

mTOR eosinophilic renal cell carcinoma: a distinctive tumor characterized by mTOR mutation, loss of chromosome 1, cathepsin-K expression, and response to target therapy.

In the spectrum of oncocytic renal neoplasms, a subset of tumors with high-grade-appearing histologic features harboring pathogenic mutations in mammalian target of rapamycin (mTOR) and hitherto clinical indolent behavior has been described. Three cases (2F,1 M) with histologically documented metastases (lymph node, skull, and liver) were retrieved and extensively investigated by immunohistochemistry, FISH, and next-generation sequencing. Tumors were composed of eosinophilic cells with prominent nucleoli (G3 by ISUP/WHO) arranged in solid to nested architecture. Additionally, there were larger cells with perinuclear cytoplasmic shrinkage and sparse basophilic Nissl-like granules, superficially resembling the so-called spider cells of cardiac rhabdomyomas. The renal tumors, including the skull and liver metastases, showed immunoexpression PAX8, CK8-18, and cathepsin-K, and negativity for vimentin. NGS identified mTOR genetic alterations in the three cases, including the skull and liver metastases. One patient was then treated with Everolimus (mTOR inhibitors) with clinical response (metastatic tumor shrinkage). We present a distinct renal tumor characterized by high-grade eosinophilic cells, cathepsin-K immunohistochemical expression, and harboring mTOR gene mutations demonstrating a malignant potential and showing responsiveness to mTOR inhibitors.

Validation of real-time prostatic biopsies evaluation with fluorescence laser confocal microscopy.

BACKGROUND: Routine processing of prostate biopsies requires conventional steps that usually take a few days. The aim of this study was to validate the use of fluorescence laser confocal microscopy (FCM) for real-time diagnostics. METHODS: We prospectively tested images from prostate needle biopsies (75 images were evaluated by FCM and conventional slides). Two pathologists reviewed the images and assessed agreements between FCM versus conventional slides and between pathologists (κ-values). Interpretation was performed on digital images from the VivaScope 2500 confocal microscope (MAVIG GmbH, Munich, Germany; Caliber I.D., Rochester, NY, USA) placed in the urological operating room. Cancerous versus benign tissue was the primary focus, then the application of the grading system. RESULTS: Cancer was diagnosed in 24 conventional slides (on 75 images) in which agreement among pathologists was high for both conventional (κ=0.96) and FMC (κ=0.84). 1/24 (4%) was ISUP/WHO grade group I, 12/24 (50%) II, 8/24 (33%) III, 2/24 (8%) IV and 1/24 (4%) grade V. Near perfect agreement was obtained for grades I, IV and V (κ=0.85). Grade III values achieved a moderate agreement (κ=0.55). The mean time for laser scanning was 9 minutes. For the remaining non-tumor images, agreement was nearly perfect (κ=0.81). CONCLUSIONS: We validated the use of FCM for real-time cancer detection in prostate biopsies.

STING is a prognostic factor related to tumor necrosis, sarcomatoid dedifferentiation, and distant metastasis in clear cell renal cell carcinoma.

STING is a molecule involved in immune reactions against double-stranded DNA fragments, released in infective and neoplastic diseases, whose role in the interactions between immune and neoplastic cells in clear cell renal cell carcinoma has not been studied yet. We investigated the immunohistochemical expression of STING in a series of 146 clear-cell renal cell carcinomas and correlated it with the main pathological prognostic factors. Furthermore, tumoral inflammatory infiltrate was evaluated and studied for the subpopulations of lymphocytes. Expression of STING was observed in 36% (53/146) of the samples, more frequently in high-grade (G3-G4) tumors (48%,43/90) and recurrent/metastatic ones (75%, 24/32) than in low grade (G1-G2) and indolent neoplasms (16%, 9/55). STING staining correlated with parameters of aggressive behavior, including coagulative granular necrosis (p = 0.001), stage (p < 0.001), and development of metastases (p < 0.001). Among prognostic parameters, STING immune expression reached an independent statistical significance (p = 0.029) in multivariable analysis, along with the stage and the presence of coagulative granular necrosis. About tumor immune-environment, no significant statistical association has been demonstrated between tumor-infiltrating lymphocytes and STING. Our results provide novel insights regarding the role of STING in aggressive clear cell renal cell carcinomas, suggesting its adoption as a prognostic marker and a potentially targetable molecule for specific immunotherapies.

The Influence of Weight Loss in Postural Control in Women Undergoing Sleeve Gastrectomy.

BACKGROUND: Bariatric surgery is the most effective procedure for obesity management, with a greater body weight loss and the remission of several diseases. The aim of this study was to analyze the relationships between the anthropometric profile and postural control outcomes in a group of obese adult women, and the effect of bariatric surgery on postural control. METHODS: eighty-eight women candidates for bariatric surgery were recruited. Static balance was measured with the ARGO stabilometric platform under two conditions: open eyes (OE) and closed eyes (CE). RESULTS: Multiple linear regression indicated BMI as the first predictor for postural control in all parameters, except for APO in open eyes, predicted mainly by height. Changes in body weight and BMI showed no statistically significant correlations with modification of postural control parameters (OE), while they appeared to exert an influence under closed eyes conditions. CONCLUSIONS: Before surgery, obese patients with a higher BMI showed a better postural control. After surgery, the sway path and antero-posterior oscillation improved under open eyes conditions, while the magnitude of weight loss was negatively correlated with differences in postural control.

CXCR4-CXCL12-CXCR7 and PD-1/PD-L1 in Pancreatic Cancer: CXCL12 Predicts Survival of Radically Resected Patients.

Pancreatic ductal adenocarcinoma (PDAC) is currently the most deadly cancer. Although characterized by 5-20% of neoplastic cells in the highly fibrotic stroma, immunotherapy is not a valid option in PDAC treatment. As CXCR4-CXCL12 regulates tumor invasion and T-cell access and PD-1/PD-L1 controls immune tolerance, 76 PDACs were evaluated for CXCR4-CXCL12-CXCR7 and PD-1/PD-L1 in the epithelial and stromal component. Neoplastic CXCR4 and CXCL12 discriminated PDACs for recurrence-free survival (RFS), while CXCL12 and CXCR7 discriminated patients for cancer-specific survival (CSS). Interestingly, among patients with radical resection (R0), high tumor CXCR4 clustered patients with worse RFS, high CXCL12 identified poor prognostic patients for both RFS and CSS, while stromal lymphocytic-monocytic PD-L1 associated with improved RFS and CSS. PD-1 was only sporadically expressed (<1%) in focal lymphocyte infiltrate and does not impact prognosis. In multivariate analysis, tumoral CXCL12, perineural invasion, and AJCC lymph node status were independent prognostic factors for RFS; tumoral CXCL12, AJCC Stage, and vascular invasion were independent prognostic factors for CSS. CXCL12's poor prognostic meaning was confirmed in an additional perspective-independent 13 fine-needle aspiration cytology advanced stage-PDACs. Thus, CXCR4-CXCL12 evaluation in PDAC identifies prognostic categories and could orient therapeutic approaches.

Muscle strength, aerobic capacity, and exercise tolerance are impaired in left ventricular assist devices recipients: A pilot study.

Background: Left ventricular assist devices (LVAD) are increasingly being used as a therapy for advanced heart failure, both as a bridge to heart transplant and, given the rapid advances in the LVAD's functionality and safety, and constant lack in availability of donor organs, as long-term destination therapy. With the diffusion of such therapy, it is crucial to assess patients' muscle strength, aerobic capacity and exercise tolerance, to improve their functional capacity. Methods: 38 LVAD recipients (33 men and five women) were included. Exercise testing including a maximal cardiopulmonary exercise test (CPET), handgrip, isometric and isokinetic strength testing of knee and ankle flexion/extension, and Romberg balance test in three conditions (eyes open, eyes closed, double task). Given the small and heterogeneous final sample size, a mostly descriptive statistical approach was chosen. Results: 12 participants were classified as "Obese" (BMI>29.9). The most common comorbidities were type II diabetes and chronic kidney disease. Only 12 participants were able to successfully complete all the assessments. CPET and isokinetic strength trials were the least tolerated tests, and the handgrip test the best tolerated. Mean VO2 peak was 12.38 ± 3.43 ml/kg/min, with 15 participants below 50% of predicted VO2 max, of which 6 below 30% VO2max. Mean handgrip strength was 30.05 ± 10.61 Kg; 25 participants were below the 25° percentile of their population's normative reference values for handgrip strength, 10 of which were below the 5° percentile. Issues with the management of the external pack of the LVAD and its influence on the test limited the validity of the balance tests data, therefore, no solid conclusions could be drawn from them. VO2 peak did not correlate with handgrip strength or with any of the lower limb strength measures. Conclusion: LVAD recipients show greatly reduced functional capacity and tolerance to exercise and exercise testing, with low overall strength levels. As strength variables appear to be independent from VO2 peak, different lower limbs strength tests should be explored to find a tolerable alternative in this population, which is subjected to muscle wasting due to old age, reduced tissue perfusion, side effects from the pharmacological therapies, and prolonged periods of bedrest.

TFE3 and TFEB-rearranged renal cell carcinomas: an immunohistochemical panel to differentiate from common renal cell neoplasms.

TFE3/TFEB-rearranged renal cell carcinomas are characterized by translocations involving TFE3 and TFEB genes. Despite the initial description of typical morphology, their histological spectrum is wide, mimicking common subtypes of renal cell tumors. Thus, the diagnosis is challenging requiring the demonstration of the gene rearrangement, usually by FISH. However, this technique is limited in most laboratories and immunohistochemical TFE3/TFEB analysis is inconsistent. We sought to identify a useful immunohistochemical panel using the most common available markers to recognize those tumors. We performed an immunohistochemical panel comparing 27 TFE3-rearranged and 10 TFEB-rearranged renal cell carcinomas to the most common renal cell tumors (150 clear cell, 100 papillary, 50 chromophobe renal cell carcinomas, 18 clear cell papillary renal cell tumors, and 50 oncocytomas). When dealing with neoplasms characterized by cells with clear cytoplasm, CA9 is a helpful marker to exclude clear cell renal cell carcinoma. GATA3, AMACR, and CK7 are useful to rule out clear cell papillary renal cell tumor. CK7 is negative in TFE3/TFEB-rearranged renal cell carcinoma and positive in papillary renal cell carcinoma, being therefore useful in this setting. Parvalbumin and CK7/S100A1 respectively are of paramount importance when TFE3/TFEB-rearranged renal cell carcinoma resembles oncocytoma and chromophobe renal cell carcinoma. Moreover, in TFEB-rearranged renal cell carcinoma, cathepsin K and melanogenesis markers are constantly positive, whereas TFE3-rearranged renal cell carcinoma stains for cathepsin K in roughly half of the cases, HMB45 in 8% and Melan-A in 22%. In conclusion, since TFE3/TFEB-rearranged renal cell carcinoma may mimic several histotypes, an immunohistochemical panel to differentiate them from common renal cell tumors should include cathepsin K, CA9, CK7, and parvalbumin.

Validation of a Novel Three-Dimensional (3D Fusion) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study.

We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3-G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.

Relationships between daily physical activity combinations and psychophysical health status of Italian breast cancer survivors.

In breast cancer survivors (BCS), the contemporaneous increase of sedentary time and reduction of physical activity (PA) requires early attention because it has negative consequences for their health. Aims of the study were to investigate: a) the correlations between PA, sedentarism, and health-related measures; b) the association between different patterns of daily activity and health-related outcomes. Two hundred and nineteen BCS (50.98 ± 6.28) were selected for this study. Psychological, anthropometric, endocrine, sleeping, and both daily sedentary time and PA variables were considered. Sedentarism and PA have opposite correlations with anthropometric variables, anxiety, depression, morning salivary cortisol, and sleeping characteristics. The first favors pathological values and the latter favors normal values. Regression tree analysis showed the impact of different daily sedentary time and PA combinations on the investigated variables and allowed the individualization of their optimal combination for health. Our results could be useful to healthcare providers and BCS.

Effects of activity tracker-based counselling and live-web exercise on breast cancer survivors' sleep and waking time during Italy's COVID-19 lockdown.

The aim of the study was to compare the effects of weekly personal feedback, based on objectively measured physical activity, on daily sleep in breast cancer survivors (BCS) with those of an intervention that also included online supervised physical exercise sessions (OSPES). BCS benefiting from both personal feedback and OSPES (n = 24), from pre-lockdown (T0) to the first month (T1) of the national lockdown, experienced an increase in both total (p ≤ 0.001) and restorative (p ≤ 0.001) sleep time, inverting their trend from the first month of lockdown to its end (total sleeping time T1 vs. T2 0.01 ≤ p < .001, T1 vs. T3 p ≤ 0.001; restorative sleeping time T1 vs. T2 0.05 ≤ p < .01, T1 vs. T3 p ≤ 0.001). Supportive technology, together with the reception of weekly tailored advice and OSPES seems to improve both quality and quantity of sleep.

TSC loss is a clonal event in eosinophilic solid and cystic renal cell carcinoma: a multiregional tumor sampling study.

Eosinophilic, solid and cystic (ESC) renal cell carcinoma (RCC) is characterized by a solid and cystic architecture with cells showing abundant eosinophilic cytoplasm with hobnail arrangement and a cytokeratin 7-negative/cytokeratin 20-positive immunophenotype. Recent studies have suggested that bi-allelic events affecting TSC genes might play an important role for such tumors. However, only indirect evidence of the clonal origin of TSC mutation has been gathered so far. Therefore, in this paper we aimed to perform multi-regional tumor sampling molecular analysis in four ESC RCC cases that had been completely embedded, three sporadic and one occurring in a patient with tuberous sclerosis complex (TSC). Histologically, the 4 cases showed cystic and solid architecture and cells with abundant eosinophilic cytoplasm with cytoplasmic stippling and round to oval nuclei. Immunohistochemistry showed at least focal expression of cytokeratin 20 in all tissue samples and negative cytokeratin 7, as well as diffuse positivity for S100A1 and at least focal expression of cathepsin K in three out of four cases. The sporadic cases showed the same somatic TSC1 mutations in all tissue samples analyzed, while the TSC-associated case showed the same TSC1 alteration in both normal tissue and all tumor samples analyzed, proving the germline nature of the alteration. In conclusion, our data demonstrate that clonal TSC loss is a key event in ESC RCC and support considering ESC RCC as an entity given its distinct morphologic, immunophenotypical and molecular characteristics.

Effects of Activity Tracker-Based Counselling and Live-Web Exercise on Breast Cancer Survivors during Italy COVID-19 Lockdown.

BACKGROUND: To prevent and fight the increase of daily sedentary time and to promote and stimulate the positive effects of physical activity and exercise on health, both traditional interventions and new strategies are important for breast cancer survivors (BCS). The research goal was to compare the effects of weekly personal feedback, based on objectively measured physical activity, on the trends of both daily sedentary time and on the physical activity of BCS (E- group) with those of an intervention also including online supervised physical exercise sessions (E+ group), during the Italy COVID-19 lockdown. METHODS: The Italian COVID-19 emergency allowed the possibility to also observe the effects of social and personal limitations. A total of 51 BCS were studied over an 18-week period and had an objective registration of day-to-day sedentary time, physical activity, and sleep. Both subsamples received weekly or fortnight personal feedback. Data were analysed considering four key periods, according to the COVID-19 emergency steps. RESULTS: Statistical analysis showed an additive effect for sedentary time and a multiplicative effect both for light-to vigorous and light-intensity physical activities. The E- group had a high overall sedentary time and a different trend of light-to vigorous and light-intensity physical activities, with a reduction from the 1st to the 2nd periods (national and personal restrictions), showing a significant rise just at the end of the national restrictions. CONCLUSIONS: The use of an activity tracker and its accompanying app, with the reception of weekly tailored advice and supervised online physical exercise sessions, can elicit proper physical activity recomposition in BCS in the COVID-19 era.

Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors.

Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.

Role of next-generation genomic sequencing in targeted agents repositioning for pancreaticoduodenal cancer patients.

BACKGROUND: Pancreaticoduodenal cancer (PDC) is a group of malignant tumors arising in the ampullary region, which lack approved targeted therapies for their treatment. METHODS: This retrospective, observational study is based on Secondary Data Use (SDU) previously collected during a multicenter collaboration, which were subsequently entered into a predefined database and analyzed. FoundationOne CDx or Liquid, a next-generation DNA sequencing (NGS) service, was used to identify genomic alterations of patients who failed standard treatments. Detected alterations were described according to ESMO Scale of Clinical Actionability for molecular Targets (ESCAT). RESULTS: NGS analysis was performed in 68 patients affected by PDC. At least one alteration ranking tier I, II, III, or IV according to ESCAT classification was detected in 8, 1, 9, and 12 patients respectively (44.1%). Ten of them (33.3%) received a matched therapy. Patients with ESCAT tier I to IV were generally younger than the overall population (median = 54, range = 26-71 years), had an EGOG performance status score = 0 (83.3%), and an uncommon histological or clinical presentation. The most common mutations with clinical evidence of actionability (ESCAT tier I-III) involved genes of the RAF (10.3%), BRCA (5.9%) or FGFR pathways (5.9%). We present the activity of the RAF kinases inhibitor sorafenib in patients with RAF-mutated advanced PDC. CONCLUSIONS: In advanced PDC, NGS is a feasible and valuable method for enabling precision oncology. This genomic profiling method might be considered after standard treatments failure, especially in young patients maintaining a good performance status, in order to detect potentially actionable mutations and offer molecularly targeted therapeutic approaches.

A clinical evaluation of VO2 kinetics in kidney transplant recipients.

PURPOSE: Aerobic exercise capacity is reduced in patients with chronic kidney disease, partly due to alterations at the muscular and microvascular level. This study evaluated oxygen uptake (VO2) kinetics as indicator of muscular oxidative metabolism in a population of Kidney Transplant Recipients (KTRs). METHODS: Two groups of KTRs enrolled 3 (n = 21) and 12 months (n = 14) after transplantation and a control group of healthy young adults (n = 16) underwent cardiopulmonary exercise testing on cycle-ergometer. The protocol consisted in two subsequent constant, moderate-load exercise phases with a final incremental test until exhaustion. RESULTS: The time constant of VO2 kinetics was slower in KTRs at 3 and 12 months after transplantation compared to controls (50.4 ± 13.1 s and 43.8 ± 11.6 s vs 28.9 ± 8.4 s, respectively; P < 0.01). Peak VO2 was lower in KTRs evaluated 3 months after transplantation compared to patients evaluated after 1 year (21.3 ± 4.3 and 26.4 ± 8.0 mL/kg/min; P = 0.04). Blood haemoglobin (Hb) concentration was higher in KTRs evaluated at 12 months (12.8 ± 1.7 vs 14.6 ± 1.7 g/dL; P < 0.01). Among KTRs, τ showed a moderate negative correlation with Peak VO2 (ρ = - 0.52) and Oxygen uptake efficiency slope (OUES) (r = - 0.57) while no significant correlation with Hb and peak heart rate. CONCLUSIONS: KTRs show slower VO2 kinetics compared to healthy controls. Hb and peak VO2 seem to improve during the first year after transplantation. VO2 kinetics were significantly associated with indices of cardiorespiratory fitness, but less with central determinants of aerobic capacity, thus suggesting a potential usefulness of adding this index of muscular oxidative metabolism to functional evaluation in KTRs.