From Tumor Macroenvironment to Tumor Microenvironment: The Prognostic Role of the Immune System in Oral and Lung Squamous Cell Carcinoma.

BACKGROUND: The interplay between cancer cells and the immune system is crucial in cancer progression and treatment. In this regard, the tumor immune microenvironment and macroenvironment, marked by systemic inflammation markers and TILs, could be considered key prognostic factors in tumors, including oral and lung squamous cell carcinoma. METHODS: We conducted a retrospective clinical study on patients with Oral Squamous Cell Carcinoma (OSCC) and Lung Squamous Cell Carcinoma (LUSCC), examining stages, comorbidities, treatments, and outcomes. We evaluated the prognostic significance of pre-surgical systemic inflammation markers and tumor microenvironment composition. RESULTS: Associations were found between systemic inflammation markers-NLR, MLR, and PLR-and tumor microenvironment factors, such as TILs and CD8+ cell prevalence-elevated inflammation markers correlated with advanced stages. Specifically, NLR was prognostic in OSCC, whereas PLR was prognostic in LUSCC. Using a cutoff value, we divided our tumor samples into two prognostic groups. Moreover, TILs levels >15% of tumor stroma correlated with prolonged overall survival in both OSCC and LUSCC, while increased CD8+ expression was linked to extended disease-free survival in LUSCC. DISCUSSION: Systemic inflammation markers and TILs can be valuable prognostic factors of survival, highlighting the immune response's role in OSCC and LUSCC. Despite limited clinical integration of the presented cohorts due to a lack of standardization, we concluded that analyzing tumor immune profiles may offer novel prognostic insights. CONCLUSIONS: Future integration into cancer classification could improve risk stratification and treatment guidance.

Translating knowledge into policy: Organizational model and minimum requirements for the implementation of a regional pancreas unit network.

Pancreatic and periampullary cancers pose significant challenges in oncological care due to their complexity and diagnostic difficulties. Global experiences underscore the crucial role of multidisciplinary collaboration and centralized care in improving patient outcomes in this context. Recognizing these challenges, Lombardy, Italy's most populous region, embarked on establishing pancreas units across its territory to enhance clinical outcomes and organizational efficiency. This initiative, driven by a multistakeholder approach involving the Lombardy Welfare Directorate, clinicians, and a patient association, emphasizes the centralization of complex care in high-volume hospitals, adopting a hub-and-spoke model and a multidisciplinary approach. This article outlines the process and criteria set forth for pancreas unit implementation, aiming to provide a structured framework for enhancing pancreatic cancer care. Central to this initiative is the establishment of structured criteria and minimal requirements, not only for surgery but also for other essential components of care, ensuring a comprehensive approach to pancreatic cancer management. The Lombardy model offers a structured framework for enhancing pancreatic cancer care, with potential applicability to other regions and countries seeking to improve their cancer care infrastructure.

The Impact of Second Opinion Expert Pathology Review in Patient Management at the Time of Transurethral Resection of the Bladder.

BACKGROUND AND OBJECTIVE: Pathological features in non-muscle-invasive bladder cancer specimens are pivotal in determining correct patients' therapeutic management. Sparse data exist regarding the importance of second opinion performed by an expert uropathologist. This study aimed to assess the importance of a second opinion by an expert uropathologist in the management of bladder cancer. METHODS: The study relied on 272 bladder cancer specimens from 231 patients seeking a pathology second opinion after transurethral resection of the bladder for a clinical suspicion of bladder cancer, relapse, or second-look procedure. Pathology second opinion was offered by an experienced fellowship-trained uropathologist. Discrepancies were recorded considering primary tumor staging, the presence of muscularis propria, and the presence of histological variants. Cases were categorized as no significant discordance, major discordance without management change, and major discordance with management change according to the European Urology Association (EAU) guidelines. KEY FINDINGS AND LIMITATIONS: Among 272 second opinion cases, 39% (108/272) had major discordance and 28% (75/272) had major discordance with change in management according to the EAU guidelines. Upstaging and downstaging were reported in 66 (24%) patients. Improper identification of the presence of muscularis propria was found in 46 (17%) cases, of which 11 (4%) were deemed clinically relevant. Differences regarding the presence of histological variants were diagnosed in 40 cases (15%), resulting in eight (3%) changes in clinical management. In ten specimens (4%), multiple clinically relevant discrepancies were found. CONCLUSIONS AND CLINICAL IMPLICATIONS: The second opinion evaluation changed the clinical management in 25% of the cases. These results support the importance of specimen review by an expert uropathologist as a major driver in the correct bladder cancer management. PATIENT SUMMARY: We investigated the importance of a second opinion performed by an expert uropathologist in the management of bladder cancer. We found that 25% had their treatment plan changed due to the revised pathological report.

Establishment of a Transplantation Model of PDAC-Derived Liver Metastases.

BACKGROUND: The highly metastatic nature of pancreatic ductal adenocarcinoma (PDAC) and the difficulty to achieve favorable patient outcomes emphasize the need for novel therapeutic solutions. For preclinical evaluations, genetically engineered mouse models are often used to mimic human PDAC but frequently fail to replicate synchronous development and metastatic spread. This study aimed to develop a transplantation model to achieve synchronous and homogenous PDAC growth with controlled metastatic patterns in the liver. METHODS: To generate an orthotopic PDAC model, the DT6606 cell line was injected into the pancreas head of C57BL/6 mice, and their survival was monitored over time. To generate a heterotopic transplantation model, growing doses of three PDAC cell lines (DT6606, DT6606lm, and K8484) were injected into the portal vein of mice. Magnetic resonance imaging (MRI) was used to monitor metastatic progression, and histologic analysis was performed. RESULTS: Orthotopically injected mice succumbed to the tumor within an 11-week period (average survival time, 78.2 ± 4.45 days). Post-mortem examinations failed to identify liver metastasis. In the intraportal model, 2 × 105 DT6606 cells resulted in an absence of liver metastases by day 21, whereas 5 × 104 DT6606lm cells and 7 × 104 K8484 cells resulted in steady metastatic growth. Higher doses caused significant metastatic liver involvement. The use of K8484 cells ensured the growth of tumors closely resembling the histopathologic characteristics of human PDAC. CONCLUSIONS: This report details the authors' efforts to establish an "optimal" murine model for inducing metastatic PDAC, which is critical for advancing our understanding of the disease and developing more effective treatments.

Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis.

Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.

Same-session endoscopic diagnosis and symptom palliation in pancreato-biliary malignancies: Clinical impact of rapid on-site evaluation (ROSE).

Background and study aims Besides increasing adequacy, rapid on-site evaluation (ROSE) during endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) may impact choices and timing of subsequent therapeutic procedures, yet has been unexplored. Patients and methods This was a retrospective evaluation of a prospectively maintained database of a tertiary, academic centre with availability of ROSE and hybrid EUS-ERCP suites. All consecutive patients referred for pathological confirmation of suspected malignancy and jaundice or gastric outlet obstruction (GOO) between Jan-2020 and Sep-2022 were included. Results Of 541 patients with underlying malignancy, 323 (59.7%) required same-session pathological diagnosis (male: 54.8%; age 70 [interquartile range 63-78]; pancreatic cancer: 76.8%, biliary tract adenocarcinoma 16.1%). ROSE adequacy was 96.6%, higher for EUS versus ERCP. Among 302 patients with jaundice, ERCP-guided stenting was successful in 83.1%, but final drainage was completed in 97.4% thanks to 43 EUS-guided biliary drainage procedures. Twenty-one patients with GOO were treated with 15 EUS-gastroenterostomies and six duodenal stents. All 58 therapeutic EUS procedures occurred after adequate ROSE. With ERCP-guided placement of stents, the use of plastic stents was significantly higher among patients with inadequate ROSE (10/11; 90.9%) versus adequate sampling (14/240; 5.8%) P <0.0001; OR 161; 95%CI 19-1352). Median hospital stay for diagnosis and palliation was 3 days (range, 2-7) and median time to chemotherapy was 33 days (range, 24-47). Conclusions Nearly two-thirds of oncological candidates for endoscopic palliation require contemporary pathological diagnosis. ROSE adequacy allows, since the index procedure, state-of-the-art therapeutics standardly restricted to pathologically confirmed malignancies (e.g. uncovered SEMS or therapeutic EUS), potentially reducing hospitalization and time to oncological treatments.

An alternative splicing signature defines the basal-like phenotype and predicts worse clinical outcome in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. PDAC presents with molecularly distinct subtypes, with the basal-like one being associated with enhanced chemoresistance. Splicing dysregulation contributes to PDAC; however, its involvement in subtype specification remains elusive. Herein, we uncover a subtype-specific splicing signature associated with prognosis in PDAC and the splicing factor Quaking (QKI) as a determinant of the basal-like signature. Single-cell sequencing analyses highlight QKI as a marker of the basal-like phenotype. QKI represses splicing events associated with the classical subtype while promoting basal-like events associated with shorter survival. QKI favors a plastic, quasi-mesenchymal phenotype that supports migration and chemoresistance in PDAC organoids and cell lines, and its expression is elevated in high-grade primary tumors and metastatic lesions. These studies identify a splicing signature that defines PDAC subtypes and indicate that QKI promotes an undifferentiated, plastic phenotype, which renders PDAC cells chemoresistant and adaptable to environmental changes.

Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer.

Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.

Periostin expression in uninvolved skin as a potential biomarker for rapid cutaneous progression in systemic sclerosis patients: a preliminary explorative study.

Objectives: This study aimed to evaluate periostin serum levels and skin expression in patients with systemic sclerosis (SSc). Methods: We enrolled 35 patients with diffuse (d-SSc) or limited (l-SSc) SSc, 15 patients with very early diagnosis of systemic sclerosis (VEDOSS), and 30 sex-matched healthy controls. Periostin serum levels were determined by an enzyme-linked immunosorbent assay (ELISA). Periostin skin expression was determined by immunohistochemistry (IHC) on paired involved and uninvolved 5-mm skin biopsy samples in a subgroup of 10 d-SSc and 10 L-SSc patients. A 12-month follow-up was considered. Results: We included 50 patients (mean age 53.1 ± 16.1 years; women 94%; mean disease duration 38.2 ± 45.1 months; anti-centromere 50%; anti-Scl70 40%), 35 of them with a definite SSc (68.8% l-SSc; 31.4% d-SSc; mean mRSS 9.0 ± 7.2) and 15 with VEDOSS; 30 controls were also included in this study. Periostin serum levels were higher in SSc patients compared to controls (32.7 ± 8.0 ng/mL vs. 27.7 ± 7.3 ng/mL; p < 0.001), while these levels were comparable among different groups of patients (29.7 ± 6.9 ng/mL in VEDOSS, 33.4 ± 7.8 ng/mL in lc-SSc; and 34.0 ± 8.5 in dc-SSc; p = ns). SSc patients with digital ulcers had higher periostin serum levels (36.2 ± 7.9 ng/mL vs. 30.6 ± 7.3 ng/mL, p < 0.02). Samples from the involved skin of l-SSc and d-SSc patients showed a significant dermal expression of periostin; an identical periostin expression was evident in the uninvolved skin of patients with d-SSc. In 7 out of 10 L-SSc patients, periostin expression was absent on uninvolved skin. In the remaining three l-SSc patients, a mild periostin expression on IHC was detectable on uninvolved skin and all of these three l-SSc patients presented a dramatic skin progression. Conclusion: Periostin skin expression may be a useful biomarker to indicate the presence of a disease at a higher risk of rapid cutaneous involvement.

Clinical and pathological characteristics of a series of patients with newly diagnosed primary renal liposarcoma: natural history and effect on survival / Características clínicas y patológicas de una serie de pacientes con liposarcoma renal de nuevo diagnóstico: Historia natural y efecto sobre la supervivencia

OBJECTIVES: Primary renal liposarcoma is an unusual malignant mesenchymal tumor. In this context, all the previous reports were based on cases with insufficient data regarding the natural history of the disease. We decided to fill this gap, reporting the largest single institution series of patients with primary RL and a review of the already available literature. METHODS: We describe 3 cases with radiologically and histologically-confirmed RL out of 3,224 surgeries performed for primary kidney cancers over 28 years (1987-2015, 0.09%) at a single tertiary care center. RESULTS: Patients underwent open radical nephrectomy with an anterior transperitoneal access with complete resection of the retroperitoneal mass and retroperitoneal lymph node dissection; all patients died from tumor progression after a mean time of 45 months. CONCLUSIONS: In conclusion, RL is a very rare mesenchymal renal tumor, with sporadic cases reported. We reported the largest case series of primary RL. The most appropriate approach for RL is nephrectomy with complete resection of all the neoplastic tissue. Stringent follow-up scheme is required due to a high rate of disease recurrence and progression. The role of adjuvant and salvage therapy remains to be investigated

OBJETIVO: El liposarcoma renal (LR) primario y secundario es un tumor maligno mesenquimal poco frecuente. En este contexto, todos los artículos previos se basan en casos clínicos con datos insuficientes sobre la historia natural de la enfermedad. Decidimos llenar este vacío comunicando la mayor serie de pacientes con liposarcoma renal primario de una institución y revisando la literatura disponible. MÉTODOS: Describimos 3 casos de LR con confirmación radiológica y anatomopatológica dentro de una serie de 3.224 cirugías realizadas por cánceres renales primarios en un periodo de 28 años (1987-2015, 0,09%) en un único centro terciario. RESULTADOS: Los pacientes fueron sometidos a nefrectomía radical con un abordaje transperitoneal anterior con resección completa de la masa retroperitoneal; todos los pacientes murieron por progresión del tumor después de una media de 45 meses. CONCLUSIONES: En conclusión, el LR es un tumor renal mesenquimal muy raro, con casos esporádicos publicados. Presentamos la mayor serie de casos de LS primario. El abordaje más apropiado para el LS es la nefrectomía con resección completa de todo el tejido tumoral. Es necesario un protocolo de seguimiento estricto debido a la alta tasa de recurrencia y progresión de la enfermedad. El papel de los tratamientos adyuvante o de salvación está por investigar