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Organ preservation for muscle-invasive bladder cancer (MIBC) may use trimodality therapy. This includes transurethral resection followed by radiation therapy. Radiosensitization has become one of the standard of care approaches for MIBC with high rates of local disease control and overall survival. The goal of organ preservation is to treat MIBC while preserving a well-functioning natural bladder. Debate remains over the best way to optimize radiation therapy in bladder cancer. In MIBC the role of partial cystectomy has been utilized in smaller solitary tumors with adequate local control and good urinary function. As radiation therapy techniques improve and modernize, smaller radiation volumes to a partial bladder may play an increasing role as we utilize imaging techniques coupled with adaptive radiation therapy planning and other techniques such as brachytherapy. In this review, we explore the use of brachytherapy and partial bladder fields of external beam radiation therapy in the treatment of MIBC.

Non-muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non-muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2-T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4-9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise.

Radical cystectomy with bilateral pelvic lymphadenectomy and trimodality bladder-sparing therapy or TMT, are both curative options for patients with nonmetastatic muscle invasive bladder cancer. Patients should be afforded the opportunity for a multidisciplinary evaluation with equipoise in discussing these options for eligible patients. We discuss the barriers to broader acceptance and utilization of TMT and encourage support of clinical trials of TMT.

Despite tremendous advances in the diagnosis and treatment of NSCLC, the morbidity and mortality of NSCLC still rank high worldwide. Epithelial-mesenchymal transition (EMT) is vital to the invasion, metastasis, and recurrence of NSCLC. Unfortunately, the mechanism behind NSCLC cancer cell EMT remains elusive. Therefore, determining the potential key molecules that induce EMT is important. TATA-binding protein-associated factor-1 (TAF1) is an important component of the preinitiation complex (PIC) that is dysregulated in carcinogenesis. However, the role of TAF1 in NSCLC development is unknown. Therefore, we studied the role of TAF1 in the pathogenesis of NSCLC. First, the expression of TAF1 was determined in human NSCLC tissues and cell lines. TAF1-overexpressing and TAF1 knockdown cell lines were established to evaluate the effect of TAF1 on NSCLC cell proliferation, invasion and migration by colony formation and Transwell assays. The target genes of TAF1 were identified by PCR array and verified by luciferase reporter assay. Our data demonstrated that TAF1 is upregulated in NSCLC. Higher TAF1 expression predicted poor outcomes in NSCLC patients. Mechanistically, TAF1 transcriptionally activated TGFβ1, thus promoting NSCLC cell EMT and the development of NSCLC. Targeting TAF1/TGFβ1 signalling may be potentially helpful as a therapeutic for NSCLC.

The prognostic role of perineural invasion (PNI) in vulvar squamous cell carcinoma (VSCC) has not been fully established since few studies on this topic are currently available in the literature. In the present study, we conducted a systematic review and metanalysis of literature data in order to determine if PNI could be an independent prognostic predictor of patient's survival in VSCC. Four electronic databases (PubMed, ISI Web of Science, Scopus and Google Scholar) were searched from their inception to December 2021 for all studies assessing the prognostic value of PNI in VSCC. Multivariate hazard ratios (HRs) for overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were pooled. Six studies with 1048 patients were included. PNI was significantly associated with decreased OS (HR = 2.687; p 0.001), DSS (HR = 2.375; p = 0.014) and PFS (HR = 1.757; p = 0.001), with no statistical heterogeneity among studies and no significant risk of bias across studies. The present meta-analysis highlights that PNI is independently associated with unfavorable prognosis in patients with VSCC. Therefore, PNI should be included in the pathological report of VSCC and considered in combination with other risk factors as a possible criteria for prognostic assessment adjuvant treatment planning inclusion.

Tumour deposits (TD) and extramural venous invasion (EMVI) are key anatomopathology prognostic criteria in rectal cancer. According to the 2018 ESGAR recommendations, they should be included in every MRI report. The present study aimed at identifying pelvic MRI survival prognostic factors in locally advanced rectal cancers before neo-adjuvant treatment, with a focus on EMVI and TD (mrEMVI and mrTD).Between 2010 and 2014, we conducted a retrospective study about 69 patients who underwent a pre-operative radiotherapy for a non-metastatic rectal cancer. All MR images were acquired on machines with a 1.5 or 3.0 Tesla field strength and were interpreted in compliance with the 2018 ESGAR recommendations.Out of the 27 patients who were mrEMVI+ (39.1%), MRF was involved in 77.7% of the cases vs. 33.3% for the mrEMVI- tumours. Fifteen (55.5%) out of the 27 mrEMVI+ tumours were mrTD+. This represents 21.7% of our population. mrEMVI/mrTD+ tumours were more RCT resistant, their downstaging happened in 6.7% of cases. In case of tumour downstaging, DFS increased significantly (P=0.02) unlike OS (P=0.2).The present study supports the fact that both mrEMVI and mrTD status are important pelvic MRI prognostic factors. Future studies could focus on relating mrTD tumours status to pathological results to define if post-RCT downstaging of TD has an impact on OS.

Prostate radiotherapy is associated with worse oncologic outcomes in patients with bladder cancer. The underlying mechanism is incompletely understood but is thought to be related to an altered microenvironment promoting tumorigenesis. However, there is a gap in the literature regarding how the effect of BCG varies according to prior radiotherapy in patients with non-muscle invasive bladder cancer (NMIBC). In this context, we sought to evaluate oncologic outcomes in NMIBC patients who have previously undergone prostate radiotherapy compared to patients with no prior history of pelvic radiotherapy.This is a retrospective cohort study that includes all patients who received intravesical for NMIBC at our institution from 2001 to 2019. Patients were stratified into 3 cohorts: prior radiotherapy (RT), radical prostatectomy (RP), and no prostate cancer (No PCa). The outcomes of interest were recurrence at 1-year, progression to muscle-invasive bladder cancer (MIBC), and progression to metastatic disease. Comparisons were also made between cohorts with respect to elapsed time from radiation therapy. Wilcoxon rank-sum test was used for comparing continuous variables, while χIn 199 total patients who underwent BCG for NMIBC, 23 had a prior history of prostate radiotherapy treatment, while 17 underwent prior radical prostatectomy. Overall, 41.2% of patients had recurrence at 1 year. There was no difference in the number of induction or maintenance BCG administrations received between the cohorts within the first year. There was no significant difference in recurrence at 1 year between the 3 cohorts (P = .56). There was also no difference in progression to MIBC or progression to metastatic disease with P = .50 and 0.89, respectively.The risk of recurrence after induction BCG treatment for high-grade NMIBC does not vary according to prior radiation treatment for prostate cancer.

Many patients with recurrent high-risk non-muscle invasive bladder cancer after intravesical bacillus calmette-guerin (BCG) face a difficult decision between radical cystectomy (RC) or salvage intravesical therapy (IVT). We sought to determine if there is a difference in overall survival RC and IVT after previous treatment with BCG.We performed a retrospective cohort study of patients with Ta, T1, and Tis bladder cancer treated with induction BCG in the SEER-Medicare dataset from 2000 to 2015. We used a proportional hazards regression model to compare differences in survival between patients having RC and IVT. We adjusted for confounding using a propensity score and stratified our analysis according to timing of treatment and stage at diagnosis.We identified 3940 patients who received either IVT (79%) or RC (21%) following induction BCG. Among patients treated within 12 months of BCG, there was no significant difference in survival between RC and IVT (HR 0.92, 95% CI 0.81-1.04) and 17% of patients having early IVT ultimately required RC. Among patients treated at least 12 months after BCG, RC was associated with worse survival than IVT (HR 1.19, 95% CI 1.06-1.35) and 10% of patients having late IVT ultimately required RC.Among patients with bladder cancer who required additional treatments after induction BCG, we did not observe a difference in overall survival between IVT and RC within 12 months of starting BCG. While RC remains the gold-standard for high risk recurrent NMIBC after BCG, bladder preservation with IVT may be appropriate for well-selected patients.

BACKGROUND: The functional status of immune cells in the tumor microenvironment and tumor characteristics may explain bacillus Calmette-Guérin (BCG) failure in high-risk non-muscle-invasive bladder cancer (NMIBC).OBJECTIVE: To characterize molecular correlates of post-BCG high-grade (HG) recurrence using multiomics analysis.DESIGN, SETTING, AND PARTICIPANTS: Patients with BCG-treated NMIBC (n = 156) were included in the study. Metachronous tumors were analyzed using RNA sequencing (n = 170) and whole-exome sequencing (n = 195). Urine samples were analyzed for immuno-oncology-related proteins (n = 190) and tumor-derived DNA (tdDNA; n = 187).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was post-BCG HG recurrence. Cox regression and Wilcoxon rank-sum, t, and Fisher's exact tests were used for analyses.RESULTS AND LIMITATIONS: BCG induced activation of the immune system regardless of clinical response; however, immunoinhibitory proteins were observed in the urine of patients with post-BCG HG recurrence (CD70, PD1, CD5). Post-BCG HG recurrence was associated with post-BCG T-cell exhaustion (p = 0.002). Pre-BCG tumors from patients with post-BCG T-cell exhaustion had high expression of genes related to cell division and immune function. A high predicted post-BCG exhaustion score for pre-BCG tumors was associated with worse post-BCG HG recurrence-free survival (HGRFS; p = 0.002). This was validated in independent cohorts. Pre-BCG class 2a and 2b tumors (UROMOL2021 scheme) were associated with worse post-BCG HGRFS (p = 0.015). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p = 0.017) and MUC4 mutations (p = 0.002). Finally, the absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p = 0.018). The retrospective design and partial overlap for analyses are study limitations.CONCLUSIONS: Post-BCG HG recurrence may be caused by T-cell exhaustion. Tumor subtype and pre-BCG tumor characteristics may identify patients at high risk of post-BCG HG recurrence. Urinary measurements have potential for real-time assessment of treatment response.PATIENT SUMMARY: A dysfunctional immune response to bacillus Calmette-Guérin (BCG) therapy may explain high-grade recurrences of bladder cancer.

Glioblastoma (GBM) is the most malignant tumor in human brain. High invasiveness of this tumor is the main reason causing treatment failure and recurrence. Previous study has found that LACTB is a novel tumor suppressor in breast cancer. Moreover, the function of LACTB in other tumors and mechanisms involving LACTB were also reported. However, the role and relevant mechanisms of LACTB in GBM invasion remains to be revealed. Our aim is to investigate the role LACTB in GBM migration and invasion. We found that LACTB was downregulated in gliomas compared to normal brain tissues. Overexpression of LACTB suppressed migration and invasion of LN229 and U87 cell lines. Mechanistically, LACTB overexpression downregulated the mesenchymal markers. Moreover, LACTB overexpression downregulated the expression of RHOC and inhibited RHOC/Cofilin signaling pathway. The study suggests that LACTB suppresses migration and invasion of GBM cell lines via downregulating RHOC/Cofilin signaling pathway. These findings suggest that LACTB may be a potential treatment target of GBM.

Item does not contain fulltext This Seminar presents the current best practice for the diagnosis and management of bladder cancer. The scope of this Seminar ranges from current challenges in pathology, such as the evolving histological and molecular classification of disease, to advances in personalised medicine and novel imaging approaches. We discuss the current role of radiotherapy, surgical management of non-muscle-invasive and muscle-invasive disease, highlight the challenges of treatment of metastatic bladder cancer, and discuss the latest developments in systemic therapy. This Seminar is intended to provide physicians with knowledge of current issues in bladder cancer.

Testicular cancer is the most common solid neoplasm of adult men between the ages of 20 and 40 years. Germ cell tumors account for 95% of all testicular tumors. The assessment of staging is essential to guide further management of patients with testicular cancer and to prognosticate cancer-related outcomes. Postradical orchiectomy treatment options, including adjuvant therapy and active surveillance, vary based on the anatomical extent of disease, serum tumor markers, pathologic diagnosis, and imaging. This review provides an update on the germ cell tumor staging system adopted by the 8th edition of the American Joint Commission on Cancer (AJCC) Staging Manual, treatment implications, risk factors, and predictors of outcomes.

To investigate and compare the performance of conventional, radiomic, combined, and delta-radiomic features to predict the invasiveness of lung adenocarcinoma manifesting as ground-glass nodules (GGNs).The present retrospective study included 216 GGNs confirmed surgically as pulmonary adenocarcinomas. All the thin-section computed tomography (CT) images were imported into the software of the United Imaging Intelligence research portal, and radiomic features were extracted with three-dimensional (3D) regions of interest. Least Absolute Shrinkage and Selection Operator was used to select the optimal radiomic features. Four models were constructed, including conventional, radiomic, combined conventional and radiomic, and delta-radiomic models. The receiver operating characteristic curves were built to evaluate the validity of these.The type, long diameter, shape, margin, vacuole, air bronchus, vascular convergence, and pleural traction exhibited significant differences between pre-invasive lesions (PILs)/minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA) groups were selected for conventional model building. Nine radiomic features were selected to build the radiomic model. The four models indicated optimal performance (AUC 0.7). The radiomic and combined models exhibited the highest diagnostic efficiency, and their AUC were 0.89 and 0.88 in the training set, and 0.87 and 0.88 in the validation set, respectively. The delta-radiomic model indicated that the AUC was 0.83 in the training set, and 0.76 in the validation set. Finally, the conventional model exhibited an AUC in the training and validation sets of 0.78 and 0.76.The radiomic model and combined model, in particular, and the delta-radiomic model all demonstrated improved diagnostic efficiency in differentiating IA from PIL/MIA than that of the conventional model.

Breast cancer (BC) is the most diagnosed carcinoma in women worldwide, which is characterized with a high incidence rate and poor prognosis. MicroRNAs (miRNAs) are promising biomarkers for early detection of BC. In this study, we demonstrated that MiR1294 was downregulated in BC. Moreover, we revealed that MiRNA1294 significantly suppressed cell proliferation, migration and invasion. Animal models revealed that MiRNA1294 reduced tumor formation. In addition, we found that ERK signaling was involved in the regulatory role of MiRNA1294 in BC. In conclusion, MiRNA1294 acted as a tumor suppressor in BC, which might serve as a potential target for the development of anti-neoplastic therapies in BC.

Trimodal therapy (TMT) - maximal transurethral resection of bladder tumour followed by chemotherapy and radiation - is an effective treatment for some patients diagnosed with muscle-invasive bladder cancer. Yet eligible patients are not always offered this option or are unclear that this option is (or was) appropriate, desirable and available to them. Communication challenges are a critical barrier to delivering the high-quality care and shared decision-making that bladder cancer patients seek. Leveraging patient and clinician feedback, a checklist was created and is proposed that proactively addresses patients' concerns and questions and ensures that patients are well-informed about TMT. By using the checklist, members of multidisciplinary bladder cancer medical teams can ensure that patients are well-informed about TMT and are confident that TMT has been appropriately and jointly explored as a treatment option. The checklist can reduce communication challenges and frustrations and ensure that, through shared decision-making, patients have chosen their most appropriate treatment.

Bladder cancer occurs mainly in older adults and surgery is not always possible when there are geriatric conditions and comorbidities. Trimodal treatment (TMT) combining trans-urethral resection of bladder tumour (TURBT) followed by concurrent chemoradiation (CRT) would be a curative alternative in such patients.All consecutive patients 75 years of age and older with non-metastatic muscle-invasive bladder cancer (MIBC) treated with TMT by Georges Pompidou European Hospital team were retrospectively analysed. Induction CRT combined hypofractionated twice-daily radiotherapy targeting bladder and pelvis to a total dose of 24 Gy (Gy) with concurrent platinum salt and 5-fluorouracil. Consolidation CRT to a total dose of 44 Gy was proposed to patients with biopsy-proven complete response after induction phase and those with persistent tumour underwent salvage cystectomy. We assessed using Kaplan-Meier method overall survival (OS), cancer specific survival (CSS), invasive recurrence-free survival (IRFS), metastasis-free survival (MFS), survival with bladder preserved (SBP), and toxicities. With a Cox model for OS and the Fine Gray method of competing risk for secondary endpoints, we analysed in univariate (u) and multivariate (m) analysis the impact of tumour characteristics and patient profiles: gender, age, age-adjusted Charlson comorbidity index, polypharmacy, and malnutrition.From 1988 to 2017, 85 patients were included. After induction, complete response rate was 83.5%. With a median follow-up of 63 months, 5 year-OS, CSS, IRFS, MFS and SBP were 61.0%, 77.6%, 71%, 82.9%, and 70.2% respectively. A persistent tumour after induction impacted SBP (SHRm 3.61; p = 0.004), CSS (SHRm 3.27; p = 0.023), and MFS (SHRm 3.68; p = 0.018). Late grade 3 urinary and gastrointestinal toxicities were 3.5% and 1.2%.We report here the largest series of bladder preservation over 75 years in a curative intent. Outcomes and tolerance in selected older adults compared favourably with surgical series and with CRT studies using classical fractionation.

Background Delay in treatment is a prognostic factor in muscle-invasive bladder cancer. Objective To evaluate clinical outcomes associated with delays in diagnosis and treatment for patients with non–muscle invasive bladder cancer (NMIBC). Design, setting, and participants In this retrospective study we analyzed data for patients treated at our center between November 2008 and December 2016 for intermediate risk (IR) or high risk (HR) NMIBC with an additional intravesical treatment. Outcome measurements and statistical analysis Time delays from diagnosis to first transurethral resection (TT-TUR), from resection to restaging resection (TT-reTUR), and from the last resection to first instillation (TT-INST) of bacillus Calmette-Guerin (BCG) or mitomycin C (MMC) were documented. To identify the interval of time from which recurrence rates significantly increased, we used nonparametric series regression. Recurrence-free survival (RFS) and progression-free survival for patients in each time delay category were compared using the Kaplan-Meier method. Factors associated with tumor recurrence were analyzed in a multivariable model. Results and limitations A total of 434 patients were included, of whom 168 (38.7%) had IR and 266 (61.3%) had HR NMIBC. Among the patients, 34.6% had reTUR, 63.6% received BCG, and 36.4% received MMC. The median TT-TUR, TT-reTUR, and TT-INST was 4.0 wk, 6.5 wk, and 7.0 wk, respectively. At 40 mo the rate of recurrence was 28.4% and the rate of progression was 7.3%. Nonparametric analysis revealed that each week in delay increased the risk of recurrence, starting from week 6 for TT-TUR for IR and HR cases, and starting from week 7 for TT-INST for IR cases. RFS was significantly lower with TT-TUR > 6 wk among patients in the IR (p 7 wk for patients in the IR group (p = 0.001). TT-reTUR >7 wk had a significant negative impact on progression (p 6 wk (p = 0.001 and p = 0.03) were independent predictors of recurrence, while TT-INST >7 wk predicted recurrence (p = 0.04) for IR NMIBC. Conclusions Our results suggest that delays of >6 wk to first TUR in IR and HR NMIBC, and >7 wk to first instillation in IR cases are associated with increases in the risk of recurrence. TT-reTUR of >7 wk is also associated with higher risk of progression. Patient summary We evaluated the impact of treatment delays on outcomes for patients with intermediate- and high-risk bladder cancer not invading the bladder wall muscle. We found that delays from diagnosis to first bladder resection, from first resection to repeat resection, and from last resection to bladder instillation treatment increase the rates of cancer recurrence and progression. The medical team should avoid delays in treatment, even for low-grade bladder cancer.

Rationale and Objectives To compare the diagnostic performance of orthogonal pelvis-axial (OPA) contrast-enhanced (CE) and orthogonal uterus-axial (OUA) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) protocols in assessing the depth of myometrial invasion (MI) of endometrial carcinoma (EC). Materials and Methods Preoperative MRI of 398 consecutive EC patients (197 patients with OPA CE-MRI protocol and 201 patients with OUA DCE-MRI protocol) was analyzed. Two radiologists independently interpreted the depth of MI, with postoperative histopathology as the reference standard. The chi-square test, Fisher's exact test, and receiver operating characteristic curve analysis were used for diagnostic performance comparison. Results OUA DCE-MRI showed a significantly larger area under the curve than OPA CE-MRI in detecting the presence of MI for radiologist 1 (0.71 versus 0.49, p 0.05). Compared to OPA CE-MRI, OUA DCE-MRI significantly improved the diagnostic accuracy of non-MI and superficial MI (radiologist 1: 45.5% versus 0 and 88.7% versus 86.4%, p = 0.045 and 0.567, respectively; radiologist 2: 45.5% versus 12.5% and 88.7% versus 78.8%, p = 0.177 and 0.027, respectively) and of EC with adenomyosis/submucous myomas, cornual tumor, and antero-posterior diameter ≤ 10 mm (radiologist 1: 86.4% versus 71.4%, 91.2% versus 67.7%, and 90.1% versus 81.1%, p = 0.048, 0.018, and 0.081, respectively; radiologist 2: 86.4% versus 64.3%, 88.2% versus 64.5%, and 87.0% versus 71.6%, p = 0.006, 0.023, and 0.019, respectively). Conclusion The OUA DCE-MRI protocol was superior to the OPA CE-MRI protocol in assessing the depth of MI of EC.

Indications for adjuvant chemotherapy for advanced gastric cancer are determined based on the pathological diagnosis. However, macroscopic diagnoses have been reported as predictors of peritoneal recurrence and survival. This study investigated the predictability of peritoneal recurrence and survival based on macroscopically (sT) and pathologically (pT) diagnosed serosal invasion to identify more sensitive predictors of peritoneal recurrence.This study included 396 patients who underwent R0 resection without adjuvant chemotherapy with S-1 in the JCOG0110 study. Tumor depth limited to the subserosa (SS) was defined as serosal invasion negative (T-), while tumors with serosal invasion (SE, SI) were defined as serosal invasion positive (T+). The predictability of peritoneal recurrence based on sT and pT was evaluated using the Fine and Gray model. Cox regression analyses were performed for overall survival (OS) and relapse-free survival (RFS) with sT or pT as covariates.A total of 150 patients (37.9%) were sT+ and 82 (26.3%) were pT+. Sixty-two patients (15.7%) were sT+/pT+, 88 (22.2%) were sT+/pT-, 20 (5.1%) were sT-/pT+, and 226 (57.1%) were sT-/pT-. Both sT and pT were found to be independent predictors of peritoneal recurrence, OS, and RFS. The 5-year RFS rates of sT+/pT+, sT+/pT-, sT-/pT+, and sT-/pT-patients were 45.2%, 63.6%, 55.0%, and 81.8%, respectively.Intraoperatively diagnosed macroscopic serosal invasion showed a similar predictive value for peritoneal recurrence as pathologically diagnosed serosal invasion. The establishment of a novel staging system incorporating macroscopic serosal invasion is recommended.

The gold standard treatment for high-risk NMIBC is BCG immunotherapy. Some studies suggested an immomodulatory effects for commonly used drugs (ie, ACE-I and ARBs). We aimed to determine whether these drugs impact the prognosis of patients with high-risk NMIBC treated with BCG.Retrospective analysis on 208 patients from a single academic center with primary high-risk NMIBC treated with transurethral resection followed by 6 weekly instillations of BCG and up to 12 monthly maintenance instillations. ARBs or ACE-I use at the time of treatment initiation was recorded. Inverse probability of treatment weighting (IPTW) was used to adjust for clinical and pathological covariates. IPTW-adjusted Kaplan-Meier curves and weighted Cox proportional hazards regression were used to compare 2-yr failure-free (2-yr FFS), failure-free (FFS), overall recurrence-free (RFS) and progression-free survival (PFS).A total of 68 patients were on ACE-I, and 38 on ARBs and treatment respectively. At a median follow-up of 26 months, ACE-I treatment had no significant impact on cancer-related outcomes. Conversely, patients treated with ARBs experienced significant improvements in 2-yr FFS (HR 0.3; 0.1-0.9, P = .004), FFS (HR 0.4, 0.1-0.9, P = .005), and PFS (HR 0.001;0.001-0.001, P.001). No significant impact was found for ARB use in RFS (HR 0.6; P = .09). Sensitivity analyses confirmed these results.our findings support a potential role of the angiotensin-renin system in bladder cancer development. We identified ARBs as potential beneficial drugs that seems to act in synergy with BCG-immunotherapy.

[Background] Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC)., [Objective] To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial., [Design, setting, and participants] ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy., [Intervention] Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected., [Outcome measurements and statistical analysis] The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements., [Results and limitations] The median follow-up time was 25 mo (95% confidence interval [CI] 25–26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21–41). Two-year DFS and OS were 68% (95% CI 58–76) and 77% (95% CI 68–85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65–94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24–1.5], p = 0.26, and 0.72 [95% CI 0.31–1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09–0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3–13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work., [Conclusions] Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future, [Patient summary] We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy., Bernadett Szabados—research funding from MSD and Roche; honoraria from Roche, MSD, and BMS. Mark Kockx—employee of CellCarta. Zoe June Assaf—employee of Roche. Pieter-Jan van Dam—employee of CellCarta. Alejo Rodriguez-Vida—research funding and honoraria from Roche, BMS, and Pfizer; research funding from Novartis and Astellas. Ignacio Duran—research funding and honoraria from Roche, BMS, Pfizer, and Johnson & Johnson; research funding from Astellas. Simon J. Crabb—research funding and honoraria from Roche, MSD, Pfizer, Exelixis, and Clovis. Michiel S. Van Der Heijden—research funding and honoraria from BMS, AstraZeneca, MSD, Novartis, Pfizer, MSD, and Seattle Genetics. Albert Font Pous—research funding and honoraria from MSD, Pfizer, and Astellas. Gwenaelle Gravis—research funding and honoraria from Roche, AstraZeneca, Pfizer, and Astellas. Urbano Anido Herranz—research funding and honoraria from Roche, MSD, Exelixis, and Astellas. Andrew Prothoroe—research funding and honoraria from Astellas, Pfizer, Novartis, and BMS. Alain Ravaud—research funding and honoraria from MSD, Roche, BMS, and Pfizer. Denis Maillet—research funding and honoraria from MSD and Roche. Maria Jose Mendez—research funding and honoraria from Roche and Pfizer. Cristina Suarez—research funding and honoraria from Pfizer, BMS, Roche, AstraZeneca, and Astellas. Mark Linch—research funding and honoraria from BMS, Roche, Pfizer, Astellas, and AstraZeneca. Aaron Prendergast and Charlotte Tyson—no conflicts. Diana Stanoeva, Sofie Daelemans, and Miche Rombouts— employee of CellCarta. Sanjeev Mariathasan—employee of Genentech. Joy S. Tea—employee of Roche. Kelly Mousa—no conflicts. Romain Banchereau—employee of Genentech. Daniel Castellano—research funding and honoraria from Astellas, BMS, Roche, and AstraZeneca. Thomas Powles—honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; research funding from AstraZeneca, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; travel/accommodation/expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen.

Background Despite years of slow progress, muscle invasive bladder cancer (MIBC) is finally entering the era of molecularly guided targeted therapy. However, tumor heterogeneity is high in MIBC and may impact treatment response and resistance. The objective of this review is to dissect recent insights into inter- and intratumor heterogeneity (ITH) in MIBC, with emphasis on the clinical implications of this heterogeneity for biomarker-driven strategies and the development of new therapies. Methods A nonsystematic review was performed in PubMed and EMBASE using the terms “tumor heterogeneity” and “bladder cancer.” Results Intertumor heterogeneity, as reflected by different clinical phenotypes in different patients, has been partially explained with next generation sequencing and other molecular profiling technologies. RNA-based molecular subtyping, for example, provides a classification of MIBC into distinct categories that can be used for further molecular analysis, biomarker discovery, risk stratification, and treatment selection. Molecular subtyping and specific genomic alterations, especially in DNA damage repair genes, may help explain why some patients respond better to systemic chemotherapy and immunotherapy. Conversely, spatial and temporal ITH threaten to confound attempts to target specific molecular lesions since not all tumor cells within a patient may carry the relevant lesion. Improved understanding and management of ITH is required for the most effective use of biomarker-driven targeted therapies. Conclusion Strategies to assess and overcome intertumor and ITH in MIBC will be critical steps toward realizing the objectives of precision oncology. Novel techniques such as analysis of circulating tumor DNA and single cell sequencing are likely to revolutionize our understanding of tumor heterogeneity.

miRNA (miR)-4742-5p is a recently identified microRNA regarding progression and metastasis in gastric cancer (GC). However, the biological function of this novel miRNA is largely unknown. We identified that the miR-4742-5p expression level was variably increased in GC cell lines. Suppression of miR-4742-5p using miR-inhibitor reduced the proliferation, migration, and invasion of GC cells with high miR-4742-5p expression, whereas overexpression of miR-4742-5p-mimic enhanced the aforementioned properties in GC cells with low miR-4742-5p expression. miR-4742-5p expression induced the decreases of Zo-1 and E-cadherin expression as well as the increases of vimentin and N-cadherin expression, leading to epithelial-mesenchymal transition (EMT) of cancer cells. RNA sequencing results indicated Ras-related GTP-binding protein 43 (Rab43) as a potential target gene. We identified that the expression of Rab43 is associated with activation of AKT and nuclear factor-kappa B (NF-κB) which are key oncogenic pathways in cancer cells. Our results demonstrate a new component in GC progression, promising a potential therapeutic strategy.

Cell surface hyaluronidase transmembrane protein 2 (TMEM2), which also serves as a reportedly functions in malignancy of several solid tumors. However, TMEM2 involvement in bladder cancer (BCa) is unknown. Therefore, we investigate potential changes in expression of TMEM2 during BCa invasion and over the course of the epithelial mesenchymal transition (EMT). Immunohistochemical analysis of 127 clinical specimens revealed that TMEM2 expression changed with pathological stage (pT) and infiltration pattern (INF) and was highest in pTa-pT1 of INFa tumors and significantly lower at stages from pTa-pT1 to pT2 or 3 in INFb or INFc. E-cadherin expression was highest in INFa and lowest in INFc, a pattern comparable to TMEM2 expression. TMEM2 protein expression analysis of BCa cell lines showed that muscle-invasive T24 and YTS-1 cells with low TMEM2 expression exhibited EMT phenotypes in vitro, in contrast to high TMEM2-expressing non-muscle invasive RT4 cells. EMT-induced non-muscle invasive RT4 cells also showed significantly decreased plasma membrane expression of TMEM2. Our data suggested TMEM2 expression is higher in non-invasive cancers, whereas invasive cancer cells are less likely to express TMEM2 during muscle-invasion and "partial EMT".

Docetaxel and gemcitabine have different mechanisms of action, are well tolerated as monotherapies, and are affordable. This combination represents a good option for the second-line, bladder-preserving standard of care for non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guérin.

The goal of the study described here was to define the predictive value of pre-operative clinical information and contrast-enhanced ultrasound (CEUS) imaging characteristics in combined hepatocellular-cholangiocarcinoma (CHC) patients with microvascular invasion (MVI). Seventy-six patients with pathologically confirmed CHC were enrolled in this study, comprising 18 patients with MVI-positive status and 58 with MVI-negative CHC nodules. The pre-operative clinical data and CEUS imaging features were retrospectively analyzed. Univariate and multivariate analyses were performed to identify the potential predictors of MVI in CHC. Recurrence-free survival (RFS) after hepatectomy was compared between patients with different MVI status using the log-rank test and Kaplan-Meier survival curves. Univariate analysis indicated that the following parameters of patients with CHC significantly differed between the MVI-positive and MVI-negative groups (p0.05): tumor size, α-fetoprotein ≥400 ng/mL, enhancement patterns in arterial phase and marked washout during the portal venous phase on CEUS. On multivariate logistic regression analysis, only the CEUS characteristics of heterogeneous enhancement (odds ratio = 6.807; 95% confidence interval [CI]: 1.099, 42.147; p = 0.039) and marked washout (odds ratio = 4.380; 95% CI: 1.050,18.270; p = 0.043) were identified as independent predictors of MVI in CHC. The combination of the two risk factors in predicting MVI achieved a better diagnostic performance than each parameter alone, with an area under the receiver operating characteristic curve of 0.736 (0.622, 0.830). After hepatectomy, CHC patients with MVI exhibited earlier recurrence compared with those without MVI (hazard ratio = 1.859; 95% CI: 0.8699-3.9722, p = 0.046). The CEUS imaging features of heterogeneous enhancement in the arterial phase and marked washout during the portal venous phase were the potential predictors of MVI in CHC. Aside from that, CHC patients with MVI had an earlier recurrence rate than those without MVI after surgery.

Colorectal cancer (CRC) outcomes vary depending on tumour biology, with several features used to predict disease behaviour. Extramural venous invasion (EMVI) is associated with negative outcomes and its presence has been established as an indicator of more aggressive disease in CRC.A prospectively maintained database was examined for patients undergoing curative resection for non-metastatic CRC between 2012 and 2018 in a tertiary institution. Clinicopathological factors were compared to assess their impact on recurrence, all-cause mortality and cancer-related death. Kaplan Meier analysis of the association between EMVI and these endpoints was performed, and univariable and multivariable analysis was carried out to establish the relationship of predictive factors in oncological outcomes.Eighty-eight (13.5%) of 654 patients developed recurrence. The mean time to recurrence was 19.8 ± 13.5 months. There were 36 (5.5%) cancer-related deaths at a mean duration of follow-up of 46.3 ± 21.6 months. Two hundred and sixty-six patients had extramural venous invasion (40.7%). EMVI was significantly associated with reduced overall recurrence-free survival, systemic recurrence-free survival, and increased cancer-related death on univariate analysis (p 0.001 for all, Fig. 1), and multivariable analysis (OR 1.8 and 2.1 respectively, p 0.05 for both).EMVI is associated with a poor prognosis, independent of stage, nodal status and other histopathological features. The presence of EMVI should be strongly considered as an indication for adjuvant therapy.

This study aimed to evaluate intercellular bridges in the depth of invasion (DOI) measurement area as prognostic factors in oral squamous cell carcinoma (OSCC).The mode of invasion was determined based on the Yamamoto-Kohama classification system by observing the hematoxylin-eosin-stained whole-slide images of specimens obtained from 78 patients with OSCC, and the clinicopathologic features were characterized. The presence of intercellular bridges was analyzed in 46 patients with Yamamoto-Kohama classification grade ≥3 whose DOI was measured by dividing the measurement area into 3 parts: the surface, center, and front of the tumor.Univariate analyses identified lymph node metastasis, loss of intercellular bridges in the DOI measurement area, DOI of ≥4500 µm, and pattern of invasion 4C-4D as negative prognostic factors. Multivariate analyses revealed that lymph node metastasis and the loss of intercellular bridges in the entire area were independent factors, with hazard ratios of 9.34 (95% confidence interval, 2.09-42.03; P = .003) and 3.64 (95% confidence interval, 1.10-11.99; P = .045), respectively.Loss of intercellular bridges in the DOI measurement area is a negative prognostic factor for OSCC and may be useful in selecting treatment.

Conflicting evidence exists regarding the role of adjuvant therapy for Invasive Intraductal Papillary Mucinous Neoplasms (i-IPMN). This meta-analysis assessed whether adjuvant therapy improves Overall Survival (OS) in patients with resected i-IPMN.A systematic review and meta-analysis was performed. The primary endpoint was the effect of adjuvant therapy on OS. Secondary endpoint evaluated adjuvant therapy with regard to nodal disease, positive resection margins, tumour grade and differentiation. A meta-analysis of pooled hazard ratios (HRs) with an inverse variance and a random-effects model was performed. Risk of bias was determined with the GRADE approach and MINORS criteria.Ten articles with a total of 3252 patients were included. No statistically significant difference in the OS was noted with adjuvant therapy for i-IPMN in the entire cohort (HR = 1; 95% CI = 0.75-1.35; P = 0.98). However, a survival benefit was noted in a subgroup of patients with an aggressive disease phenotype; nodal involvement (HR = 0.56; 95% CI = 0.39-0.79; P = 0.001) and advanced staged tumours (≥stage 2, HR = 1.42; 95% CI = 1.11-1.82; P = 0.005) CONCLUSIONS: The concurrent evidence base for adjuvant therapy for i-IPMN is limited. After acknowledging the limitations of the data, the current literature suggests that adjuvant therapy should be reserved for patients with resected i-IPMN that have adverse tumour biology.

Patients factors in addition to radiological characteristics could predict the presence of pathologic venous invasion in patients undergoing pancreatectomy with venous resection.We tested the predictive value of 6 radiological classification methods for predicting pathologic venous invasion-the Nakao, Ishikawa, MD Anderson, Lu, Raptopoulos, and National Comprehensive Cancer Network methods-on a cohort of 198 pancreatectomies (160 pancreaticoduodenectomies and 38 total pancreatectomies) with venous resection for pancreatic adenocarcinomas. Radiological and clinical factors determining pathologic venous invasion were identified by multivariable logistic analysis.Pathologic venous invasion was detected in 124 patients (63.2%). The multivariable logistic regression analysis identified Lu classification (odds ratio = 1.77, 95% confidence interval =1.34-2.35; P.0001), elevated serum CA19-9 values (odds ratio = 1.97, 95% confidence interval = 1.00-3.90; P = .04), and preoperative neoadjuvant chemotherapy (odds ratio = 0.38, 95% confidence interval = 0.18-0.79; P = .009) as independent factors associated with pathologic venous invasion. Radiological tumor-vessel contact greater than 50% of the circumference or venous wall deformity was associated with a significantly higher rate of pathological venous invasion (80% vs 52%; P.0001), deeper (media-intima) venous invasion (47% vs 25%; P.0001), R1 resection (58% vs 41%; P = .03), higher transfusions (84% vs 66%; P = .005), and arterial resection rates (43% vs 27%; P.0001). Tumor-vein circumference contact of50% and/or venous wall deformity was still associated with significantly higher rates of pathologic venous invasion, regardless of whether neoadjuvant chemotherapy was used or not and CA19-9 normalized or not under preoperative treatment.Preoperative radiological detection of tumor-vein circumference contact50% and/or venous wall deformity is associated with up to 80% of cases of pathological venous invasion. The combination of radiologic features with biological (CA19-9) and clinical (presence of preoperative chemotherapy) factors could better refine preoperatively the need for venous resection.

The aim of this study was to assess the relevance of highlighting T1a invasive intraductal papillary mucinous carcinoma as a separate subcategory and to compare the tumor biology between invasive intraductal papillary mucinous carcinoma and pancreatic ductal adenocarcinoma.A total of 144 and 328 consecutive patients with intraductal papillary mucinous neoplasms and pancreatic ductal adenocarcinoma, respectively, were analyzed.Patients with T1a invasive intraductal papillary mucinous carcinoma comprised 25% (11/44) of the overall subject population with invasive intraductal papillary mucinous carcinoma with 5-year disease-specific survival rate being 100%. None of the patients with pancreatic ductal adenocarcinoma were classified as having T1a disease. When patients with invasive intraductal papillary mucinous carcinoma and pancreatic ductal adenocarcinoma were compared after excluding patients with T1a invasive intraductal papillary mucinous carcinoma, the 5-year disease-specific survival rates were 63% vs 40% in node-negative status (P = .018); and they were 20% vs 13% in node-positive status (P = .385). Subsequent analyses revealed that this survival superiority was limited to patients without evidence of lymphatic invasion.T1a invasive intraductal papillary mucinous carcinoma is a clinical entity specifically observed in patients with intraductal papillary mucinous carcinoma, but not in patients with pancreatic ductal adenocarcinoma, and is associated with excellent postoperative survival outcomes. In the survival comparison after exclusion of patients with T1a tumors, when the analysis was limited to patients without lymphatic invasion or lymph node metastasis, the disease-specific survival rate remained higher in patients with invasive intraductal papillary mucinous carcinoma compared with those with pancreatic ductal adenocarcinoma, and this difference was considered as being attributable to the intrinsic indolent biological behavior of invasive intraductal papillary mucinous carcinoma. However, this survival advantage was lost once lymphatic invasion occurred.

To investigate the clinical application of novel dual-layer spectral detector computed tomography (CT) for differentiating the invasiveness of pure ground-glass nodules (pGGNs).A total of 42 patients with 43 pGGNs, who underwent preoperative dual-layer spectral detector CT and were identified by pathology, were evaluated retrospectively. The nodules were divided into two groups: minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Lesion inhomogeneity was observed visually on the iodine density map. Normalised iodine concentrations (NICs) in the arterial and venous phases and the effective atomic number (ZThere were significant differences in the maximum diameter, CT attenuation value, ED and the ED-Zeff ratio in three phase, ZNovel dual-layer spectral detector CT can indicate the invasiveness of pGGNs. Lesion inhomogeneity and the ratio of the ED to Z

The presence of lymph node metastasis plays a decisive role in the selection of treatment options in patients with early gastric cancer. However, there is currently no established protocol to predict the risk of lymph node metastasis before/after endoscopic resection. The aim of this study was to develop and validate several machine learning algorithms for clinical practice.A total of 2,348 patients with early gastric cancer were selected from 5 major tertiary medical centers. We applied 6 machine learning algorithms to develop lymph node metastasis prediction models for clinical feature variables. The partial dependence plots were used to explain the prediction of the models. The area under the receiver operating characteristic curve and area under the precision recall curve were measured to assess the detection performance. The R shiny interactive web application was used to translate the prediction model in a clinical setting.The incidence of lymph node metastasis in patients with early gastric cancer was 13.63% (320/2348) and significantly higher in young women, in the lower third of the stomach, with a size2 cm, depressed type, poorly/nondifferentiated, lymphovascular invasion, nerve invasion, and submucosal infiltration. In terms of age, there is a nonlinear and younger trend. XGBOOST displayed the best predictive performance at the initial and postendoscopy evaluation. In addition, the machine learning algorithm was converted to a user-friendly web tool for patients and clinicians.XGBOOST can predict the risk of lymph node metastasis with best accuracy in patients with early gastric cancer. Our online web application may help determine the optimal best surgical option for patients with early gastric cancer.

Background and study aims Data from Japanese series show that surface morphology of laterally spreading tumors (LST) in the colon identifies lesions with different incidence and pattern of submucosal invasion. Such data from western countries are scarce. We compared clinical and histological features of LST in a western country and an eastern country, with special interest on mucosal invasiveness of LST, and investigated the effect of clinical factors on invasiveness in both countries. Patients and methods Patients with LST lesions ≥20 mm were included from a multicenter prospective registry in Spain and from a retrospective registry from the National Cancer Center Hospital East, Japan. The primary outcome was the presence of submucosal invasion in LST. The secondary outcome was the presence of high-risk histology, defined as high-grade dysplasia or submucosal invasion. Results We evaluated 1102 patients in Spain and 663 in Japan. Morphological and histological characteristics differed. The prevalence of submucosal invasion in Japan was six-fold the prevalence in Spain (Prevalence Ratio PR = 5.66; 95%CI: 3.96, 8.08), and the prevalence of high-risk histology was 1.5 higher (PR = 1.44; 95%CI: 1.31, 1.58). Compared to the granular homogeneous type and adjusted by clinical features, granular mixed, flat elevated, and pseudo-depressed types were associated with higher odds of submucosal invasion in Japan, whereas only the pseudo-depressed type showed higher risk in Spain. Regarding high-risk histology, both granular mixed and pseudo-depressed were associated with higher odds in Japan, compared with only the granular mixed type in Spain. Conclusion This study reveals differences in location, morphology and invasiveness of LST in an eastern and a western cohort.

Objective : The objective of this study was to evaluate CELSR3 expression and explore its potential mechanism in oral squamous cell carcinoma. Study design : CELSR3 mRNA expression was analyzed using The Cancer Genome Atlas (TCGA) database. CELSR3 protein expression in 135 surgical oral squamous cell carcinoma specimens was observed by immunohistochemical staining. Staining results were used to investigate association between CELSR3 expression and clinicopathological characteristics and prognosis. Bioinformatics analyses were used to explore the potential mechanism of CELSR3 in head and neck squamous cell carcinoma. Results : CELSR3 mRNA expression was upregulated in patients with head and neck squamous cell carcinoma in the TCGA-HNSC dataset. Increased CELSR3 protein expression was associated with perineural invasion and poor clinical outcomes in oral squamous cell carcinoma patients. Bioinformatics analyses revealed that CELSR3 is involvement in axonogenesis, neuron migration and cell-cell adhesion, all of which are involved in the process of perineural invasion. Conclusion : CELSR3 may play a pro-oncogenic role in oral squamous cell carcinoma and can predict perineural invasion and poor survival. CELSR3 may be involved in oral squamous cell carcinoma progression by modulating perineural invasion.

Background Lymphovascular invasion (LVI) is an aggressive histologic finding but is excluded from current staging systems due to lack of demonstrated independent prognostic significance. Objective To evaluate the impact of LVI on CSCC tumor outcomes. Methods 10,707 CSCC tumors from a 20-year retrospective multicenter cohort were stratified by presence (LVI+) or absence (LVI-) of LVI. Outcomes (local recurrence, in transit metastasis, nodal metastasis, disease specific death) were compared based on low (Brigham and Women’s Hospital (BWH) stage T1/T2a) and high (BWH T2b/T3)-tumor stage. Results Of the 10,707 tumors, 78 tumors had LVI. Analysis of low-stage BWH tumors showed the LVI+ group had a significantly higher 5-year cumulative incidence of LR (LVI+: 12.3% vs. LVI-: 1.1%, p Limitations Retrospective study design. Conclusion LVI+ CSCCs have a higher rate of metastasis and death at 5-years. Future staging systems should consider incorporating LVI.

Glioblastoma is a lethal, diffusely invasive brain cancer that is robustly regulated by the activity of the brain itself, in part through neuron-to-glioma synaptic communication. Venkataramani et al. have conceptually advanced understanding of glioblastoma interactions with neural circuits, demonstrating that conduction of electrochemical signals via neuron-to-glioma synapses drives glioma invasion.

The use of sequential intravesical instillation of gemcitabine and docetaxel in the management of bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer should not be recommended as a second-line treatment. First, technical issues are a barrier to broad adoption of this strategy. Second, the low level of evidence supporting this treatment remains weak and needs proper assessment.

Patients with early-stage lung cancer who underwent R0 resection often encounter disease recurrence, especially during the early phase; thus, it is deemed vital to determine the predictive factors for recurrence after surgery. In this study, we aimed to identify the independent variables associated with recurrence after complete surgical resection of pathological stage I lung adenocarcinoma.We retrospectively reviewed the medical records of 169 patients who underwent pulmonary resection for primary lung adenocarcinoma pathological stage I with curative intent lung cancer surgery from 2015 to December 2018 at our institution for information on the recurrence of the disease.Per the multivariate analysis, the presence of micropapillary pattern and vessel invasion were found to be independent predictors of disease recurrence after surgery (odds ratio [OR]: 9.36, 95% confidence interval [CI]: 2.42-36.2, P = 0.0012; and OR: 4.50, 95% CI: 1.52-13.4, P = 0.0068, respectively). Vessel invasion was also found to be an independent predictor of disease recurrence after surgery within a year (OR 11.4, 95% CI 3.08-42.5, P = 0.0003).The presence of vessel invasion may help in distinguishing patients with the highest risk of early-phase disease recurrence after surgery. Patients with stage I adenocarcinoma with vessel invasion should undergo intensive surveillance after surgery.

MT1-MMP plays a crucial role in promoting the cellular invasion of cancer cells by degrading the extracellular matrix to create a path for migration. During this process, its localization at the leading edge of migrating cells is critical, and it is achieved by targeted transport of MT1-MMP-containing vesicles along microtubules by kinesin superfamily motor proteins (KIFs). Here we identified three KIFs involved in MT1-MMP vesicle transport: KIF3A, KIF13A, and KIF9. Knockdown of KIF3A and KIF13A effectively inhibited MT1-MMP-dependent collagen degradation and invasion, while knockdown of KIF9 increased collagen degradation and invasion. Our data suggest that KIF3A/KIF13A dependent MT1-MMP vesicles transport takes over upon KIF9 knockdown. Live-cell imaging analyses have indicated that KIF3A and KIF13A coordinate to transport the same MT1-MMP-containing vesicles from the trans-Golgi to the endosomes, and KIF13A alone transports the vesicle from the endosome to the plasma membrane. Taken together, we have identified a unique interplay between three KIFs to regulate leading edge localization of MT1-MMP and MT1-MMP-dependent cancer cell invasion.

The aim of the present study was to investigate the imaging features observed in pre-operative Sonazoid contrast-enhanced ultrasound (SZ-CEUS) and the correlations with the presence of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients. In this single-center retrospective study, 31 patients with surgically and histopathologically confirmed HCC lesions were included. Patients were classified according to the presence of MVI into the MVI-positive group (n = 15) and MVI-negative group (n = 16). The CEUS examinations were performed within 2 or 3 d before surgery. Features, including tumor necrosis and ultrasound contrast agent (UCA) distribution characteristics in the arterial phase (AP), tumor types (single nodular [SN] or non-single nodular [non-SN]) in the post-vascular phase (PVP), wash-in time, wash-in slope, time to peak (TTP) and peak intensity (PI), were assessed. Univariate analysis revealed statistically significant differences between the two groups with respect to tumor necrosis (p = 0.002), inhomogeneous distribution of contrast agent in the AP (p = 0.001) and non-SN type in the PVP (p0.001). There was no significant difference in the quantitative parameters. Multivariate analysis revealed that non-SN type in the PVP was a significant independent risk factor for MVI of HCC (odds ratio = 30.51, 95% confidence interval [CI]: 2.335-398.731, p = 0.009). The area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.873, 93.3%, 81.3%, 82.4% and 92.9%, respectively. Thus, SZ-CEUS can provide useful information for the diagnosis of MVI in HCC.

To determine whether magnetic resonance imaging volumetry on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) could be used to assess lymph node metastases (LNM) and lymphovascular invasion (LVSI) in resectable cervical cancer.Sixty-five consecutive patients with cervical cancer were enrolled retrospectively. Tumour size, including maximum transverse diameter, tumour length, and gross tumour volume (GTV), was evaluated on DWI and T2WI. Apparent diffusion coefficient (ADC) values were measured. Univariate, multivariate, and receiver operating characteristic (ROC) curve analyses were performed to determine whether tumour size and ADC could be used to assess LNM and LVSI.Tumour length on both T2WI and DWI, and T2WI-based and DWI-based GTVs could be used to assess LNM (p=0.002, 0.004, 0.001, and0.001, respectively). Tumour length on T2WI, T2WI-based GTV, DWI-based GTV, and ADC value could be used assess LVSI (p=0.039, 0.038, 0.012, 0.039, respectively). Multivariate analyses showed both T2WI-based GTV (odds ratio [OR] = 1.044; p=0.008) and DWI-based GTV (OR=1.941; p=0.019) were independent risk factors for LNM. T2WI-based GTV (OR=1.023, p=0.038) and DWI-based GTV (OR=3.275, p=0.008) were independent risk factors for LVSI. No statistically significant difference was identified between the area under the ROC curve (AUC) of the DWI-based GTV and the T2WI-based GTV (0.790 versus 0.775, p=0.113), or the tumour length on both T2WI (0.790 versus 0.734, p=0.185) and DWI (0.790 versus 0.737, p=0.333) for LNM. For LVSI, the AUC of DWI-based GTV was higher than T2WI-based GTV (0.720 versus 0.682, p=0.006).GTV on both T2WI and DWI could be used assess LNM and LVSI. DWI-based GTV might show the greatest potential for assessing LNM and LVSI in resectable cervical cancer.

Spread through air spaces (STAS) is reportedly associated with worse prognosis in sublobar resections of lung adenocarcinoma. Recently, it was proposed that STAS detected on frozen sections can be an indication for lobectomy instead of sublobar resection. We undertook this study to evaluate the reliability of STAS assessment on frozen sections compared to permanent sections, as well as the associations among STAS, tumor grade, and recurrence-free survival (RFS) after sublobar resection. A total of 163 stage I lung adenocarcinoma resections with frozen sections were identified retrospectively. For each case, and for frozen and permanent sections separately, the presence or absence of STAS, as well as the tumor grade, were recorded. Compared to permanent sections, STAS detection on frozen sections had low sensitivity (55%), low positive predictive value (48%), and fair agreement (K = 0.34), whereas there was higher specificity (80%) and negative predictive value (85%). Accuracy was 74%. Tumor grade assessment on frozen sections showed higher sensitivity (77%), positive predictive value (90%), agreement (K = 0.72), specificity (94%), and accuracy (87%), and the same negative predictive value (85%). High-grade histology on frozen sections was associated with shorter RFS (p = 0.02), whereas STAS on frozen sections was not (p = 0.47). Our results suggest that the intraoperative detection of STAS has low sensitivity and positive predictive value. False-positive results may lead to overtreatment of patients with lung cancer. The determination of tumor grade on frozen sections offers better sensitivity and specificity, plus it is associated with RFS, whereas STAS on frozen sections is not. Further study is needed to explore the utility of assessing tumor grade on frozen sections.

Despite being standard tools for decision-making, the European Organisation for Research and Treatment of Cancer (EORTC), European Association of Urology (EAU), and Club Urologico Espanol de Tratamiento Oncologico (CUETO) risk groups provide moderate performance in predicting recurrence-free survival (RFS) and progression-free survival (PFS) in non-muscle-invasive bladder cancer (NMIBC). In this retrospective combined-cohort data-mining study, the training group consisted of 3570 patients with de novo diagnosed NMIBC. Predictors included gender, age, T stage, histopathological grading, tumor burden and diameter, EORTC and CUETO scores, and type of intravesical treatment. The models developed were externally validated using an independent cohort of 322 patients. Models were trained using Cox proportional-hazards deep neural networks (deep learning; DeepSurv) with a proprietary grid search of hyperparameters. For patients treated with surgery and bacillus Calmette-Guérin-treated patients, the models achieved a c index of 0.650 (95% confidence interval [CI] 0.649-0.650) for RFS and 0.878 (95% CI 0.873-0.874) for PFS in the training group. In the validation group, the c index was 0.651 (95% CI 0.648-0.654) for RFS and 0.881 (95% CI 0.878-0.885) for PFS. After inclusion of patients treated with mitomycin C, the c index for RFS models was 0.6415 (95% CI 0.6412-0.6417) for the training group and 0.660 (95% CI 0.657-0.664) for the validation group. Models for PFS achieved a c index of 0.885 (95% CI 0.885-0.885) for the training set and 0.876 (95% CI 0.873-0.880) for the validation set. Our tool outperformed standard-of-care risk stratification tools and showed no evidence of overfitting. The application is open source and available at https://biostat.umed.pl/deepNMIBC/. PATIENT SUMMARY: We created and validated a new tool to predict recurrence and progression of early-stage bladder cancer. The application uses advanced artificial intelligence to combine state-of-the-art scales, outperforms these scales for prediction, and is freely available online.

The treatment landscape for advanced urothelial cancer has changed dramatically owing to the US Food and Drug Administration approval and introduction of antibody-drug conjugates (ADCs), including enfortumab vedotin and sacituzumab govitecan. Efforts have begun to use these therapies in earlier disease states, specifically bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). We assessed gene expression associated with these newly approved therapies in a novel cohort of treatment-naïve NMIBC tumors before and after BCG therapy. Multiple genes, including Nectin-4, Trop-2, and Her-2, exhibited increased expression after BCG therapy compared to baseline. However, few of the tumors with increased expression of ADC targets also exhibited increased PD-L1/PD-1 expression. Taken together, these data demonstrate the heterogeneous genomic landscape of BCG-exposed NMIBC, and provide evidence supporting the evaluation of ADCs in NMIBC. PATIENT SUMMARY: We evaluated the potential role of targeted therapies that have been approved in the USA for advanced non-muscle-invasive bladder cancer (NMIBC) that has recurred after treatment with bacillus Calmette-Guérin (BCG). By assessing levels of specific genes and proteins linked to the targeted therapies, we demonstrate that there is rationale for further evaluation of these therapies in NMIBC.

The 2021 European Association of Urology (EAU) guidelines contain updated prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC). These groups are based on the following predictors of progression: tumour stage, grade, number, and size; concomitant carcinoma in situ; and age. However, the groups were derived from datasets excluding patients treated with bacillus Calmette-Guérin (BCG).To determine the validity of the updated EAU prognostic factor risk groups in patients with NMIBC treated with BCG.We reviewed patients treated with BCG at our institution between 2000 and 2018. Patients were analysed according to the receipt of "at least induction" and "adequate" BCG (as defined by the US Food and Drug Administration). Risk groups were assigned according to the 2021 EAU NMIBC risk calculator (https://nmibc.net/).The Kaplan-Meier method was used to estimate the risks of progression at 1 and 5 yr. Probabilities of progression obtained with the updated prognostic factor risk groups in our series were compared with those reported by the EAU. Discrimination was assessed using the concordance index (c-index).A total of 529 patients received at least induction BCG with a median follow-up of 47.3 mo (interquartile range 25.3-86.9). Of these patients, 494 received adequate BCG. We found lower progression rates at 1 yr in the very-high-risk group patients receiving at least induction (6.9%) and adequate BCG (4.0%) versus 16.0% for the EAU predicted rates. Additionally, progression rates were also lower at 5 yr in the high-risk group-7.4% for at least induction and 5.3% for adequate BCG versus 9.6% for EAU predicted rates; the rates in the very-high-risk group were as follows: 16.7% for at least induction and 14.9% for adequate BCG versus 40.0% for EAU predicted rates. The c-index in our series was lower than that reported by the EAU (0.63 vs 0.80). Of interest, our multivariable analysis identified grade, stage, and age (p0.02) to be the predictors of progression after BCG therapy.While the 2021 EAU prognostic factor risk groups successfully stratified progression risks in our cohort, treatment with BCG reduced their discriminative ability. Furthermore, the groups overestimate progression risks in BCG-treated patients. These findings should be used in conjunction with the updated risk groups to counsel patients with higher-risk NMIBC about their risk of progression with and without BCG.Although the updated European Association of Urology prognostic factor risk groups are able to stratify patients with non-muscle-invasive bladder cancer according to their risk of progression to muscle-invasive bladder cancer, this risk is overestimated in patients treated with bacillus Calmette-Guérin (BCG).

Background Hepatocellular carcinoma (HCC) is usually diagnosed at late stages, making it the second cause of malignancy-related death across the world. Long noncoding RNAs (lncRNAs) are of significance to tumorigenesis, highly suggestive of their functional roles as novel biomarkers for cancer therapy. The current study investigated the specific role of lncRNA TPTE pseudogene 1 (TPTEP1) in HCC. Methods Expression of lncRNA TPTEP1, microRNA-454-3p (miR-454-3p) and discs large homolog 5 (DLG5) was determined in tissues samples from the recruited patients with HCC. Cell proliferation, migration and invasion assays were performed to determine effects of lncRNA TPTEP1, miR-454-3p and DLG5 on the malignant phenotype of tumor cells. Finally, the mouse HCC model was also established to disclose the tumor suppressor effects of lncRNA TPTEP1 in vivo. Results LncRNA TPTEP1 was downregulated both in HCC cells and tissues, and played a negative regulatory role in HCC cell proliferation, migration and invasion. Mechanistically, lncRNA TPTEP1 competitively bound to miR-454-3p, thereby upregulating its endogenous target DLG5. Moreover, lncRNA TPTEP1 hindered activation of the protein kinase B signaling pathway, causing inhibited malignant phenotypes of HCC cells. Also, lncRNA TPTEP1 suppressed tumor growth and extrahepatic metastasis (lung) via miR-454-3p/DLG5 axis. Conclusion Taken together, this research revealed a concrete mechanism of lncRNA TPTEP1 in HCC.

Purpose Head and neck cancer is often associated with pain and perineural invasion (PNI). The purpose of this study was to determine the association of pain complaints and the microscopic identification of PNI in patients with oropharyngeal squamous cell carcinoma (OPSCC). Patients and Methods A retrospective cohort study was performed including patients diagnosed with OPSCC from 2010 to 2019. Patients diagnosed and operated on with curative intent at 2 institutions were included. The primary predictor variable was pain (measured as no pain, ear pain, throat pain, or simultaneous pain). Other variables were patient demographics, p16 status, and TNM staging. The primary outcome variable was the histologic presence of PNI. Chi-square analysis was performed to test for any significant associations between pain, T stage, overall stage, and p16 status in relation to PNI outcome. Multivariate logistic regression analysis was used to control for cancer staging variables when testing the association between pain and PNI. Results The final sample was composed of 157 subjects of whom 126 were men. The mean age was 59.7 years. Seventy-seven (49.0%) presented with no pain, while 35 (22.3%), 39 (24.8%), and 6 (3.8%) presented with both throat/ear pain, throat pain only, and ear pain only, respectively. Patients with simultaneous pain had 3.41 times higher odds of PNI compared to the no pain group (P = .02), although only pathologic T stage 4 and a diagnosis on the base of the tongue were independent postoperative predictors of PNI (P Conclusions Our study demonstrates that otalgia is a preoperative predictor of PNI in OPSCC and also demonstrates a trend of increasing pain complaints with PNI.