Assessment of cephalometric parameters and correlation with the severity of the obstructive sleep apnea syndrome.

BACKGROUND: In individuals diagnosed with obstructive sleep apnea syndrome (OSAS), variations in craniofacial structure have been inconsistently documented, showing differing degrees of alteration between obese and nonobese patients. In addition, sleep disturbance has also been shown to induce disequilibrium in this population of patients. This pilot observational study aimed to assess craniofacial values in obese and nonobese subpopulations of patients with OSAS and their correlation and association with the severity of OSAS. We also assessed whether OSAS patients are characterized by an impaired equilibrium in relation to and associated with the severity of OSAS. METHODS: We included all consecutive adult patients with OSAS. Through cephalometry, we assessed the upper (UPa-UPp) and lower (LPa-LPp) pharynx diameters, superior anterior facial height (Sor-ANS), anterior facial height (ANS-Me), anterior vertical dimension (Sor-Me), posterior facial height (S-Go) and craniovertebral angle (CVA). Furthermore, we analyzed postural equilibrium through a stabilometric examination. RESULTS: Forty consecutive OSAS patients (45% female with a mean age of 56 ± 8.2 years) were included. The subgroup of nonobese patients had a reduced UPa-UPp (p = 0.02). Cephalometric measurements were correlated with the severity of OSAS in nonobese patients, whereas only Sor-ANS was correlated with the severity of OSAS in the obese subpopulation. In the overall population, altered craniofacial values are associated with severe OSAS. Although there are differences in equilibrium between obese and nonobese OSAS patients, the stabilometric measurements were not correlated or associated with OSAS severity. CONCLUSION: Altered craniofacial values and compromised equilibrium in OSAS patients are linked to OSAS severity. Therefore, the management of OSAS should be tailored not only to weight management but also to craniofacial and postural rehabilitation to enhance patient outcomes.

Open versus Minimally Invasive Nephroureterectomy: Contemporary Analysis from a Wide National Population-Based Database.

BACKGROUND: It is generally perceived that minimally invasive nephroureterectomy (MINU), especially in the form of robotic-assisted laparoscopy, is gaining an increasing role in many institutions. OBJECTIVE: The aim of our study was to investigate contemporary trends in the adoption of MINU in the United States compared with open nephroureterectomy (ONU). METHODS: Patients who underwent ONU or MINU between 2011 and 2021 were retrospectively analyzed using PearlDiver Mariner, an all-payer insurance claims database. International Classification of Diseases diagnosis and procedure codes were used to identify the type of surgical procedure, patients' characteristics, social determinants of health (SDOH), and perioperative complications. The primary objective assessed different trends and costs in NU adoption, while secondary objectives analyzed factors influencing the postoperative complications, including SDOH. Outcomes were compared using multivariable regression models. RESULTS: Overall, 15,240 patients underwent ONU (n = 7675) and MINU (n = 7565). Utilization of ONU declined over the study period, whereas that of MINU increased from 29 to 72% (p = 0.01). The 60-day postoperative complication rate was 23% for ONU and 19% for MINU (p < 0.001). At multivariable analysis, ONU showed a significantly higher risk of postoperative complications (odds ratio 1.33, 95% CI 1.20-1.48). Approximately 5% and 9% of patients reported at least one SDOH at baseline for both ONU and MINU (p < 0.001). CONCLUSIONS: Contemporary trend analysis of a large national dataset confirms that there has been a significant shift towards MINU, which is gradually replacing ONU. A minimally invasive approach is associated with lower risk of complications. SDOH are non-clinical factors that currently do not have an impact on the outcomes of nephroureterectomy.

Assessing Functional Outcomes of Partial Versus Radical Nephrectomy for T1b-T2 Renal Masses: Results from a Multi-institutional Collaboration.

BACKGROUND: Deterioration of renal function is associated with increased all-cause mortality. In renal masses larger than 4 cm, whether partial versus radical nephrectomy (PN vs. RN) might affect long-term functional outcomes is unknown. This study tested the association between PN versus RN and postoperative acute kidney injury (AKI), recovery of at least 90% of the preoperative estimated glomerular filtration rate (eGFR) at 1 year, upstaging of chronic kidney disease (CKD) one stage or more at 1 year, and eGFR decline of 45 ml/min/1.73 m2 or less at 1 year. METHODS: Data from 23 high-volume institutions were used. The study included only surgically treated patients with single, unilateral, localized, clinical T1b-2 renal masses. Multivariable logistic regression analyses were performed. RESULTS: Overall, 968 PN patients and 325 RN patients were identified. The rate of AKI was lower in the PN versus the RN patients (17% vs. 58%; p < 0.001). At 1 year after surgery, for the PN versus the RN patients, the rate for recovery of at least 90% of baseline eGFR was 51% versus 16%, the rate of CKD progression of ≥ 1 stage was 38% versus 65%, and the rate of eGFR decline of 45 ml/min/1.73 m2 or less was 10% versus 23% (all p < 0.001). Radical nephrectomy independently predicted AKI (odds ratio [OR], 7.61), 1-year ≥ 90% eGFR recovery (OR, 0.30), 1-year CKD upstaging (OR, 1.78), and 1-year eGFR decline of 45 ml/min/1.73 m2 or less (OR, 2.36) (all p ≤ 0.002). CONCLUSIONS: For cT1b-2 masses, RN portends worse immediate and 1-year functional outcomes. When technically feasible and oncologically safe, efforts should be made to spare the kidney in case of large renal masses to avoid the hazard of glomerular function loss-related mortality.

Addition of neoadjuvant chemotherapy to a 'quadrifecta' composite in radical cystectomy.

OBJECTIVES: To evaluate the impact of incorporating neoadjuvant chemotherapy (NAC) into the 'quadrifecta' outcomes composite for reporting outcomes of radical cystectomy (RC) creating a pentafecta score. PATIENTS AND METHODS: This is a retrospective multicentre analysis of patients treated with RC, with or without NAC, for bladder cancer between 2002 and 2023. The primary outcome was the effect of adding NAC to a quadrifecta outcomes composite on cancer-specific (CSS) and overall survival (OS). The quadrifecta outcomes composite included a yield of ≥16 lymph nodes, negative soft tissue surgical margin, absence of major complication within 30 days from surgery, and no delay in RC. RESULTS: A total of 590 patients were included in the analyses. A total of 233 (39.5%) patients achieved all quadrifecta outcomes and 82 (13.9%) patients were additionally treated with NAC, achieving the pentafecta. Achieving the quadrifecta outcomes composite was significantly associated with better CSS (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.32-0.75; P = 0.001) and OS (HR 0.48, 95% CI 0.34-0.69; P < 0.01). The addition of NAC to the quadrifecta composite outcomes significantly improved the discrimination of patients more likely to have better CSS (HR 0.21, 95% CI 0.08-0.57; P = 0.002) and OS (HR 0.26, 95% CI 0.12-0.55; P < 0.01). CONCLUSION: We propose a new pentafecta that may serve as a tool for standardising outcomes reporting and measuring the quality of RC.

Trimodal therapy vs radical cystectomy in patients with muscle-invasive bladder cancer: a systematic review and meta-analysis of comparative studies.

OBJECTIVE: To perform a systematic review and meta-analysis of trials comparing trimodal therapy (TMT) and radical cystectomy (RC), evaluating differences in terms of oncological outcomes, quality of life, and costs. MATERIALS AND METHODS: In July 2023, a literature search of multiple databases was conducted to identify studies analysing patients with cT2-4 N any M0 muscle-invasive bladder cancer (MIBC; Patients) receiving TMT (Intervention) compared to RC (Comparison), to evaluate survival outcomes, recurrence rates, costs, and quality of life (Outcomes). The primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS) and metastasis-free survival (MFS). Hazard ratios (HRs) were used to analyse survival outcomes according to different treatment modalities and odds ratios were used to evaluate the likelihood of receiving each type of treatment according to T stage. RESULTS: No significant difference in terms of OS was observed between RC and TMT (HR 1.07, 95% confidence interval [CI] 0.81-1.4; P = 0.6), even when analysing radiation therapy regimens ≥60 Gy (HR 1.02, 95% CI 0.69-1.52; P = 0.9). No significant difference was observed in CSS (HR 1.12, 95% CI 0.79-1.57, P = 0.5) or MFS (HR 0.88, 95% CI 0.66-1.16; P = 0.3). The mean cost of TMT was significantly higher than that of RC ($289 142 vs $148 757; P < 0.001), with greater effectiveness in terms of cost per quality-adjusted life-year. TMT ensured significantly higher general quality-of-life scores. CONCLUSION: Trimodal therapy appeared to yield comparable oncological outcomes to RC concerning OS, CSS and MFS, while providing superior patient quality of life and cost effectiveness.

Impact of the extent of lymph node dissection on survival outcomes in clinically lymph node-positive bladder cancer.

OBJECTIVE: To determine the oncological impact of extended pelvic lymph node dissection (ePLND) vs standard PLND (sPLND) during radical cystectomy (RC) in clinically lymph node-positive (cN+) bladder cancer (BCa). PATIENTS AND METHODS: In this retrospective, multicentre study we included 969 patients who underwent RC with sPLND (internal/external iliac and obturator lymph nodes) or ePLND (sPLND plus common iliac and presacral nodes) with or without platin-based peri-operative chemotherapy for cTany N1-3 M0 BCa between 1991 and 2022. We assessed the impact of ePLND on recurrence-free survival (RFS) and the distribution of recurrences (locoregional and distant recurrences). The secondary endpoint was overall survival (OS). We performed propensity-score matching using covariates associated with the extent of PLND in univariable logistic regression analysis. The association of the extent of PLND with RFS and OS was investigated using Cox regression models. RESULTS: Of 969 cN+ patients, 510 were 1:1 matched on propensity scores. The median (interquartile range [IQR]) time to recurrence was 8 (4-16) months, and median (IQR) follow-up of alive patients was 30 (13-51) months. Disease recurrence was observed in 104 patients in the ePLND and 107 in the sPLND group. Of these, 136 (27%), 47 (9.2%) and 19 patients (3.7%) experienced distant, locoregional, or both distant and locoregional disease recurrence, respectively. When stratified by the extent of PLND, we did not find a difference in recurrence patterns (P > 0.05). ePLND improved neither RFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.70-1.19; P = 0.5) nor OS (HR 0.78, 95% CI 0.60-1.01; P = 0.06) compared to sPLND. Stratification by induction chemotherapy did not change outcomes. CONCLUSION: Performing an ePLND at the time of RC in cN+ patients improved neither RFS nor OS compared to sPLND, regardless of induction chemotherapy status. Pretreatment risk stratification is paramount to identify ideal candidates for RC with ePLND as part of a multimodal treatment approach.

Thromboprophylaxis during neoadjuvant chemotherapy for bladder cancer reduces thromboembolism and bleeding.

OBJECTIVES: To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients scheduled for radical cystectomy. MATERIALS AND METHODS: We conducted a retrospective cohort study in 4886 patients with non-metastatic bladder cancer undergoing cystectomy across 28 centres in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis on VTE and bleeding. RESULTS: In 147 patients (3%) VTEs were recorded within the first year. These occurred a median (interquartile range [IQR]) of 127 (82-198) days after bladder cancer diagnosis. Bleeding events occurred in 131 patients (3%) within the first year. These occurred a median (IQR) of 101 (83-171) days after cancer diagnosis. In inverse probability weighting analyses, compared to patients without thromboprophylaxis during chemotherapy, patients with thromboprophylaxis had not only a lower risk of VTE (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12-0.81; P = 0.016) but also a lower bleeding risk (HR 0.03, 95% CI 0.09-0.12; P <0.0001). The retrospective nature of the study was its main limitation. CONCLUSIONS: In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomised trials in other malignancies. Our data suggest thromboprophylaxis is protective against VTEs and should be the standard of care during neoadjuvant chemotherapy.

Injectable Thermogelling Nanostructured Ink as Simultaneous Optical and Magnetic Resonance Imaging Contrast Agent for Image-Guided Surgery.

The development of efficient and biocompatible contrast agents is particularly urgent for modern clinical surgery. Nanostructured materials raised great interest as contrast agents for different imaging techniques, for which essential features are high contrasts, and in the case of precise clinical surgery, minimization of the signal spatial dispersion when embedded in biological tissues. This study deals with the development of a multimodal contrast agent based on an injectable hydrogel nanocomposite containing a lanthanide-activated layered double hydroxide coupled to a biocompatible dye (indocyanine green), emitting in the first biological window. This novel nanostructured thermogelling hydrogel behaves as an efficient tissue marker for optical and magnetic resonance imaging because the particular formulation strongly limits its spatial diffusion in biological tissue by exploiting a simple injection. The synergistic combination of these properties permits to employ the hydrogel ink simultaneously for both optical and magnetic resonance imaging, easy monitoring of the biological target, and, at the same time, increasing the spatial resolution during a clinical surgery. The biocompatibility and excellent performance as contrast agents are very promising for possible use in image-guided surgery, which is currently one of the most challenging topics in clinical research.

Surgical outcomes of novel retroperitoneal low anterior vs posterior and transperitoneal access in single-port partial nephrectomy.

PURPOSE: Single-Port Robot-Assisted Partial Nephrectomy (SP-RAPN) can be performed by transperitoneal and retroperitoneal approaches. However, there is a lack of surgical outcomes for novel Retroperitoneal Low Anterior Access (LAA) in SP-RAPN. The study compared outcomes of the standard approach (SA), considering transperitoneal (TP) and posterior retroperitoneal (RP) access vs LAA in SP-RAPN series. METHODS: 102 consecutive patients underwent SP-RAPN between 2019 and 2023 at a tertiary referral robotic center were identified. Baseline characteristics, peri- and post-operative outcomes were collected. Patients were stratified according to surgical approach into standard (RP or TP) vs LAA and, subsequently, RP vs LAA. Multivariable logistic regression analysis was used to test the probability of the same-day discharge adjusting for comorbidity indexes. RESULTS: Overall, 102 consecutive patients were included in this study (68 SA - 26 TP and 42 posterior RP vs 34 LAA). Median age was 60 (IQR 51.5-66) years and median BMI was 31 (IQR 26.3-37.6). No baseline differences were observed. LAA exhibited significantly shorter length of stay (LOS) (median 10 [IQR 8-12] vs 24 [IQR 12-30.2.] hours, p < .0001), reduced post-operative pain (p < .0001) and decreased narcotic use on 0-1 PO Day (p < .001) compared to SA and RP only. Multivariate analysis, adjusting for comorbidities, identified LAA as a strong predictor for Same-Day Discharge. CONCLUSION: LAA is an effective approach as well as RP and TP, regardless of the renal mass location, whether it is anterior or posterior, upper/mid or lower pole, yielding favorable outcomes in LOS, post-operative pain and decreased narcotics use compared to SA in SP-RAPN.

Single-port robot-assisted simple prostatectomy: techniques and outcomes.

PURPOSE: To describe the surgical techniques and to analyse the outcomes of single-port robot-assisted simple prostatectomy (SP RASP) procedure for the surgical treatment of benign prostatic hyperplasia (BPH). METHODS: Three databases (PubMed®, Web of Science™, and Scopus®) were queried to identify studies reporting on the technical aspects and outcomes of SP RASP. Different combinations of keywords were used, according to a free-text protocol, to identify retrospective and prospective studies, both comparative and non-comparative, systematic reviews (SR) and meta-analysis (MA) describing surgical techniques for SP RASP and the associated surgical and functional outcomes. RESULTS: The transvesical approach represents the most common approach for SP RASP. A decrease in terms of estimated blood loss was observed when SP RASP was compared to open simple prostatectomy (OSP) and multi-port (MP) RASP. Furthermore, this technique allowed for a shorter length of hospital stay (LoS) and a lower post-operative complication rate, compared to OSP. Post-operative subjective and objective functional outcomes are satisfying and comparable to OSP and MP RASP. CONCLUSION: SP RASP represents a safe and feasible approach for the surgical management of BPH. It provides comparable surgical and functional outcomes to MP RASP, enabling for minimal invasiveness, enhanced recovery, and potential for improving patient care.

Antibiotic prophylaxis in invasive urodynamics, a Delphi consensus of the Italian Society of Urodynamics (SIUD).

INTRODUCTION: Although antibiotic prophylaxis (AB) demonstrated a statistically significant reduction in bacteriuria after invasive urodynamics (UDS), no significant decrease in the incidence of urinary tract infections (UTI) has been confirmed. No absolute recommendations on the use of AB in case of relevant potential risk of UTI have been reported, though some categories of patients at increased infective probability after UDS have been recognized. The aim of this study is to report the experts' consensus on the best practice for the use of AB before UDS in the main categories of patients at potential risk of developing UTI. MATERIALS AND METHODS: A systematic literature review was performed on AB before UDS in males and females. A panel of experts from the Italian Society of Urodynamics, Continence, Neuro-Urology, and Pelvic Floor (SIUD) assessed the review data and decided by a modified Delphi method on 16 statements proposed and discussed by the panel. The cut-off percentage for the consensus was a ≥70% of positive responses to the survey. The study was a Delphi consensus with experts' opinions, not a clinical trial involving directly patients. RESULTS: The panel group was composed of 57 experts in functional urology and UDS, mainly urologists, likewise gynaecologists, physiatrists, infectivologists, pediatric urologists, and nurses. A positive consensus was achieved on 9/16 (56.25%) of the statements, especially on the need for performing AB before UD in patients with neurogenic bladder and immunosuppression. Urine analysis and urine culture before UDS are mandatory, and in the event of their positivity, UDS should be postponed. A consensus was reached on avoiding AB in menopausal status, diabetes, age, gender, bladder outlet obstruction, high postvoid residual, chronic catheterization, previous urological surgery, lack of urological abnormalities, pelvic organ prolapse, and negative urine analysis. CONCLUSIONS: Antibiotic prophylaxis is not recommended for patients without notable risk factors and with a negative urine test due to the potential morbidities that may result from antibiotic administration. However, AB can be used for risk categories such as neurogenic bladder and immunosuppression. The evaluation of urine analysis and urine culture and postponing UDS in cases of positive tests were considered good practices, as well as performing AB in the neurogenic bladder and immunosuppression.

Does thyroglossal duct arborization play a role in the post-surgical outcome of Sistrunk procedure in children?

PURPOSE: The purpose of the present study is to analyze thyroglossal duct cyst (TGDC) histopathological features, with focus on "arborization", in a cohort of pediatric patients who underwent surgical removal, and evaluate a possible correlation with clinical recurrences. METHODS: A retrospective analysis of all patients who underwent surgical resection for TGDC at the division of Pediatric Surgery of the University of Pisa from 2015 to 2020 was performed; for each patient, the following data were recorded: age, sex, clinical presentation, localization, size of the lesion, diagnostic tools, histopathological features, perioperative complications, recurrence and follow-up. RESULTS: With respect to arborization, following histopathological analysis 25/30 patients (83.3%) presented thyroglossal duct branching. After a median follow-up of 3.5 years, only 2 out of 30 patients (6.7%), one male and one female, respectively aged 4 y.o. and 6 y.o., presented recurrence within one year from first surgery. CONCLUSION: Surgery for TGDC remains a challenge for pediatric surgeons, while arborization was present in most of our cases which underwent surgery. With respect to the role of arborization, our study did not highlight sufficient conclusive data regarding their role in recurrence: instead, it showed wide resection as satisfactory, being the arborization present in most of the cases at histopathology.

Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN-ALK Fusion In Vitro.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid carcinoma (ATC) is an extremely difficult disease to tackle, with an overall patient survival of only a few months. The currently used therapeutic drugs, such as kinase inhibitors or immune checkpoint inhibitors, can prolong patient survival but fail to eradicate the tumor. In addition, the onset of drug resistance and adverse side-effects over time drastically reduce the chances of treatment. We recently showed that Twist1, a transcription factor involved in the epithelial mesenchymal transition (EMT), was strongly upregulated in ATC, and we wondered whether it might represent a therapeutic target in ATC patients. To investigate this hypothesis, the effects of harmine, a ß-carboline alkaloid shown to induce degradation of the Twist1 protein and to possess antitumoral activity in different cancer types, were evaluated on two ATC-derived cell lines, BHT-101 and CAL-62. The results obtained demonstrated that, in both cell lines, harmine reduced the level of Twist1 protein and reverted the EMT, as suggested by the augmentation of E-cadherin and decrease in fibronectin expression. The drug also inhibited cell proliferation and migration in a dose-dependent manner and significantly reduced the anchorage-independent growth of both ATC cell lines. Harmine was also capable of inducing apoptosis in BHT-101 cells, but not in CAL-62 ones. Finally, the activation of PI3K/Akt signaling, but not that of the MAPK, was drastically reduced in treated cells. Overall, these in vitro data suggest that harmine could represent a new therapeutic option for ATC treatment.

The 2012 Briganti nomogram not only predicts lymph node involvement but also disease progression in surgically treated intermediate-risk prostate cancer patients with PSA <10 ng/mL, ISUP grade group 3, and clinical stage up to cT2b.

PURPOSE: We assessed the prognostic impact of the 2012 Briganti nomogram on prostate cancer (PCa) progression in intermediate-risk (IR) patients presenting with PSA <10ng/mL, ISUP grade group 3, and clinical stage up to cT2b treated with robot assisted radical prostatectomy eventually associated with extended pelvic lymph node dissection. MATERIALS AND METHODS: From January 2013 to December 2021, data of surgically treated IR PCa patients were retrospectively evaluated. Only patients presenting with the above-mentioned features were considered. The 2012 Briganti nomogram was assessed either as a continuous and a categorical variable (up to the median, which was detected as 6%, vs. above the median). The association with PCa progression, defined as biochemical recurrence, and/or metastatic progression, was evaluated by Cox proportional hazard regression models. RESULTS: Overall, 147 patients were included. Compared to subjects with a nomogram score up to 6%, those presenting with a score above 6% were more likely to be younger, had larger/palpable tumors, presented with higher PSA, underwent tumor upgrading, harbored non-organ confined disease, and had positive surgical margins at final pathology. PCa progression, which occurred in 32 (21.7%) cases, was independently predicted by the 2012 Briganti nomogram both considered as a continuous (Hazard Ratio [HR]:1.04, 95% Confidence Interval [CI]:1.01-1.08;p=0.021), and a categorical variable (HR:2.32; 95%CI:1.11-4.87;p=0.026), even after adjustment for tumor upgrading. CONCLUSIONS: In IR PCa patients with PSA <10ng/mL, ISUP grade group 3, and clinical stage up to cT2b, the 2012 Briganti nomogram independently predicts PCa progression. In this challenging subset of patients, this tool can identify prognostic subgroups, independently by upgrading issues.

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.

Neutrophil extracellular traps in cancer.

Beyond their well-known functions in the acute phases of the immune response, neutrophils play important roles in the various phases of tumor initiation and progression, through the release of their stored or newly synthesized mediators. In addition to reactive oxygen species, cytokines, chemokines, granule proteins and lipid mediators, neutrophil extracellular traps (NETs) can also be released upon neutrophil activation. NET formation can be achieved through a cell-death process or in association with the release of mitochondrial DNA from viable neutrophils. NETs are described as extracellular fibers of DNA and decorating proteins responsible for trapping and killing extracellular pathogens, playing a protective role in the antimicrobial defense. There is increasing evidence, however, that NETs play multiple roles in the scenario of cancer-related inflammation. For instance, NETs directly or indirectly promote tumor growth and progression, fostering tumor spread at distant sites and shielding cancer cells thus preventing the effects of cytotoxic lymphocytes. NETs can also promote tumor angiogenesis and cancer-associated thrombosis. On the other hand, there is some evidence that NETs may play anti-inflammatory and anti-tumorigenic roles. In this review, we focus on the main mechanisms underlying the emerging effects of NETs in cancer initiation and progression.

Molecular targets of tyrosine kinase inhibitors in thyroid cancer.

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

Primary cell cultures for the personalized therapy in aggressive thyroid cancer of follicular origin.

Thyroid cancer (TC) is the most prevalent endocrine malignancy. More than 90 % of TC is represented by differentiated TC (DTC) arising from the follicular thyroid cells. DTC includes papillary TC (PTC), follicular TC (FTC), and Hürthle cell TC. Anaplastic TC (ATC) accounts for 1% of TC, and it represents 15-40 % of TC death. Current treatment strategies are not completely effective against aggressive DTC or ATC, and mortality is one of the most important challenges. Recently, progresses have been obtained in the understanding of the molecular/genetic basis of TC progression, and new drugs have been introduced [i.e. tyrosine kinase inhibitors (TKIs)], able to block the oncogenic or signaling kinases, associated with cellular growth. Thyroid cell lines, obtained from tumoral cells and chosen for high proliferation in vitro, have been used as preclinical models. Actually, these cells lose the characteristic features of the primary tumor, because they adapt to in vitro growth conditions. For these reasons, the use of these cell lines has important limitations, and more recently human primary cell cultures have been established as monolayer cultures, and investigated for their biological behavior. Moreover, in the past, primary TC cells could be collected only through surgical biopsies, while recently human primary cell cultures can be established also from samples of fine-needle aspiration citology from aggressive dedifferentiated DTC or ATC. Testing in vitro different TKIs in each patient can help to develop new personalized treatments, without using ineffective drugs. In conclusion, personalized medicine and precise oncology, which consider both patients and their disease features, represent the future of the treatment approach, and further progress is needed in this direction.

Effect of positive surgical margins at radical prostatectomy on cancer-specific mortality in high/very high-risk prostate cancer patients with Gleason Grade Group 4-5.

BACKGROUND: The effect of positive surgical margins (PSM) on cancer specific mortality (CSM) in high/very high-risk (HR/VHR) prostate cancer (PCa) with aggressive Gleason Grade Group (GGG) is unknown. We tested PSM effect on CSM in this setting, in addition to testing of radiotherapy (RT) benefit in PSM patients. METHODS: We relied on Surveillance, Epidemiology, and End Results database (2010-2015), focusing on HR/VHR patients with exclusive GGG 4-5 at radical prostatectomy (RP). Kaplan-Meier plots and multivariable Cox regression models tested the relationship between PSM and CSM. Moreover, the effect of RT on CSM was explored in PSM patients. RESULTS: Of 3383 HR/VHR patients, 15.1% (n = 511) exhibited PSM. Patients with PSM harbored higher rates of GGG 5 (60.1% vs. 50.9%, p < 0.001), pathologic tumor stage T3a (69.1% vs. 45.2%, p < 0.001) and lymph node involvement (14.1% vs. 9.4%, p < 0.001), relative to patients without PSM. PSM rates decreased over time (2010-2015) from 16.0% to 13.6%. Seven-year CSM-free survival rates were 91.6% versus 95.7% in patients with and without PSM, respectively. In multivariable Cox regression models, PSM was an independent predictor of CSM (hazard ratio = 1.6, p = 0.040) even after adjustment for age, prostate specific antigen, pathologic tumor stage and lymph node status. Finally, in PSM patients, RT delivery did not reduce CSM in either univariable or multivariable Cox regression models. CONCLUSIONS: In HR/VHR PCa patients with exclusive GGG 4-5, PSM at RP adversely affect survival. Moreover, RT has no protective effect on CSM. In consequence, lowest possible PSM rates are crucial in such patients.