ABSTRACT
PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.
Subject(s)
BCG Vaccine , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/mortality , Male , Female , BCG Vaccine/administration & dosage , BCG Vaccine/therapeutic use , Administration, Intravesical , Follow-Up Studies , Aged , Middle Aged , Carcinoma in Situ/pathology , Carcinoma in Situ/therapy , Carcinoma in Situ/drug therapy , Neoplasm Invasiveness , Treatment Outcome , Adenoviridae/genetics , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/therapeutic use , Aged, 80 and overABSTRACT
Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.
ABSTRACT
PURPOSE: The long-term toxicities of chemotherapy and radiotherapy can represent a significant burden to testicular cancer survivors. Retroperitoneal lymph node dissection (RPLND) is an established treatment for testicular germ cell tumors with minimal late morbidity although little data exist on its efficacy in early metastatic seminoma. Surgery in early metastatic seminoma is a prospective phase II single-arm, multi-institutional trial of RPLND as first-line treatment for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy. PATIENTS AND METHODS: Twelve sites in the United States and Canada prospectively enrolled adult patients with testicular seminoma and isolated retroperitoneal lymphadenopathy (1-3 cm). Open RPLND was performed by certified surgeons with a primary end point of 2-year recurrence-free survival (RFS). Complication rates, pathologic up/downstaging, recurrence patterns, adjuvant therapies, and treatment-free survival were assessed. RESULTS: A total of 55 patients were enrolled, with a median (IQR) largest clinical lymph node size of 1.6 cm (1.3-1.9). RPLND pathology demonstrated a median (IQR) largest lymph node size of 2.3 cm (0.9-3.5); nine patients (16%) were pN0, 12 (22%) pN1, 31 (56%) pN2, and 3 (5%) pN3. One patient received adjuvant chemotherapy. With a median (IQR) follow-up of 33 months (12.0-61.6), 12 patients experienced recurrence, with a 2-year RFS of 81% and a recurrence rate of 22%. Of the patients who experienced recurrence, 10 were treated with chemotherapy and two underwent additional surgery. At last follow-up, all patients who experienced a recurrence were disease-free and the 2-year overall survival was 100%. Four patients (7%) experienced short-term complications, and four patients experienced long-term complications including incisional hernia (1) and anejaculation (3). CONCLUSION: RPLND is a treatment option for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy and is associated with low long-term morbidity.
Subject(s)
Lymphadenopathy , Neoplasms, Germ Cell and Embryonal , Seminoma , Testicular Neoplasms , Male , Adult , Humans , Testicular Neoplasms/surgery , Seminoma/surgery , Prospective Studies , Retroperitoneal Space/pathology , Retroperitoneal Space/surgery , Lymph Node Excision/adverse effects , Neoplasms, Germ Cell and Embryonal/pathology , Retrospective Studies , Lymphadenopathy/etiology , Lymphadenopathy/pathology , Lymphadenopathy/surgery , Neoplasm StagingABSTRACT
Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8+ T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8+ T cells. Murine tumor models revealed that tumor-specific CD8+ T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8+ T cell activation in response to cancer is different from that of canonical CD8+ T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8+ T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.
Subject(s)
CD8-Positive T-Lymphocytes , Neoplasms , Humans , Animals , Mice , Neoplasms/pathology , Lymph Nodes , Lymphocyte Activation , Cell DifferentiationABSTRACT
INTRODUCTION: This study examined the clinical accuracy of ultrasonography compared to magnetic resonance imaging (MRI) and intraoperative findings for evaluation of tumor thrombi level in patients with renal cell carcinoma. MATERIALS AND METHODS: We retrospectively identified 38 patients at our institution who underwent both ultrasonography and MRI before undergoing open radical nephrectomy with tumor thrombectomy between 2010 and 2019. We compared tumor thrombus level findings of both ultrasonography and MRI, as well as the diagnostic accuracy of each to intraoperative findings. Agreement between ultrasonography, MRI, and surgery was tested with kappa. Logistic regression models identified factors that predict a mismatched thrombus level between an imaging modality and surgical findings. RESULTS AND CONCLUSIONS: Tumor thrombus levels determined by ultrasonography matched with MRI in 26 (68.4%) cases. Compared to operative findings, ultrasonography accurately identified the cephalad extent of thrombi in 30 (79.0%) cases, under-staged five (13.2%) cases, and over-staged three (7.9%). Magnetic resonance imaging agreed with operative findings in 30 (79.0%) cases, under-staged five (13.2%) and over-staged three (7.9%) cases. On univariable regression assessment, M1 stage was predictive of a mismatched result between MRI and surgery (OR: 6.0, 95% CI: 1.02-35.3, p = 0.047), but this association did not hold-up in a multivariable model. Ultrasonography and magnetic resonance imaging identified the preoperative tumor thrombus level at a rate of 79%. Ultrasonography is an effective preoperative imaging modality for evaluating tumor thrombi associated with kidney cancer, notably as an adjunct to magnetic resonance imaging.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Thrombosis , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/surgery , Humans , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/surgery , Nephrectomy/methods , Retrospective Studies , Thrombectomy/methods , Thrombosis/diagnostic imaging , Thrombosis/etiology , Thrombosis/surgery , Ultrasonography , Vena Cava, Inferior/diagnostic imagingABSTRACT
OBJECTIVE: To examine the safety, feasibility and durability of robotic reimplantation of ureteroenteric stricture after radical cystectomy. MATERIALS AND METHODS: A retrospective multi-institutional review was performed for all patients undergoing robotic repair of ureteroenteric stricture from January 2010 to January 2019. Functional outcomes and complications were followed and data were analyzed with SPSS statistical software. RESULTS: A total of 46 patients and 58 renal units were identified, of which 15 had right sided, 19 left sided and 12 patients had bilateral strictures. Presentation of stricture was asymptomatic in 14 (30.4%) patients. Symptomatic presentations included infection in 22 (47.8%), worsening renal function in 11 (23.9%) and pain in 3 (6.5%) patients. Median time from cystectomy to diagnosis of stricture was 5 months (1-40). Median stricture length was 1.5 cm (range 0.5-10). All strictures were of benign etiology except for 4 (6.9%), which were due to malignancy. Overall, 49 (84.5%) ureters underwent primary re-implantation, while 9 (15.5%) required Boari-like advancement flaps prior to re-implantation. Median operative time was 190 min (range 45-540) with median estimated blood loss of 50 mL (range 25-2000) and median length of stay of 2 days (range 1-33, IQR 2-4). Seven (15.2%) patients experienced complications; 3 (6.5%) were low grade and 4 (8.7%) high grade. With median follow up of 18 months (range 1-51) the stricture recurrence rate was 8.6%. CONCLUSION: Robotic reimplantation of ureteroenteric strictures following radical cystectomy is safe and feasible in experienced centers with high success rates.
Subject(s)
Robotic Surgical Procedures , Ureter , Urinary Diversion , Constriction, Pathologic/etiology , Constriction, Pathologic/surgery , Cystectomy/adverse effects , Humans , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/surgery , Retrospective Studies , Robotic Surgical Procedures/adverse effects , Ureter/pathology , Ureter/surgery , Urinary Diversion/adverse effectsABSTRACT
A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.
Subject(s)
Antineoplastic Agents , Urinary Bladder Neoplasms , Adjuvants, Immunologic/therapeutic use , Administration, Intravesical , Antineoplastic Agents/therapeutic use , BCG Vaccine/therapeutic use , Female , Humans , Male , Neoplasm Invasiveness , Neoplasm Recurrence, Local/drug therapy , Prospective Studies , Urinary Bladder Neoplasms/drug therapyABSTRACT
INTRODUCTION: Practice guidelines recommend early consideration for palliative care for patients with advanced malignancies, and there has been limited research regarding the use of palliative care for patients with advanced bladder cancer. Our aim is to describe the rate and determinants of the use of palliative care consultation for patients treated with radical cystectomy at our institution. METHODS: A retrospective review was performed to identify patients who underwent cystectomy for bladder cancer between September 2014 and June 2019 at our institution. Our primary outcome was receipt of palliative care, defined as receiving a palliative care consult. We tested for associations between factors and our outcome of interest, and then estimated the impact on various determinants of palliative care use by fitting a multivariable logistic regression model. RESULTS: Over the study period, 294 patients underwent radical cystectomy. Of those patients, 29 (9.9%) received palliative care. Mean time from surgery to palliative care consult was 11.4 months. Palliative care consults were initiated by urologists in 32.1% of cases. On multivariable analysis, patients were more likely to receive palliative care if they had pT3+ disease (P < 0.001), were readmitted after surgery (Pâ¯=â¯0.028), or had any major complication after surgery (Pâ¯=â¯0.025). CONCLUSION: Rates of palliative care consults in patients with advanced bladder cancer at our institution are higher than other population-based estimates nationally. The majority of palliative care consults were requested by medical oncologists, highlighting an opportunity for educational initiatives for urologic oncologists to promote earlier consideration of palliative care referrals.
Subject(s)
Cystectomy/methods , Palliative Care/methods , Urinary Bladder Neoplasms/surgery , Aged , Female , Humans , Male , Retrospective Studies , Urinary Bladder Neoplasms/pathologyABSTRACT
Radical cystectomy/cystoprostatectomy with pelvic lymph node dissection (with or without neoadjuvant chemotherapy) is the gold standard in the management of patients with urothelial carcinoma (UCa) with muscularis propria (detrusor muscle) invasion. However, it remains controversial how extensive the lymph node dissection should be. In this article, we analyzed the clinicopathologic findings in patients who had radical cystectomy/cystoprostatectomy with extended versus standard lymph node dissection. A search was made through our Urologic Pathology files for radical cystectomy/cystoprostatectomy cases with extended and standard lymph node dissection for UCa. A total of 264 cases were included in the study (218 cystoprostatectomy and 46 cystectomy specimens). Mean patients age was 68 years (range = 32-92 years). Patients in all stage categories had more extended lymph node dissection performed compared with standard lymph node dissection: pT0 (20 vs 7), pTis (40 vs 12), pTa (8 vs 4), pT1 (27 vs 5), pT2 (39 vs 8), pT3 (51 vs 17), and pT4 (18 vs 8). In cases with neoadjuvant therapy there was a 19% lymph node positivity rate compared with a 24% positivity rate in those with no presurgical therapy. The only cases categorized as pT2 and below with positive lymph node metastasis were those that had extended lymph node dissection performed. Positive lymph nodes were more frequently detected in cases that had extended lymph node dissection. More than 35% of the positive lymph nodes were in nonregional distribution. Extended lymph node dissection should be considered in patients with UCa even in the low stage or post-neoadjuvant chemotherapy setting.
Subject(s)
Carcinoma, Transitional Cell/therapy , Lymph Node Excision/methods , Lymph Nodes/pathology , Lymphatic Metastasis/diagnosis , Urinary Bladder Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/diagnosis , Carcinoma, Transitional Cell/secondary , Cystectomy/statistics & numerical data , Female , Humans , Lymph Node Excision/statistics & numerical data , Lymph Nodes/surgery , Lymphatic Metastasis/pathology , Lymphatic Metastasis/therapy , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Prostate/pathology , Prostate/surgery , Prostatectomy/statistics & numerical data , Retrospective Studies , Treatment Outcome , Urinary Bladder/pathology , Urinary Bladder/surgery , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/pathologyABSTRACT
BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3â×â1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.
Subject(s)
Adenoviridae/genetics , BCG Vaccine/administration & dosage , Carcinoma in Situ/therapy , Drug Resistance, Neoplasm , Genetic Therapy , Genetic Vectors , Interferon alpha-2/genetics , Urinary Bladder Neoplasms/therapy , Administration, Intravesical , Aged , BCG Vaccine/adverse effects , Carcinoma in Situ/genetics , Carcinoma in Situ/mortality , Carcinoma in Situ/pathology , Disease Progression , Female , Genetic Therapy/adverse effects , Genetic Therapy/mortality , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Time Factors , Treatment Outcome , United States , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathologyABSTRACT
F-fluciclovine is a PET radiotracer approved for detection of recurrent prostate cancer, with utility in other malignancies being investigated. We present the case of a 71-year-old man with high-risk primary prostate cancer (Gleason score 9, prostate-specific antigen 34 ng/mL) and newly diagnosed lung adenocarcinoma. As part of a clinical trial (NCT03081884), preoperative F-fluciclovine PET/CT showed localized abnormal uptake in the prostate gland with extracapsular extension. Additionally, an incidental anterior mediastinal mass measuring 2.2 × 1.8 cm demonstrated abnormal radiotracer uptake. Biopsy of the mediastinal mass confirmed invasive lung adenocarcinoma with solid and acinar patterns and high programmed death 1 ligand expression.
Subject(s)
Adenocarcinoma of Lung/diagnostic imaging , Carboxylic Acids , Cyclobutanes , Incidental Findings , Mediastinum/pathology , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms/diagnostic imaging , Adenocarcinoma of Lung/pathology , Aged , Biopsy , Humans , MaleABSTRACT
OBJECTIVE: To evaluate the relationship between dynamic changes in the modified Glasgow Prognostic Scale (mGPS) and postnephrectomy survival among localized clear cell renal cell carcinoma (ccRCC) patients. METHODS: We retrospectively identified patients who underwent nephrectomy for localized ccRCC with preoperative mGPS = 0 from 2005 to 2018. The primary exposure of interest was ΔmGPS between 2 points - 60 days prior to surgery and 1 year after surgery. We assessed the relationship between ΔmGPS and survival outcomes. Kaplan-Meier curves were generated to determine survival estimates and Cox proportional hazards models were fit to estimate hazard ratios (HRs). Multivariable models were constructed using both ΔmGPS and clinical variables known to be associated with differences in survival. RESULTS: We identified 313 patients for our analytic cohort with a median follow-up time of 20.2 months. Thirty-seven (11.9%) patients died and 39 (12.54%) showed recurrence during follow-up. Two hundred sixty-three (84.6%) patients had unchanged mGPS before and after surgery, while 48 (15.4%) patients showed an increase in postoperative mGPS from preoperative mGPS. Compared to patients with unchanged mGPS, patients with a higher postoperative mGPS had an increased risk of death (HR = 3.05 [1.39-6.68], P = .005) and recurrence (HR = 2.98 [1.34-6.64], P = .008). CONCLUSION: Patients with an increase in mGPS following nephrectomy for ccRCC were more likely to die and experience cancer recurrence. Assessing dynamic changes in this cheap, validated, and reproducible test may be useful in identifying patients at higher risk for more aggressive disease or for counseling patients regarding risk of cancer recurrence.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Multivariate Analysis , Neoplasm Recurrence, Local/diagnosis , Nephrectomy , Survival Analysis , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , Female , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Male , Middle Aged , Neoplasm Staging , Nephrectomy/adverse effects , Nephrectomy/methods , Prognosis , Proportional Hazards Models , Reproducibility of ResultsABSTRACT
PURPOSE: Accurate preoperative staging of prostate cancer is essential for treatment planning. Conventional imaging is limited in detection of metastases. Our primary aim was to determine if [18F]fluciclovine positron emission tomography/computerized tomography is an early indicator of subclinical metastasis among patients with high risk prostate cancer. MATERIALS AND METHODS: A total of 68 patients with unfavorable intermediate to very high risk prostate cancer without systemic disease on conventional imaging were recruited before robotic radical prostatectomy with extended pelvic lymph node dissection. Diagnostic performance of [18F]fluciclovine positron emission tomography/computerized tomography and conventional imaging for detection of metastatic disease, and correlation of positivity to node and metastatic deposit size were determined. RESULTS: Overall 57 of 68 patients completed the protocol, of whom 31 had nodal metastasis on histology. [18F]Fluciclovine positron emission tomography/computerized tomography sensitivity and specificity in detecting nodal metastasis was 55.3% and 84.8% per patient, and 54.8% and 96.4% per region (right and left pelvis, presacral and nonregional), respectively. Compared with conventional imaging [18F]Fluciclovine positron emission tomography/computerized tomography had significantly higher sensitivity on patient based (55.3% vs 33.3%, p <0.01) and region based (54.8% vs 19.4%, p <0.01) analysis, detecting metastasis in 7 more patients and 22 more regions, with similar high specificity. Four additional patients had distant disease or other cancer detected on [18F] fluciclovine positron emission tomography/computerized tomography which precluded surgery. Detection of metastasis was related to size of metastatic deposits within lymph nodes and overall metastatic burden. CONCLUSIONS: [18F]Fluciclovine positron emission tomography/computerized tomography detects occult metastases not identified on conventional imaging and may help guide treatment decisions and lymph node dissection due to high specificity for metastatic disease.
Subject(s)
Carboxylic Acids , Cyclobutanes , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Aged , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Positron Emission Tomography Computed Tomography/methods , Preoperative Period , Prospective Studies , Prostatic Neoplasms/surgeryABSTRACT
BACKGROUND: We developed a novel risk scoring system for urothelial cancer (UC) patients receiving immune checkpoint inhibitors (ICI). METHODS: We conducted a retrospective review of 67 UC patients treated with ICI at Winship Cancer Institute of Emory University from 2015 to 2018. Using stepwise variable selection in Cox proportional hazard model and Sullivan's weighting schema, baseline platelet-to-lymphocyte ratio (PLR), presence of liver metastasis, baseline albumin, and baseline Eastern Cooperative Oncology Group performance status (ECOG PS) were used for risk scoring. Patients were categorized into good risk (risk score 0-1), intermediate risk (risk score 2-3), and poor risk (risk score 4-6). Univariable (UVA) and multivariable analysis (MVA) and Kaplan-Meier method were used to assess overall survival (OS) and progression free survival (PFS). RESULTS: The Emory Risk Scoring System had C-statistics of 0.74 (Standard Error = 0.047) in predicting OS and 0.70 (Standard Error = 0.043) in predicting PFS. Compared to good risk patients, poor risk patients had significantly shorter OS and PFS in both UVA and MVA (all P < .001), and intermediate risk patients had significantly shorter OS and PFS in both UVA and MVA (all P < .03). CONCLUSIONS: Risk scoring using baseline PLR, presence of liver metastasis, baseline albumin, and baseline ECOG PS may effectively predict OS and PFS in UC patients receiving ICI.
Subject(s)
Immune Checkpoint Inhibitors/therapeutic use , Liver Neoplasms/secondary , Risk Assessment/methods , Urologic Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Liver Neoplasms/drug therapy , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Survival Rate , Urologic Neoplasms/drug therapyABSTRACT
Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy1-8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.
Subject(s)
CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation , Lymphocytes, Tumor-Infiltrating/cytology , Lymphocytes, Tumor-Infiltrating/immunology , Neoplasms/immunology , Stem Cells/cytology , Animals , Antigen Presentation/genetics , Antigen Presentation/immunology , CD8-Positive T-Lymphocytes/metabolism , Disease Progression , Epigenesis, Genetic , Hepatocyte Nuclear Factor 1-alpha/metabolism , Humans , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Neoplasms/pathology , Stem Cell Niche/immunology , Transcription, Genetic , Tumor Escape/genetics , Tumor Escape/immunologyABSTRACT
INTRODUCTION: The use of an electrocautery device (monopolar loop) for patients undergoing transurethral resection of bladder tumors (TURBT) is standard of care. The aim of this study is to establish non-inferiority of complication rates for a bipolar energy device, the PK PlasmaButton (PK Button), when compared to the monopolar loop. MATERIALS AND METHODS: Seventy-eight subjects (41 monopolar loop and 37 PK Button), were enrolled in a single-center, prospective, randomized study with cystoscopically detected bladder tumors that were judged endoscopically resectable with only one trip into the operating room. Intra and postoperative data on complication rates, operative time, catheterization time and disease recurrence rates at 3 month follow up were collected. RESULTS: Overall complication rates after TURBT with the monopolar loop or PK Button were similar, (56% versus 38% respectively, p = 0.107), however there were more bladder perforations in the monopolar loop arm compared to the PK Button arm (12.2% versus 0%, respectively, p = 0.028). There was no difference in overall operative time (p = 0.170), catheterization time (p = 0.709) and disease recurrence (p = 0.199). CONCLUSION: The results of this study demonstrated no difference between the monopolar loop and PK Button in regard to overall complications; however, there was a higher rate of bladder perforation with monopolar TURBT. PK Button vaporization for bladder tumors represents a promising alternative to traditional monopolar TURBT without compromising short term (3 month) cancer recurrence rates.
Subject(s)
Electrocoagulation/adverse effects , Electrocoagulation/methods , Neoplasm Recurrence, Local/pathology , Urinary Bladder Neoplasms/surgery , Urinary Bladder/injuries , Adult , Aged , Aged, 80 and over , Cystoscopy , Electrocoagulation/instrumentation , Female , Humans , Male , Middle Aged , Operative Time , Prospective Studies , Time Factors , Urethra , Urinary Bladder Neoplasms/pathology , Urinary Catheterization , Young AdultABSTRACT
Urothelial carcinoma with an inverted/endophytic growth pattern can occasionally mimic inverted urothelial papilloma and pose diagnostic challenges when assessing the presence or absence of invasion. Making these distinctions is critical for guiding appropriate treatment and improving patient outcomes. Here we conducted one of the largest studies to date of invasive high-grade urothelial carcinoma arising in a background of urothelial carcinoma with an inverted growth pattern. Primary sites examined included bladder, renal pelvis, ureter, and prostatic urethra. Clinicopathological parameters including extent of invasion, variant histology, presence of urothelial carcinoma in situ, and clinical follow-up were obtained. Ninety-one cases from 82 patients were included in the study. Lamina propria invasion was present in 81% of bladder, 60% of ureter, 20% of renal pelvis, and 100% of prostatic urethra cases. Muscularis propria invasion was identified in 19% of bladder, 14% of ureter, and 20% of renal pelvis cases. Urothelial carcinoma invaded periureteric fat in 29% of ureter cases and invaded the renal parenchyma in 60% of renal pelvis cases. Clinical follow-up was available for 77 of 82 (94%) patients with a mean duration of 18â¯months. Recurrent urothelial carcinoma persisted in 63 of 82 (77%) patients, 16 of 82 (19%) progressed with metastatic disease, and 20 of 77 (26%) patients with bladder involvement died of disease. This study further emphasizes the importance of distinguishing these tumors from benign mimickers of urothelial carcinoma. Recognition of invasive foci is also critical in view of the potentially high frequency of recurrence and the possibility of advanced disease in a subset of these patients.
Subject(s)
Carcinoma, Transitional Cell/pathology , Papilloma, Inverted/pathology , Urologic Neoplasms/pathology , Urothelium/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/diagnosis , Diagnosis, Differential , Female , Humans , Kidney Pelvis/pathology , Male , Middle Aged , Papilloma, Inverted/diagnosis , Ureter/pathology , Urethra/pathology , Urinary Bladder/pathology , Urologic Neoplasms/diagnosisABSTRACT
We evaluated 18F-fluciclovine uptake parameters that correlate with true positivity for local recurrence in non-prostatectomy-treated patients. Methods: Twenty-one patients (prostate-specific antigen level, 7.4 ± 6.8 ng/mL) with biochemical recurrence after nonprostatectomy local therapy (radiotherapy and cryotherapy) underwent dual-time-point 18F-fluciclovine (364.1 ± 37.7 MBq) PET/CT from pelvis to diaphragm. Prostatic uptake over background was delineated and coregistered to a prostate-biopsy-planning ultrasound. Transrectal biopsies of 18F-fluciclovine-defined targets were completed using a 3-dimensional visualization and navigation platform. Histologic analyses of lesions were completed. Lesion characteristics including SUVmax, target-to-background ratio (TBR), uptake pattern, and subjective reader's suspicion level were compared between true-positive (malignant) and false-positive (benign) lesions. Univariate analysis was used to determine the association between PET and histologic findings. Receiver-operating-characteristic curves were plotted to determine discriminatory cutoffs for TBR. Statistical significance was set at a P value of less than 0.05. Results: Fifty lesions were identified in 21 patients on PET. Seventeen of 50 (34.0%) targeted lesions in 10 of 21 patients were positive for malignancy. True-positive lesions had a significantly higher SUVmax (6.62 ± 1.70 vs. 4.92 ± 1.27), marrow TBR (2.57 ± 0.81 vs. 1.69 ± 0.51), and blood-pool TBR (4.10 ± 1.17 vs. 2.99 ± 1.01) than false-positive lesions at the early time point (P < 0.01) and remained significant at the delayed time point, except for blood-pool TBR. Focal uptake (odds ratio, 12.07; 95% confidence interval, 2.98-48.80; P < 0.01) and subjective highest suspicion level (odds ratio, 10.91; 95% confidence interval, 1.19-99.69; P = 0.03) correlated with true positivity. Using the receiver-operating-characteristic curve, optimal cutoffs for marrow TBR were 1.9 (area under the curve, 0.82) and 1.8 (area under the curve, 0.85) at early and delayed imaging, respectively. With these cutoffs, 15 of 17 malignant lesions were identified at both time points; however, fewer false-positive lesions were detected at the delayed time point (5/33) than at the early time point (11/33). Conclusion: True positivity of 18F-fluciclovine-targeted prostate biopsy in non-prostatectomy-treated patients correlates with focal uptake, TBR (blood pool and marrow), and subjective highest suspicion level. A marrow TBR of 1.9 at the early time point and 1.8 at the delayed time point had optimal discriminating capabilities. Despite the relatively low intraprostate positive predictive value (34.0%) with 18F-fluciclovine, application of these parameters to interpretative criteria may improve true positivity in the treated prostate.
Subject(s)
Carboxylic Acids , Cyclobutanes , Positron Emission Tomography Computed Tomography , Prostate/pathology , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Aged , Biological Transport , Biopsy , Carboxylic Acids/metabolism , Cyclobutanes/metabolism , Humans , Male , Prostate/diagnostic imaging , Prostatic Neoplasms/metabolism , ROC Curve , RecurrenceABSTRACT
OBJECTIVE: To educate surgeons of distal colon urinary diversion as an alternative to ileal conduit. To assess perioperative outcomes of distal colon conduit in pelvic exenteration including conduit-related, gastrointestinal, infectious, metabolic, and wound complications within 30 days, 31-89 days, and greater than 90 days from the time of surgery. MATERIALS AND METHODS: Forty-one patients who underwent distal colon urinary diversion for malignancy, fistula, or neurogenic bladder were identified in our IRB approved database from 1/2007 to 7/2017. RESULTS: Twenty-six (63.4%) were male with mean age of 54.1 years. Complications were stratified by early (≤30 days), intermediate (31-89 days), and late (≥90 days). Within 30 days, 2 (4.9%) had partial small bowel obstructions requiring nasogastric tube (NGT) placement and total parenteral nutrition (TPN); 8 (19.5%) prolonged ileus with 6 (14.6%) requiring TPN and 5 (12.2%) requiring NGT placement; 1 (2.4%) enterocutaneous fistula; 1 (2.4%) conduit hemorrhage, 10 (24.4%) treated urinary tract infections (UTIs). Between 31 and 89 days, 1 patient (2.4%) had urinary conduit leak and 3 (7.3%) treated UTIs. At ≥90 days, 2 (4.9%) had partial small bowel obstructions requiring NGT placement, 4 (9.8%) ureterocolonic strictures and 1 (2.4%) parastomal hernia, 3 (7.3%) treated UTIs. Readmission rate in ≤30 days was 10 (24.4%), 31-89 days was 13 (31.7%), and 90+ days was 16 (39%). Long-term metabolic complications at ≥90 days included 16 (39%) with hypokalemia, 10 (24.4%) with hyperchloremia, and 14 (34.1%) with metabolic acidosis. CONCLUSION: Distal colon urinary conduit is a relatively safe and feasible option and obviates the need for small bowel anastomosis and possible associated complications.
Subject(s)
Colon, Descending/surgery , Colon, Sigmoid/surgery , Pelvic Exenteration/adverse effects , Postoperative Complications/epidemiology , Urinary Diversion/methods , Urologic Diseases/surgery , Anastomosis, Surgical/methods , Female , Follow-Up Studies , Georgia/epidemiology , Humans , Incidence , Male , Middle Aged , Pelvic Exenteration/methods , Retrospective Studies , Time FactorsABSTRACT
BACKGROUND: The incidence of node-positive prostate cancer has risen and might be partially explained by evolving use of lymphadenectomy at a population level. We assessed trends of node-positive prostate cancer in context of extent of lymphadenectomy among men treated surgically for prostate cancer. PATIENTS AND METHODS: This was a retrospective study using data from a population-based cancer registry to identify men older than 50 years of age diagnosed with prostate cancer from 2010 to 2015 without distant metastases. We considered extent of node dissection as ordinal (1-4, 5-9, 10-14, 15-19, ≥20) and dichotomous (1-14, ≥15) variables. We fit multivariable models to assess trends in receipt of extended lymphadenectomy and then estimated odds of node-positive cancer on the basis of extent of lymphadenectomy. RESULTS: We identified 280,156 men diagnosed from 2010 to 2015; 5355 men (1.9%) had positive lymph nodes. Incidence of positive nodes increased from 6.4 to 8.4 cases per 100,000 men from 2010 to 2015 (standardized rate ratio, 1.31; 95% confidence interval [CI], 1.20-1.44). Compared with 2010, prostatectomy patients with high-risk (odds ratio [OR], 1.66; 95% CI, 1.42-1.95) and intermediate-risk tumors (OR, 1.66; 95% CI, 1.47-1.88) were more likely to undergo extended lymphadenectomy in 2015. Among high-risk patients, men with ≥20 nodes removed were 7 times more likely to have positive nodes, versus <5 removed (6.1% for 1-4 vs. 32.4% for ≥20; OR, 7.32; 95% CI, 6.16-8.71). After adjusting for extent of dissection, odds of node-positive disease did not increase between 2010 and 2015 (OR, 1.17; 95% CI, 0.98-1.39) among high-risk patients. CONCLUSION: Increased incidence of node-positive prostate cancer in the United States is partially explained by more frequent use of extended lymphadenectomy.