Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer.

PURPOSE: Rescue intravesical therapies for patients with bacillus Calmette-Guérin failure nonmuscle invasive bladder cancer remain a critical focus of ongoing research. Sequential intravesical gemcitabine and docetaxel therapy has shown safety and efficacy in 2 retrospective, single institution cohorts. This doublet has since been adopted as an intravesical salvage option at multiple institutions. We report the results of a multi-institutional evaluation of gemcitabine and docetaxel. MATERIALS AND METHODS: Each institution retrospectively reviewed all records of patients treated with intravesical gemcitabine and docetaxel for nonmuscle invasive bladder cancer between June 2009 and May 2018. Only patients with recurrent nonmuscle invasive bladder cancer and a history of bacillus Calmette-Guérin treatment were included in the analysis. If patients were disease-free after induction, maintenance was instituted at the treating physician's discretion. Posttreatment surveillance followed American Urological Association guidelines. Survival analysis was performed using the Kaplan-Meier method and risk factors for treatment failure were assessed with Cox regression models. RESULTS: Overall 276 patients (median age 73 years, median followup 22.9 months) received treatment. Nine patients were unable to tolerate a full induction course. One and 2-year recurrence-free survival rates were 60% and 46%, and high grade recurrence-free survival rates were 65% and 52%, respectively. Ten patients (3.6%) had disease progression on transurethral resection. Forty-three patients (15.6%) went on to cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasion. Analysis identified no patient, disease or prior treatment related factors associated with gemcitabine and docetaxel failure. CONCLUSIONS: Intravesical gemcitabine and docetaxel therapy is well tolerated and effective, providing a durable response in patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin therapy. Further prospective study is warranted.

Clinical significance of urothelial carcinoma ambiguous for muscularis propria invasion on initial transurethral resection of bladder tumor.

PURPOSE: To evaluate the clinical significance of invasive urothelial carcinoma that is ambiguous for muscularis propria invasion on initial transurethral resection of bladder tumor (TURBT). METHODS: All consecutive in-house TURBTs with invasive urothelial carcinoma from 1999 to 2017 that underwent radical cystectomy (RC) were grouped as follows: invasion of the lamina propria (INLP; n = 102; 24%), invasion of muscularis propria (INMP; n = 296; 69%) and ambiguous for muscularis propria invasion (AMP; n = 30; 7%). AMP was defined as extensive invasive carcinoma displaying thin muscle bundles where it is difficult to determine with certainty if those muscle bundles represent muscularis mucosae or muscularis propria (detrusor). Cases with any amount of small cell carcinoma or prior therapy were excluded. RESULTS: The average age was 66 years in INLP, 67 years in INMP, and 65 years in AMP. RC showed invasive carcinoma stage pT2 or above in 50/102 (49%) of INLP vs. 255/296 (86%) of INMP (P ≤ 001) vs. 25/30 (83.33%) of AMP (P = 0.002). Lymph nodes showed metastatic carcinoma in 18/98 (18.36%) of INLP vs. 96/272 (35.29%) of INMP (P = 0.002), and 6/25 (24%) in AMP (P = 0.729). The average follow-up was 48 months (range 0-192). Survival of AMP patients was similar to INLP and both were significantly better than INMP (P = 0.002 and P = 0.016). CONCLUSION: The great majority of patients with AMP on initial TURBT have advanced disease on RC and emphasizes the need for early repeat TURBT or even consideration of early cystectomy to lower the risk of worse pathological findings and to prolong survival.

Computed tomography-based radiomics diagnostic approach for differential diagnosis between early- and late-stage pancreatic ductal adenocarcinoma.

BACKGROUND: One of the primary reasons for the dismal survival rates in pancreatic ductal adenocarcinoma (PDAC) is that most patients are usually diagnosed at late stages. There is an urgent unmet clinical need to identify and develop diagnostic methods that could precisely detect PDAC at its earliest stages. AIM: To evaluate the potential value of radiomics analysis in the differentiation of early-stage PDAC from late-stage PDAC. METHODS: A total of 71 patients with pathologically proved PDAC based on surgical resection who underwent contrast-enhanced computed tomography (CT) within 30 d prior to surgery were included in the study. Tumor staging was performed in accordance with the 8th edition of the American Joint Committee on Cancer staging system. Radiomics features were extracted from the region of interest (ROI) for each patient using Analysis Kit software. The most important and predictive radiomics features were selected using Mann-Whitney U test, univariate logistic regression analysis, and minimum redundancy maximum relevance (MRMR) method. Random forest (RF) method was used to construct the radiomics model, and 10-times leave group out cross-validation (LGOCV) method was used to validate the robustness and reproducibility of the model. RESULTS: A total of 792 radiomics features (396 from late arterial phase and 396 from portal venous phase) were extracted from the ROI for each patient using Analysis Kit software. Nine most important and predictive features were selected using Mann-Whitney U test, univariate logistic regression analysis, and MRMR method. RF method was used to construct the radiomics model with the nine most predictive radiomics features, which showed a high discriminative ability with 97.7% accuracy, 97.6% sensitivity, 97.8% specificity, 98.4% positive predictive value, and 96.8% negative predictive value. The radiomics model was proved to be robust and reproducible using 10-times LGOCV method with an average area under the curve of 0.75 by the average performance of the 10 newly built models. CONCLUSION: The radiomics model based on CT could serve as a promising non-invasive method in differential diagnosis between early and late stage PDAC.

Comparison between solid pseudopapillary neoplasms of the pancreas and pancreatic ductal adenocarcinoma with cystic changes using computed tomography.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPN) share similar imaging findings with pancreatic ductal adenocarcinoma with cystic changes (PDAC with cystic changes), which may result in unnecessary surgery. AIM: To investigate the value of computed tomography (CT) in differentiation of SPN from PDAC with cystic changes. METHODS: This study retrospectively analyzed the clinical and imaging findings of 32 patients diagnosed with SPN and 14 patients diagnosed with PDAC exhibiting cystic changes, confirmed through pathological diagnosis. Quantitative and qualitative analysis was performed, including assessment of age, sex, tumor size, shape, margin, density, enhancement pattern, CT values of tumors, CT contrast enhancement ratios, "floating cloud sign," calcification, main pancreatic duct dilatation, pancreatic atrophy, and peripancreatic invasion or distal metastasis. Multivariate logistic regression analysis was used to identify relevant features to differentiate between SPN and PDAC with cystic changes, and receiver operating characteristic curves were obtained to evaluate the diagnostic performance of each variable and their combination. RESULTS: When compared to PDAC with cystic changes, SPN had a lower age (32 years vs 64 years, P < 0.05) and a slightly larger size (5.41 cm vs 3.90 cm, P < 0.05). SPN had a higher frequency of "floating cloud sign" and peripancreatic invasion or distal metastasis than PDAC with cystic changes (both P < 0.05). No significant difference was found with respect to sex, tumor location, shape, margin, density, main pancreatic duct dilatation, calcification, pancreatic atrophy, enhancement pattern, CT values of tumors, or CT contrast enhancement ratios between the two groups (all P > 0.05). The area under the receiver operating characteristic curve of the combination was 0.833 (95% confidence interval: 0.708-0.957) with 78.6% sensitivity, 81.3% specificity, and 80.4% accuracy in differentiation of SPN from PDAC with cystic changes. CONCLUSION: A larger tumor size, "floating cloud sign," and peripancreatic invasion or distal metastasis are useful CT imaging features that are more common in SPN and may help discriminate SPN from PDAC with cystic changes.

Residual CIS after neoadjuvant chemotherapy and radical cystectomy for muscle invasive bladder cancer: Implications for neoadjuvant trials.

PURPOSE: To better define surrogate endpoints for neoadjuvant chemotherapy (NAC) trials in patients with muscle-invasive bladder cancer. We compared survival in patients with carcinoma in-situ (CIS) only vs. complete response following NAC and radical cystectomy (RC). MATERIALS AND METHODS: Patients with cT2-4N0M0 disease treated with NAC and RC between 2001 and 2018 were stratified by response: complete response (CR, pT0N0), partial response (PR, pTaN0, pT1N0+/-CIS), CIS-only (pTisN0), stable disease (SD, pT2N0), or progressive disease (PD, >pT2N0). Primary endpoints were overall survival (OS) and risk of recurrence in patients with CIS-only vs. CR. Multivariable Cox proportional hazards regression model was used for OS and a competing risks proportional hazards model was used for risk of recurrence. RESULTS: Of 1,406 patients in our institution cohort, 340 patients met inclusion criteria. Kaplan-Meier mean estimates of OS for CR and CIS-only were 108.9 months (95% CI 89.7-127.9) and 125.8 months (95% CI 112.3-139.3), respectively (P = 0.13). Cox proportional hazards model found no difference in OS between patients with PR (HR 1.06, 95% CI 0.33-2.58, P = 0.897) or CIS-only (HR 0.422, 95% CI 0.15-1.18, P = 0.101) when compared to CR. The risk of recurrence was similar between patients with CIS-only (HR 0.73, 95% 0.29-1.84, P = 0.49) and PR (HR 1.32, 95% CI 0.54-3.29, P = 0.54) when compared to CR on competing risks analysis. CONCLUSIONS: Residual CIS-only after NAC and RC demonstrated similar survival outcomes when compared to patients with pathologic CR. Further study in large multi-institutional cohorts may further validate CIS-only as an additional surrogate endpoint after NAC and may inform future trials.

Strategic Radiology Outreach Planning for Underserved Populations Using Geographic Information Systems.

PURPOSE: Geographic information systems (GIS) are widely used in public health research but rarely used in radiology research. GIS can be an impactful tool in radiology global health to locate medically underserved populations and poor transportation infrastructure, characterize medical needs, and design outreach programs. Using the example of aircraft-based outreach in Alaska, we demonstrate the utility of GIS in radiological program planning for global health. METHODS: Multicriteria GIS evaluations were performed to create a health severity index, using life expectancy and percentage uninsured data, and an accessibility severity index, using distance from roads and health centers or hospitals. These indices were combined with population density to create a final health access severity index (HASI). A map presenting suitable hybrid airship operating areas was produced using land cover data. Alaskan health care facilities were georeferenced to create a coordinate data set. Infrastructure was obtained from OpenStreetMap. Health data were accessed from the 2017 American Community Survey and CDC US Small-area Life Expectancy Estimates Project. RESULTS: GIS analyzed 738,050 Alaskans. The health severity index identified decreased health outcomes (high or very high severity) in 285,446 (39%) Alaskans, and the accessibility severity index determined decreased access to care in 218,201 (30%). Combined, the HASI established 165,108 (22%) Alaskans as underserved with high or very high overall severity. Thirty-nine percent of Alaska land area is suitable for hybrid airship operations, including 27% of HASI high and very high severity areas. CONCLUSIONS: GIS identified underserved populations for mobile radiology outreach in Alaska and may be useful for global health outreach planning and resource allocation.

Preoperative differentiation of serous cystic neoplasms from mucin-producing pancreatic cystic neoplasms using a CT-based radiomics nomogram.

PURPOSE: To develop and validate a CT-based radiomics nomogram in preoperative differential diagnosis of SCNs from mucin-producing PCNs. MATERIAL AND METHODS: A total of 89 patients consisting of 31 SCNs, 30 IPMNs, and 28 MCNs who underwent preoperative CT were analyzed. A total of 710 radiomics features were extracted from each case. Patients were divided into training (n = 63) and validation cohorts (n = 26) with a ratio of 7:3. Least absolute shrinkage and selection operator (LASSO) method and logistic regression analysis were used for feature selection and model construction. A nomogram was created from a comprehensive model consisting of clinical features and the fusion radiomics signature. A decision curve analysis was used for clinical decisions. RESULTS: The radiomics features extracted from CT could assist with the differentiation of SCNs from mucin-producing PCNs in both the training and validation cohorts. The signature of the combination of the plain, late arterial, and venous phases had the largest areas under the curve (AUCs) of 0.960 (95% CI 0.910-1) in the training cohort and 0.817 (95% CI 0.651-0.983) in the validation cohort with good calibration. The value and efficacy of the nomogram was verified using decision curve analysis. CONCLUSION: A comprehensive nomogram incorporating clinical features and fusion radiomics signature can differentiate SCNs from mucin-producing PCNs.

Exogenous HMGB1 Promotes the Proliferation and Metastasis of Pancreatic Cancer Cells.

Background: Exogenous HMGB1 plays a vital role in tumor recurrence, and HMGB1 is ubiquitous in the tumor microenvironment. However, the mechanism of action is still unclear. We investigated the role of exogenous HMGB1 in tumor proliferation and metastasis using human SW1990 and PANC-1 cells after radiotherapy and explored the possible molecular mechanism. Materials and Methods: Residual PANC-1 cells and SW1990 cells were isolated after radiotherapy. The supernatant after radiotherapy was collected. The relative expression of HMGB1 was evaluated by Enzyme Linked Immunosorbent Assay (ELISA). Electron microscope (EMS) was used to collect the images of pancreatic cancer cells pre and post radiotherapy treatment. The proliferation of pancreatic cancer cells which were treated with different radiation doses was measured by Carboxy Fluorescein Succinimidyl Ester (CFSE). The migration rates of pancreatic cancer cells were measured by wound healing assays. Subsequently, the expression of related proteins was detected by Western Blot. In vivo, the subcutaneous pancreatic tumor models of nude mice were established, and therapeutic capabilities were tested. Results: HMGB1 was detected in the supernatant of pancreatic cancer cells after radiotherapy. The results of CFSE showed that exogenous HMGB1 promotes the proliferation and metastasis of pancreatic cancer cells. The western blot results showed activation of p-GSK 3ß and up-regulation of N-CA, Bcl-2, and Ki67 in response to HMGB1 stimulation, while E-CA expression was down-regulated in pancreatic cancer cells in response to HMGB1 stimulation. In vivo, ethyl pyruvate (EP, HMGB1 inhibitor) inhibits the growth of tumors and HMGB1 promotes the proliferation of tumors after radiation. Conclusion: Radiotherapy induces HMGB1 release into the extracellular space. Exogenous HMGB1 promotes the proliferation and metastasis of PANC-1 cells and SW1990 cells by activation of p-GSK 3ß which is mediated by Wnt pathway.

Evaluation of contrast-enhanced computed tomography for the differential diagnosis of hypovascular pancreatic neuroendocrine tumors from chronic mass-forming pancreatitis.

PURPOSE: To assess the role of contrast-enhanced computed tomography (CECT) for differentiation of hypovascular pancreatic neuroendocrine tumors (hypo-PNETs) from chronic mass-forming pancreatitis (CMFP). METHODS: A retrospective study of 59 patients (27 hypo-PNETs patients vs 32 CMFP patients) who underwent preoperative CECT between July 2012 and July 2019 was performed. Qualitative and quantitative analysis was performed, including mass location, size, margin, cystic changes, calcification, pancreatic or bile duct dilatation, pancreatic atrophy, local vessels involvement, mass contrast enhancement and mass-to-pancreas enhancement ratio. Multivariate logistic regression analyses were used to identify relevant CT imaging findings in differentiation between hypo-PNETs and CMFP. RESULTS: When compared to CMFP, hypo-PNETs more frequently had a well-defined margin and cystic changes and less frequently had a history of pancreatitis and calcification. CMFP had higher mass contrast enhancement and mass-to-pancreas enhancement ratio in the portal and delayed phases than hypo-PNETs. After multivariate logistic regression analyses, areas under the curve (AUCs) were 0.795 (95 % CI: 0.652-0.899), 0.752 (95 % CI: 0.604-0.866), 0.859 (95 % CI: 0.726-0.943), and 0.929 (95 % CI: 0.814-0.983) for Model 1(clinical factors), Model 2 (qualitative parameters), Model 3 (quantitative parameters), and their combinations, respectively. CONCLUSION: Combined assessment of clinical factors, qualitative, and quantitative imaging characteristics can improve the differentiation between hypo-PNETs and CMFP at CECT.

An evaluation of monthly maintenance therapy among patients receiving intravesical combination gemcitabine/docetaxel for nonmuscle-invasive bladder cancer.

PURPOSE: To report our experience with sequential maintenance intravesical gemcitabine/docetaxel (GEM/DOCE) for patients with nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: Fifty-nine patients who received full GEM/DOCE for nonmuscle-invasive bladder cancer between 2013 and 2018, per the protocol adapted from University of Iowa, were identified and characterized. Patients were treated with 6 weekly instillations of GEM/DOCE and subsequent monthly maintenance installations for those with no evidence of disease at the first surveillance. Student's t test and χ2 test were used to compare continuous and categorical variables as appropriate. For survival analyses, Kaplan-Meier (KM) curves were created to assess disease-free survival (DFS). Overall comparisons of KM survival analysis were conducted using the Wilcoxon test. RESULTS: Among all patients, median follow-up was 24 months. Sixty-six percent of patients received ≥2 intravesical induction therapies prior to receiving GEM/DOCE. Thirty-one patients (63%) failed ≥2 induction courses of Bacillus Calmette-Guérin (BCG) before receiving GEM/DOCE. Overall DFS was 49% at 1 year and 29% at 2 years. For patients who failed ≥1 induction courses of BCG, overall DFS was 48% at 1 year and 32% at 2 years. GEM/DOCE appears to be effective for therapy naïve and patients who have failed previous intravesical therapies (P = 0.39). There were 41 (69.5%) patients who had no evidence of disease at the first surveillance and were eligible for maintenance therapy. Among these patients, 24 were managed with observation alone and 17 with monthly maintenance. Median follow-up for observed patients was 36 months and 26 months for patients with maintenance. DFS at 1 year was 42% for observed patients and 81% for patients receiving maintenance (P = 0.04). DFS at 2 years was 32% for observed patients and 59% for patients receiving maintenance therapy (P = 0.45). For maintenance eligible patients who received ≥1 induction courses of BCG, DFS was 42% for observed patients and 81% for patients receiving maintenance therapy at 1 year and 34% for observed patients and 59% for patients receiving maintenance therapy at 2 years. Pathologic stage at recurrence was similar between observed patients and those receiving maintenance (P = 0.83). KM analyses showed greater DFS for patients receiving maintenance therapy compared to observed patients (P = 0.04). CONCLUSION: Patients who demonstrate initial complete response to GEM/DOCE may benefit from maintenance GEM/DOCE.

Contemporary oncologic outcomes of second induction course BCG in patients with nonmuscle invasive bladder cancer.

PURPOSE: According to the 2016 American Urological Association (AUA) guidelines for nonmuscle invasive bladder cancer (NMIBC), clinicians should offer a 2nd intravesical induction course of Bacillus Calmette-Guérin (BCG) to patients with persistent or recurrent Ta or CIS disease after a 1st BCG induction course. However, evidence for a 2nd course is limited, and some patients forego a 2nd induction of BCG in favor of a clinical trial or alternate intravesical therapy. We sought to investigate contemporary oncologic outcomes of a 2nd induction course of BCG in a multi-institutional cohort. MATERIALS AND METHODS: Three hundred fifty-three patients who received full induction BCG for NMIBC since 2001 at 2 institutions were identified. Patients were categorized as receiving primary 6-week induction therapy or subsequent 2nd 6-week induction therapy for patients who recurred or persisted. The baseline differences in demographic and tumor characteristics were compared between the 2 groups, and Kaplan-Meier curves were constructed to assess high-grade recurrence free survival (HgRFS) among both groups. Univariable logistic regression was used to determine factors associated with recurrence after 2nd course BCG RESULTS: A total of 353 patients received 1st induction BCG (BCG1) and 116 patients received a 2nd induction course (BCG2). Maintenance therapy was given to 117 (33.1%) patients after BCG1 and 43 (37.1%) patients after BCG2. Both cohorts were similar in demographics including age, sex, and race. Pathologic stage before treatment differed as BCG1 patients were more likely to have T1 (40.8% vs. 25%) and less likely to have CIS (13.9% vs. 33.6%) (P < 0.001). Complete response (CR) 3 months after BCG1 was observed in 276 patients (78.2%) and 104 patients (89.7%) after BCG2. Responses remained durable, with 36-month CR of 54.7% in BCG1 and 65.6% in BCG2. Progression to MIBC was identified in 1.4% of BCG1 patients vs. 3.4% in BCG2 patients (P = 0.17). Pathologic stage before BCG2 does not predict progression to MIBC (P = 0.21) after BCG2. The time interval between the 1st and 2nd induction of BCG was not significantly associated with response to 2nd induction BCG (P = 0.47). Maintenance therapy after BCG2 was associated with decreased recurrence after 2nd induction course of BCG. CONCLUSION: A 2nd course of BCG is efficacious with a durable HgRFS, validating the recommendations of the 2016 AUA guidelines.

Adaptive Immune Resistance to Intravesical BCG in Non-Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials.

PURPOSE: To characterize immune cell expression among patients with non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG). EXPERIMENTAL DESIGN: Patients with NMIBC treated with intravesical BCG (2008-2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1+ staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naïve population was then validated in a separate cohort. RESULTS: The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders (P < 0.01). PD-L1+ cells in BCG nonresponders colocalized with CD8+ T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretreatment CD4+ T cells was very low among PD-L1+ nonresponders (12%) and high among PD-L1- nonresponders (50%, P < 0.01). In a separate cohort of 57 patients with NMIBC undergoing BCG, baseline PD-L1 (22C3) staining was similar (26%). CONCLUSIONS: One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.