Active surveillance for clinical complete responders after chemoradiotherapy for oesophageal squamous cell carcinoma.

BACKGROUND: Guidelines on the treatment of oesophageal squamous cell carcinoma (SCC) recommend neoadjuvant chemoradiotherapy plus surgery or definitive chemoradiotherapy. The aim of this study was to evaluate the outcome of patients with a cCR after chemoradiotherapy who underwent active surveillance. METHODS: Patients with oesophageal SCC who were treated with chemoradiotherapy between January 2016 and June 2022 were identified from an institutional database. Survival and recurrence of patients with a cCR who underwent active surveillance were compared with those of patients who underwent planned surgery. Survival was calculated according to the Kaplan-Meier method and compared between groups using the log rank test. RESULTS: The 37 patients who underwent active surveillance were older and tumours were more often located in the middle/upper-third of the oesophagus than in the surgery group of 57 patients. Median follow-up was 28.1 (i.q.r. 17.2-47.1) months for the active surveillance group and 20 (12.9-39.1) months for the surgery group. Overall survival was comparable between the two groups, with 3-year survival rates of 50 (95% c.i. 31 to 67) and 59 (40 to 73)% for the active surveillance and surgery groups respectively (P = 0.55). Three-year progression-free survival for patients who underwent active surveillance was better than in the surgery group: 70 (43 to 85) versus 58 (40 to 72)% (P = 0.02). Overall and progression-free survival was comparable between patients in the active surveillance group and 23 patients in the surgery group who had a pCR (ypT0 N0). The overall recurrence rate was comparable between the groups: 7 of 37 (19.4%) in active surveillance group versus 16 of 49 (32.6%) in surgery group (P = 0.26). Locoregional recurrence was noted more often in the active surveillance group and systemic recurrence in the surgery group. CONCLUSION: Active surveillance is feasible and safe for patients with oesophageal SCC who have a cCR after chemoradiotherapy.

International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape : Bertinoro Workshop, November 2022.

BACKGROUND: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible. METHODS: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement. RESULTS: The assembly agreed to define oligometastases as a "dynamic" disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy. CONCLUSION: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment.

Risk of obstructive sleep apnea among health workers: results of a screening in a large Italian University Hospital.

PURPOSE: Obstructive sleep apnea (OSA) is a common respiratory sleep disorder, related to increased mortality, poor quality of life, and higher risk of work accidents and injuries. Studies on the risk of OSA (rOSA) among health workers (HW) are scant. The aims of this study were to investigate this issue in a large University Hospital and to assess the effectiveness of a screening program. METHODS: The STOP-BANG questionnaire (SBQ) was sent via e-mail to the 5031 HW employed at the University Hospital of Verona. HW who completed the SBQ were classified at low, moderate, and high rOSA. HW at high rOSA were invited to undergo nocturnal polygraphy. The determinants of rOSA were studied by non-parametric Kruskal-Wallis test, Pearson's chi-squared, and multinomial logistic model. RESULTS: Of 5031 HW, 1564 (31.1%) completed the online questionnaire. Responders with low, moderate, and high rOSA were 72.7%, 13.7%, and 13.6%. Male gender, older age, and higher body mass index (BMI) were significant predictors of high rOSA, as expected. Physicians had the lowest probability of being in the high-risk category. Polygraphy was performed in 64 subjects. The positive predictive value of the self-administered SBQ was 68.8% (95%C.I. 55.9-79.8%) but raised to 96.9% (95%C.I. 89.2-99.6%) when re-administered by medical staff. CONCLUSION: SBQ showed its effectiveness as a screening tool in detecting undiagnosed OSA in HW. Systematic screening for OSA in work settings could allow early diagnosis and treatment, reducing short- and long-term health effects of OSA.

Prevalence of FMS Diagnosis According to ACR 2016 Revised Criteria in a Pain Therapy Centre in Italy: Observational Study.

Background and Objectives: Fibromyalgia syndrome (FMS) is a multifaceted disease with a strong preference for the female sex. It is characterised by chronic widespread pain, sleep-wake disorders, fatigue, cognitive disturbances, and several other somatic symptoms. Materials and Methods: In this prospective observational study, we analysed data regarding 302 patients who were referred to our pain centre for a first clinical assessment evaluation and were then inspected for the physician-based 2016 revision of the ACR diagnostic criteria for FMS, regardless of the final diagnosis previously made by the pain therapist. Results: Among the 280 patients who adhered to the 2016 ACR questionnaire, 20.3% displayed positive criteria for FMS diagnosis. The level of agreement between the FMS discharge diagnosis made by the pain clinician and the ACR 2016 criteria-positivity was moderate (kappa = 0.599, with moderate agreement set at a kappa value of 0.6). Only four patients (1.7%) diagnosed as suffering from FMS at discharge did not satisfy the minimal 2016 ACR diagnostic criteria. Conclusions: This prospective observational study confirmed the diagnostic challenge with FMS, as demonstrated by the moderate grade of agreement between the FMS diagnosis at discharge and the positivity for 2016 ACR criteria. In our opinion, the use of widely accepted diagnostic guidelines should be implemented in clinical scenarios and should become a common language among clinicians who evaluate and treat patients reporting widespread pain and FMS-suggestive symptoms. Further methodologically stronger studies will be necessary to validate our observation.

Bidirectional Approach with PIPAC and Systemic Chemotherapy for Patients with Synchronous Gastric Cancer Peritoneal Metastases (GCPM).

BACKGROUND: This study evaluated the efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with systemic chemotherapy as a bidirectional approach for gastric cancer (GC) patients with synchronous peritoneal metastases (SPM). METHODS: A retrospective analysis of a prospective PIPAC database was queried for patients who underwent a bidirectional approach between October 2019 and April 2022 at two high-volume GC surgery units in Italy (Verona and Siena). Surgical and oncological outcomes were analyzed. RESULTS: Between October 2019 and April 2022, 74 PIPAC procedures in 42 consecutive patients with Eastern Cooperative Oncology Group performance status ≤2 were performed-32 patients treated in Verona and 10 in Siena. Twenty-seven patients (64%) were female and median age at first PIPAC was 60.5 years (I-III quartiles: 49-68 years). Median Peritoneal Cancer Index (PCI) was 16 (I-III quartiles: 8-26) and 25 patients (59%) had at least two PIPAC procedures. Major complications according to the Common Terminology Criteria for Adverse Events (CTCAE; 3 and 4) occurred in three (4%) procedures, and, according to the Clavien-Dindo classification (>3a), one (1%) severe complication occurred. There were no reoperations or deaths within 30 days. Median overall survival (mOS) from diagnosis was 19.6 months (range 14-24), and mOS from first PIPAC was 10.5 months (range 7-13). Excluding cases with very heavy metastatic peritoneal burden, with PCI from 2 to 26, treated with more than one PIPAC, mOS from diagnosis was 22 months (range 14-39). Eleven patients (26%) underwent curative-intent surgery after a bidirectional approach. R0 was achieved in nine (82%) patients and complete pathological response was obtained in three (27%) cases. CONCLUSIONS: Patient selection is associated with bidirectional approach efficacy and feasibility for SPM GC treatment, which may allow potentially curative surgical radicalization in highly selected cases.

The "Weekday Effect" on Enhanced Recovery after Surgery Protocol for Gastrectomy.

INTRODUCTION: While enhanced recovery after surgery (ERAS) protocol demonstrated to improve outcomes after gastrectomy, some papers evidenced a detrimental effect on postoperative morbidity related to the "weekday effect." We aimed to understand whether the day of gastrectomy could affect postoperative outcomes and compliance with ERAS items. METHODS: We included all patients that underwent gastrectomy for cancer between January 2017 and September 2021. Cohort was divided considering the day of surgery: Early group (Monday-Wednesday) and Late group (Thursday-Friday). Compliance with protocol and postoperative outcomes were compared. RESULTS: Two hundred twenty-seven patients were included in Early group, while 154 were in Late group. The groups were comparable in preoperative characteristics. No significant difference in pre/intraoperative and postoperative ERAS items' compliance was apparent between Early and Late groups, with most items exceeding the 70% threshold. Median length of stay was 6.5 days and 6 days in Early and Late groups (p = 0.616), respectively. Morbidity was 50% in both groups, with severe complications that occurred in 13% of Early patients and 15% of Late patients. Ninety-day mortality was 2%, and it was similar between the two groups. CONCLUSIONS: In a center with a standardized ERAS protocol, the weekday of gastrectomy has no significant impact on the success of each ERAS item and on postoperative surgical and oncological outcomes.

Treatment of EGJ Cancer within or outside Clinical Trials: Does the Setting Matter? A Monocentric Prospective Observational Study.

INTRODUCTION: RCTs support neoadjuvant chemoradiotherapy (nCRT) followed by surgery in locally advanced esophago-gastric junction (LA-EGJ) adenocarcinoma. However, RCTs are performed in highly controlled settings with limited representativeness of real-life patients (RLS). The aim of the study was to compare the outcomes in RLS and clinical trial settings. METHODS: The outcomes of RLS, which comprised 125 patients consequently treated for LA-EGJ adenocarcinoma between 2012 and 2017, were compared with the phase II trial (PIIS), performed on 65 patients from 2003 to 2011. RESULTS: About half of RLS (51.2%) were treated with nCRT according to VR protocol, 20.8% with standard CRT according to CROSS/Al-Sarraf, 20% with chemotherapy (CT) alone. pCR was 36.8%, 28.6%, and 9.1% after VR protocol, standard CRT, and CT, respectively (p = 0.082), while 3-year overall survival (OS) was 58.6% (95% CI 43.2-71.1%), 32.8% (14.6-52.4%), and 44.8% (21.3-65.9%), respectively (p = 0.030). With respect to PIIS, RLS had a higher proportion of cN+ (94% vs. 54%; p < 0.001) and a lower proportion of pCR after CT/CRT (23% vs. 39%; p = 0.041). Three-year OS was slightly higher, although not significantly, in PIIS (58.9%, 45.1-70.2%) than RLS (47.9%, 37.4-57.7%) and nearly identical to 3-year OS in RLS treated with VR protocol. CONCLUSION: Real-life patients with EGJ adenocarcinoma have more advanced cancer at baseline, lower pathologic response to neoadjuvant treatment than patients enrolled in clinical trials, but similar survival.

Accuracy of Computer-Guided Implantology with Pilot Drill Surgical Guide: Retrospective 3D Radiologic Investigation in Partially Edentulous Patients.

Background and Objectives: Implant placement with static navigation enables the reaching of a correct position of implants from an anatomical and prosthetic point of view. Different approaches of static navigation are described in the scientific literature, and the pilot-guided approach is one of the least investigated. The aim of the present study is the evaluation of the accuracy of implant insertion using a pilot drill template. Materials and Methods: Fifteen partially edentulous patients, requiring an implant rehabilitation of at least one implant, were enrolled. Pre- and post-operative low-dose CTs were acquired to measure the differences between final positions of implants and virtually planned ones. Three linear discrepancies (coronal, apical, and depth), two angular ones (bucco-lingual and mesio-distal), and the imprecision area were evaluated. Correlations between accuracy and rehabilitated jaws, sectors, and implant length and diameters were also analyzed. Results: Forty implants were inserted in fifteen patients using pilot drill templates. Mean coronal deviation was 1.08 mm, mean apical deviation was 1.77 mm, mean depth deviation was -0.48 mm, mean bucco-lingual angular deviation was 4.75°, and mean mesio-distal one was 5.22°. The accuracy was statistically influenced only by the rehabilitated jaw for coronal discrepancy and sectors and implant diameter for bucco-lingual angular deviations. Conclusions: The pilot drill template could represent a predictable solution to obtain a correct implant placement. Nonetheless, a safety margin of at least 2 mm should be respected during implant planning to prevent damages to anatomical structures. Therefore, the tool is helpful in order to prosthetically drive the implants; still, great attention must be paid in fully relying on this procedure when approaching dangerous structures such as nerves and vessels.

[The role of exposure to airborne pollutants in the workplace on the prevalence and severity of chronic respiratory disease in Italy]. / Il ruolo dell'esposizione a inquinanti aerodispersi nel luogo di lavoro sulla prevalenza e gravità della malattia respiratoria cronica in Italia.

OBJECTIVES: occupational exposure to vapours, gases, dusts and fumes (VGDF) plays an important role in the development and exacerbation of respiratory diseases. The aim of this study is to evaluate the possible association of occupational exposure to airborne pollutants and chronic respiratory diseases. DESIGN: multicase-control study. SETTING AND PARTICIPANTS: cases of chronic respiratory diseases and controls from the Italian multicentric study Gene Environment Interaction in Respiratory Diseases (GEIRD). MAIN OUTCOME MEASURES: the occurrence of rhinitis, asthma, chronic bronchitis/chronic obstructive pulmonary disease (COPD), asthma severity, spirometry data, exhaled nitric oxide (FeNO) were examined in relation to chronic and acute occupational exposures to airborne pollutants using multiple regression models. RESULTS: 2,943 subjects were enrolled in the study. Regularm exposure to VGDF was associated with a higher prevalence of chronic bronchitis/COPD (OR 1.40, 95%CI 0.98-1.99), especially in those also having asthma (OR 1.80, 95%CI 1.14-2.85), a lower prevalence of remittent asthma (OR 0.53, 95%CI 0.29-0.96) and, in those with asthma, an increased activity of the disease (severity score) (OR 1.77, 95%CI 1.20-2.60). No associations were observed between occupational exposure and prevalence of rhinitis, spirometry and FeNO data. Finally, an association was found between acute exposure to airborne pollutants (occupational and non-occupational) and the respiratory diseases investigated, in particular active asthma and asthma associated chronic bronchitis/BPCO. CONCLUSIONS: these data confirm a significant role of occupational exposure to airborne pollutants on respiratory health, underlying the importance of workplace exposure prevention, in particular for more susceptible subjects, as those with respiratory diseases.

Poorly Cohesive Gastric Cancers Showing the Transcriptomic Hallmarks of Epithelial-Mesenchymal Transition Behave Aggressively.

HYPOTHESIS: Poorly cohesive (PC) gastric cancer (GC) exhibits variable clinical behavior, being extremely aggressive in most cases but more indolent at times. We hypothesized that the integrative genomic and gene expression characterization of a PC GC series could help identifying molecular subtypes with potential clinical implications. MATERIALS AND METHODS: 64 PC GCs were assessed for alterations in 409 genes and 30 cases were subjected to transcriptomic profiling of 20,815 genes. RESULTS: A median of 8.2 mutations per Mb (interquartile range 6.9-10.4) was found and a tumor mutational load >10 muts/Mb was significantly associated with patients' worse survival ( P =0.0024). The most frequent mutated genes were CDH1 and TP53 (each 32.8%) followed by PIK3CA (10.9%). In 15 samples (23.4%), at least 1 chromatin remodeling gene was mutated: KMT2D (5 cases); ARID1A and BAP1 (4 cases each); EZH2 , KMT2A , PBRM1 (1 case each). Eight samples (12.5%) had fusion genes involving CLDN18 gene. Gene expression profiling identified 4 different clusters: cluster A associated with epithelial to mesenchymal transition (EMT) signature; cluster B associated to proliferative signature and EMT; cluster C correlated to hedgehog signaling; cluster D showing no enrichment for any of the previous signatures. Notably, cluster A and B showed a worse prognosis compared with clusters C and D ( P =0.0095). CONCLUSION: integrated genomic and transcriptomic analysis suggest the existence of 4 molecular subtypes of PC GC with prognostic significance where EMT features are associated with a worse outcome.

Enhanced Recovery After Surgery can Improve Patient Outcomes and Reduce Hospital Cost of Gastrectomy for Cancer in the West: A Propensity-Score-Based Analysis.

BACKGROUND: Data on ERAS for gastrectomy are scarce, and the majority of the studies come from Eastern countries. Patients in the West are older and suffer from more advanced tumors that impair their clinical condition and often require neoadjuvant treatment. This retrospective study assessed the feasibility and safety of an Enhanced Recovery After Surgery (ERAS) protocol for gastrectomy in a Western center. METHODS: We conducted a single-center study of 351 patients operated for gastric cancer: 103, operated from January 2015 to December 2016, followed the standard pathway, while 248, operated from January 2017 to December 2019, followed the ERAS program. The primary outcomes considered were length of hospital stay (LOS) and direct costs. Secondary outcomes were 90-day morbidity and mortality, readmission rate, and compliance with ERAS items. A propensity score (PS) was built on confounding variables. RESULTS: Compliance with ERAS items after the program was ≥ 70%. Univariable analysis evidenced a 2-day median reduction in LOS and a median cost reduction of €826 per patient in the ERAS group. PS-based multivariable analysis confirmed a significant, 2-day decrease in median LOS and a €1097 saving after ERAS introduction. Ninety-day mortality decreased slightly in ERAS group, while complications and readmissions did not change significantly. When complications were included in the multivariable analysis, ERAS retained its significance, although the effects on LOS and cost were blunted to a median reduction of 1 day and €775, respectively. CONCLUSIONS: ERAS for gastrectomy improved patients' recovery and reduced hospital costs without changes in morbidity, mortality, or readmission.

Pretreatment Primary Tumor Stage is a Risk Factor for Recurrence in Patients with Esophageal Squamous Cell Carcinoma Who Achieve Pathological Complete Response After Neoadjuvant Chemoradiotherapy.

BACKGROUND: Although pathological complete response (pCR) after multimodal treatment for esophageal cancer is associated to the best prognosis, recurrence may occur in 20-40% of cases. The present study investigated the recurrence pattern and predictive factors of recurrence after pCR in patients with esophageal cancer. METHODS: In this study, 427 patients received preoperative treatment for either esophageal squamous cell carcinoma (SCC) or adenocarcinoma at Verona University Hospital between 2000 and 2018. Of these, 145 patients (34%) achieved a pCR. Long-term prognosis, recurrence pattern, and risk factors for relapse in pCR patients were analysed. RESULTS: During a median follow-up of 52 months, 37 relapses (25.5%) occurred, mostly at distant level (n = 28). Nearly all locoregional relapses (8/9) were detected in SCC cases. The 5-year overall survival and cancer-related survival were 71.7% (95% confidence interval [CI] 62.6-78.9%) and 77.5% (95% CI 68.5-84.2%) respectively. Male sex, higher body mass index, and cT4 were significant risk factors for recurrence at univariate analysis. The multivariate analysis confirmed the role of cT4 as predictor of recurrence only in SCCs. CONCLUSIONS: Esophageal cancer recurs in about one-fourth of pCR cases. A fair number of local recurrences occurs in SCCs, but the main problem is the systemic disease control. According to our analysis, SCCs patients with cT4 stage have an increased risk to recur, so they should be managed differently by a personalized approach in terms of adjuvant treatment and follow-up.

Digital Customized Titanium Mesh for Bone Regeneration of Vertical, Horizontal and Combined Defects: A Case Series.

Background and Objective: Guided bone regeneration allows new bone formation in anatomical sites showing defects preventing implant rehabilitation. Material and Methods: The present case series reported the outcomes of five patients treated with customized titanium meshes manufactured with a digital workflow for achieving bone regeneration at future implant sites. A significant gain in both width and thickness was achieved for all patients. Results: From a radiographic point of view (CBTC), satisfactory results were reached both in horizontal and vertical defects. An average horizontal gain of 3.6 ± 0.8 mm and a vertical gain of 5.2 ± 1.1 mm. Conclusions: The findings from this study suggest that customized titanium meshes represent a valid method to pursue guided bone regeneration in horizontal, vertical or combined defects. Particular attention must be paid by the surgeon in the packaging of the flap according to a correct method called the "poncho" technique in order to reduce the most frequent complication that is the exposure of the mesh even if a partial exposure of one mesh does not compromise the final outcome of both the reconstruction and the healing of the implants.

The amount of signet ring cells is significantly associated with tumour stage and survival in gastric poorly cohesive tumours.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate whether the amount of signet ring cells (SRCs) affects clinicopathological characteristics and prognosis of poorly cohesive (PC) gastric tumours. STUDY DESIGN: One hundred seventy-three patients with PC tumours treated at three European centres from 2004 to 2014 were reclassified in three categories: (a) pure SRC cancers (SRC1) (≥90% SRCs); (b) PC carcinoma with SRC component (SRC2) (>10%, <90% SRCs); (c) PC carcinoma not otherwise specified (SRC3) (≤10% SRCs). RESULTS: The percentage of SRCs was inversely related to the pT stage (Spearman's ρ = -0.174, P < .001) and the number of positive nodes coded as a continuous variable (P = .009). Five year cancer-related survival was significantly higher (58%, 95% confidence interval [CI]: 36%-75%) in SRC1 compared with SRC2 (39%, 95% CI: 28%-50%) and SRC3 (38%, 95% CI: 22%-53%), (P = .048). In multivariable analysis, the impact of PC categories on cancer-related survival was significant when controlling for sex, age, pT, pN, and curativity (hazard ratio [HR] of sSRC2 vs SRC1 = 2.08, 95% CI: 1.01-4.29, P = .046; HR of SRC3 vs SRC1 = 2.38, 95% CI: 1.05-5.41, P = .039). CONCLUSION: The percentage of SRCs was inversely related to tumour aggressiveness, with long-term survival significantly higher in SRC1 compared with SRC2 and SRC3 tumours.

Pancreatic Cancer and Obesity: Molecular Mechanisms of Cell Transformation and Chemoresistance.

Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20⁻40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy.

Influence of Tumor Stroma on the Aggressiveness of Poorly Cohesive Gastric Carcinoma.

Tumor-stroma crosstalk promotes the adaptation of cancer cells to the local microenvironment and sustains their growth. We assessed the quantitative and qualitative impact of intralesional stroma on clinic-pathological features and the prognosis of poorly cohesive gastric cancer (PCGC) variants. Tissue microarrays including 75 PCGC specimens were immunostained for cytokeratin 8/18 and α-smooth muscle actin to assess the relative proportion of neoplastic cells versus stromal components and the cases were subsequently divided into stroma-rich (SR) and stroma-poor (SP) tumors. Stromal status is significantly associated with the depth of tumor invasion. Patient survival rate was found to be higher in the SP compared to the SR tumor group and, hence, abundant stroma was identified as a significant risk factor in univariable analysis but had no independent prognostic impact. We also investigated the mRNA levels of KRT8 and the associated transcriptional signatures using the molecular data of 82 PCGC cases divided into KRT8-high and KRT8-low groups. KRT8-high tumors were enriched in proteins localized in the extracellular compartment and their expression levels correlated with longer survival in the KRT8-high group and shorter overall survival in the KRT8-low group. Comprehensively, we find that relative intralesional stromal content is a marker of aggressiveness in PCGC tumors and that extracellular proteins characterize functionally and clinically different PCGC subgroups.