Low-grade Disease Research Articles

Thulium Laser Treatment of Upper Urinary Tract Carcinoma: A Multi-Institutional Analysis of Surgical and Oncological Outcomes.

To evaluate the efficacy and safety of ureteroscopic thulium laser (TL) treatment of upper urinary tract carcinoma (UTUC). Forty-two consecutive patients underwent conservative TL treatment for UTUC at two referral institutions. All patients underwent preliminary biopsy and then laser vaporization. A 272 μm and 365 μm laser fibers were used with a flexible and semirigid scope, respectively. Ablation was carried out with a 10 to 20 W power. Mean age at surgery was 68 years (SD 10.7). Mean tumor size was 14.3 mm (range 2-30 mm). Preliminary biopsy revealed the presence of low-grade disease in 29 (69.1%) patients, high-grade disease in 4 (9.5%) and 1 carcinoma in situ 1 (2.4%), whereas it was not conclusive in 8 (19%) cases. Final stage was pTa and pTis in 41 (97.6%) and 1 (2.4%) patients, respectively. Thirty eight percent (16) experienced Clavien-Dindo grade I complication, 47.6% (20) grade II, and 2.4% (1) grade III. Five (12%) patients underwent a second-look procedure due to residual disease. Eight (19%) patients experienced clinical recurrence. The median estimated recurrence-free survival was 44 months (SE 3.68). Four patients (9.5%) underwent a nephroureterectomy. Final pathological stage was pTis, pT3 high grade, pTa low grade, and pT0. Median follow-up was 26.3 months (range 2-54 months), and no progression or upstaging of disease occurred. TL management of UTUC is a safe and efficacious conservative treatment. Our experience shows optimal vaporization and hemostatic control in the absence of major complications.

A study of intravesical bacillus Calmette-Guerin (BCG) in combination with ALT-803 in patients with non-muscle invasive bladder cancer.

TPS545 Background: The current standard of care for patients with high risk NMIBC is a transurethral resection of the bladder tumor (TURBT) or biopsy followed by a 6-week induction course of intravesical BCG treatment and supplementary maintenance instillations every 3 months thereafter (Lamm 2000). While clinical response is significantly improved with BCG treatment, 50% of patients are still expected to recur within the first 12 months (Sfakianos 2014). Thus, the pursuit of novel agents to prevent progression and recurrence of NMIBC remains critical. This clinical trial evaluates the safety and efficacy of ALT-803, an IL-15 superagonist, plus BCG in BCG-naïve NMIBC patients. Methods: Patients with high-risk NMIBC (any high-grade disease, T1, or CIS) who are BCG naïve, will be randomized and enrolled into one of two study arms to be treated with either ALT-803 plus BCG or BCG alone. Patients will receive treatment via a urinary catheter in the bladder, weekly for 6 consecutive weeks during induction. A response assessment will be performed at Week 12: Patients with no disease or low-grade Ta disease will receive a maintenance course of therapy (3 weekly instillations of either ALT-803 plus BCG or BCG alone). Presence of Ta will require a TURBT procedure. Patients with presence of high-grade Ta, CIS or low-grade T1 disease will receive a re-induction course of therapy (6 weekly instillations of either ALT-803 plus BCG or BCG alone). Presence of Ta/T1 will require a TURBT procedure. Patients with high-grade T1 or greater disease (including disease progression) will be considered a treatment failure. Patients with no disease or low-grade Ta disease at months 6, 12, and 18 are eligible for maintenance treatment according to their assigned randomization. Patients with presence of disease greater than low-grade Ta will be considered a treatment failure. The primary endpoint of the study is the proportion of patients receiving ALT-803 plus BCG who are responders by Month 12 or earlier. Responders are defined as patients who experience a complete response (CIS patients) or no disease recurrence (defined as reappearance of high-risk disease). Enrollment is underway. Clinical trial information: NCT02138734.

Integrative molecular profiling challenges robustness of prognostic signature scores in multifocal prostate cancer.

96 Background: Tissue based biomarkers are increasingly utilized in men diagnosed with low grade prostate cancer (PCa) to guide definitive management vs. active surveillance. PCa is uniquely multifocal, suggesting ideal prognostic biomarkers should be robust to both undersampling of a high grade component of a mixed-grade tumor focus, as well as unsampled multifocal high grade tumor foci. Methods: To assess the robustness of prognostic biomarkers to multifocality, we designed a comprehensive multiplexed targeted RNA sequencing assay (mxRNAseq) capable of assessing multiple classes of transcriptional alterations and deriving available prognostic signature scores (e.g. Prolaris CCP and OncotypeDX GPS). We applied this assay to a retrospective cohort of 176 FFPE tissue samples representing the range of PCa progression. Single candidate biomarkers and derived prognostic signatures were analyzed in multifocal cases with only low-grade disease as well as those with extreme grade differences across tumor foci. Results: Our mxRNAseq assay robustly detected known coding gene/lncRNA expression, gene fusions, splice variants, and expressed somatic and germline mutations. Supervised clustering of target gene expression confirmed expected transcriptional module deregulation and derived prognostic signatures across PCa progression. Prognostic biomarkers (including derived signatures) showed no significant expression differences between low grade foci from prostates with and without high grade disease foci and were uniformly higher in high vs. low grade foci from the same case. In four cases of extreme multifocality (Gleason score 6 vs. ≥ 8 foci), prognostic signatures were significantly lower in low vs. high grade foci. In a clinical prostatectomy cohort of 1,418 men with diagnostic biopsy Gleason score 3+3 = 6 or 3+4 = 7, 21 (1.5%) had Gleason score ≥ 4+4 = 8, suggesting the initial biopsy missed or undersampled the most clinically relevant focus. Conclusions: Using a novel comprehensive mxRNAseq assay, our results challenge the robustness of prognostic biomarkers between multifocal low and high grade PCa foci, critically important in the context of un/under-sampled aggressive tumor foci.

U-SMART: (UCSD-small mass alt renal score tumor diameter) a novel scoring system of preoperative predictors to stratify oncologic risk of small renal mass.

700 Background: Small renal masses (SRMs, < 4 cm in diameter) are heterogeneous, with significant proportions of benign as well as high-grade malignancy. We developed a scoring system incorporating patient factors, serum markers, and morphometric characteristics to elucidate benign and high grade pathology and guide decision making. Methods: Single institution retrospective analysis of surgically treated SRMs from 2003-2017. Demographic and clinical factors, including RENAL score, were analyzed. Patients were categorized into 3 groups: benign (BNGN), low grade (LG), or high grade (HG) disease and uni- and multivariable logistic regression were used to screen for association between potential parameters and the 3 groups. Each significant variable was analyzed by risk group and broken into quartiles. The 75th percentile of the HG group was assigned a value of 3. Below the 75th percentile of the BNGN group was assigned a value of 1; values that fell between these cutoffs were assigned 2 points. Tumor diameter was weighted twice that of other factors. Receiver-operating-characteristic (ROC) analysis was used to assess for predictive capability. Results: 312 patients were analyzed (65 BNGN, 204 LG, 43 HG). Factors associated with increased risk of HG were male sex (OR 1.868, p = 0.045), higher ALT (OR 1.036, p = 0.022), higher RENAL score (OR 1.318, p = 0.002), and larger tumor diameter (OR 2.415, p < 0.001). Patients with low (5-8), intermediate (9-11) and high (12-14) scores had 32.8%, 5.2%, and 0% frequency of BNGN pathology. Patients with low, intermediate, and high scores had 7.7%, 18.6%, and 34.9% frequency of HG pathology. ROC analysis revealed AUC of 0.767. Conclusions: Preoperative clinical parameters were incorporated into a model that significantly predicts benign and aggressive pathology for SRMs. This risk stratification may provide a non-invasive method to aid in clinical decision making. External validation is requisite.[Table: see text]

Performance of a clinically validated urine exosome gene expression test to predict high grade prostate cancer in men with a prior negative biopsy.

119 Background: The over-diagnosis of low grade, indolent prostate cancer (PCa) initiates significant patient anxiety regarding treatment options and health risk. To address this clinical need, we developed and subsequently validated a noninvasive, easy to administer, supportive diagnostic test (ExoDx Prostate(IntelliScore), EPI) to guide the initial prostate biopsy decision process for men with PSA 2-10ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GS 7 PCa) from low-grade (GS 6) and benign disease, thereby potentially reducing the number of unnecessary biopsies. As many men have had prior negative/ benign biopsies, we sought to understand the performance of EPI in this selected population. Methods: Utilizing men with prior negative biopsies from two clinical trials we evaluated performance of the EPI test with respect to subsequent biopsy outcomes. We used the previously validated and alternative EPI cut-points of 15.6 and 20, respectively, to assess performance with AUC, sensitivity, and NPV. Results: A total of N = 286 patients with a prior negative biopsy; mean age 65 years, mean PSA 6.2 ng/mL, 22% positive family history, 15% African American; 32% positive biopsy rate: 20% GS6 (ISUP1) and 12% > / = GS7 PCa (ISUP≥2). AUC 0.68 vs. AUC 0.59 for standard of care (i.e. PSA, age, race, family history) and AUC 0.51 for PSA alone. By comparison the EPI initial biopsy AUC was 0.71. Using the previously validated EPI cut-points of 15.6 (or alternative 20) yielded NPVs of 92% and 95%, and number of avoided biopsies of 23% and 32%, respectively, and sensitivity of 85.7% for both cut-points. Notably, EPI in the initial biopsy setting had a sensitivity of 92 vs. 87% and an NPV of 91 vs. 90%, for the 15.6 and 20 cut-points, respectively. Conclusions: The EPI test is a noninvasive, first-catch, non-DRE gene expression array that accurately discriminates low-grade and benign biopsy outcomes from high-grade prostate cancer. The test performs well in both the initial and prior negative biopsy patients and has the potential to reduce the overall number of unnecessary biopsies in both settings.

Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) benefits selected patients with peritoneal mesothelioma. We present the outcomes of this treatment strategy in a UK peritoneal malignancy national referral centre.Methods: Observational retrospective analysis of data prospectively collected in a dedicated peritoneal malignancy database between March 1998 and January 2016.Results: Of 1586 patients treated for peritoneal malignancy, 76 (4.8%) underwent surgery for peritoneal mesothelioma. Median age was 49 years (range 21–73 years). 34 patients (45%) were female. Of the 76 patients, 39 (51%) had low grade histological subtypes (mostly multicystic mesothelioma), and 37 (49%) had diffuse malignant peritoneal mesothelioma (DMPM; mostly epithelioid mesothelioma). Complete cytoreduction was achieved in 52 patients (68%) and maximal tumour debulking (MTD) was performed in 20 patients (26%); the remaining 4 patients (5%) underwent a laparotomy with biopsy only. HIPEC was administered in 67 patients (88%). Median overall (OS) and disease-free survival (DFS) after CRS was 97.8 (80.2–115.4) and 58.8 (47.4–70.3) months, respectively. After complete cytoreduction, 100% overall survival was observed amongst patients with low-grade disease. Ki-67 proliferation index was significantly associated with survival outcomes after complete cytoreduction for DMPM and was an independent predictor of decreased survival.Conclusion: With adequate patient selection (guided by histological classification and Ki-67 proliferation index) and complete cytoreduction with HIPEC, satisfactory outcomes can be achieved in selected patients with peritoneal mesothelioma.

Effect of strenuous exercise on mediators of inflammation in patients with coronary artery disease

BackgroundCoronary artery disease (CAD) is considered a low-grade inflammatory disease. We aimed to identify effects of short-term strenuous exercise on mediators of systemic inflammation, endothelial and platelet activation in patients with angiographically verified CAD. We hypothesized that a more pronounced inflammatory response would be present in patients with CAD than in those without CAD. MethodsIn subjects with symptoms indicative of stable CAD, an exercise stress test on a bicycle ergometer was performed. Venous blood samples, taken at rest and within 5 min after end of exercise, were analyzed for the following markers by ELISAs: TNF-α, IL-6, MCP-1, ICAM-1, VCAM-1, E-selectin, P-selectin, CD40L and RANTES. All participants underwent conventional coronary angiography. CAD was defined as having any degree of atherosclerosis. ResultsA total of 110 patients were included, of whom 74 were found to have CAD. Mean exercise duration was 10:06 ± 3:56 min with no significant difference between the two groups. All measured markers changed significantly during exercise (p ≤ 0.012). A significantly less pronounced increase in CD40L in the CAD group than in the no CAD group was observed (p = 0.050), however, after adjustment for hematocrit this difference was no longer significant. ConclusionAn instant inflammatory response was observed during short-term strenuous exercise in patients with symptoms of CAD. However, the exercise mediated response was not more pronounced in patients with CAD.

Diagnostic and Prognostic Biomarkers of Adrenal Cortical Carcinoma.

The diagnosis of low-grade adrenal cortical carcinoma (ACC) confined to the adrenal gland can be challenging. Although there are diagnostic and prognostic molecular tests for ACC, they remain largely unutilized. We examined the diagnostic and prognostic value of altered reticulin framework and the immunoprofile of biomarkers including IGF-2, proteins involved in cell proliferation and mitotic spindle regulation (Ki67, p53, BUB1B, HURP, NEK2), DNA damage repair (PBK, γ-H2AX), telomere regulation (DAX, ATRX), wnt-signaling pathway (beta-catenin) and PI3K signaling pathway (PTEN, phospho-mTOR) in a tissue microarray of 50 adenomas and 43 carcinomas that were characterized for angioinvasion as defined by strict criteria, Weiss score, and mitotic rate-based tumor grade. IGF-2 and proteins involved in cell proliferation and mitotic spindle regulation (Ki67, p53, BUB1B, HURP, NEK2), DNA damage proteins (PBK, γ-H2AX), regulators of telomeres (DAXX, ATRX), and beta-catenin revealed characteristic expression profiles enabling the distinction of carcinomas from adenomas. Not all biomarkers were informative in all carcinomas. IGF-2 was the most useful biomarker of malignancy irrespective of tumor grade and cytomorphologic features, as juxtanuclear Golgi-pattern IGF-2 reactivity optimized for high specificity was identified in up to 80% of carcinomas and in no adenomas. Loss rather than qualitative alterations of the reticulin framework yielded statistical difference between carcinoma and adenoma. Angioinvasion defined as tumor cells invading through a vessel wall and intravascular tumor cells admixed with thrombus proved to be the best prognostic parameter, predicting adverse outcome in the entire cohort as well as within low-grade ACCs. Low mitotic tumor grade, Weiss score, global loss of DAXX expression, and high phospho-mTOR expression correlated with disease-free survival, but Weiss score and biomarkers failed to predict adverse outcome in low-grade disease. Our results underscore the importance of careful morphologic assessment coupled with ancillary diagnostic and prognostic biomarkers of ACC.

Concordance of Gleason grading with three-dimensional ultrasound systematic biopsy and biopsy core pre-embedding.

To determine the value of a three-dimensional (3D) greyscale transrectal ultrasound (TRUS)-guided prostate biopsy system and biopsy core pre-embedding method on concordance between Gleason scores of needle biopsies and radical prostatectomy (RP) specimens. Retrospective analysis of prostate biopsies and subsequent RP for PCa in the Jeroen Bosch Hospital, the Netherlands, from 2007 to 2016. Two cohorts were analysed: conventional 2D TRUS-guided biopsies and RP (2007-2013, n=266) versus 3D TRUS-guided biopsies with pre-embedding (2013-2016, n=129). The impact of 3D TRUS-guidance with pre-embedding on Gleason score (GS) concordance between biopsy and RP was evaluated using the κ-coefficient. Predictors of biopsy GS 6 upgrading were assessed using logistic regression models. Gleason concordance was comparable between the two cohorts with a κ=0.44 for the 3D cohort, compared to κ=0.42 for the 2D cohort. 3D TRUS-guidance with pre-embedding, did not significantly affect the risk of biopsy GS 6 upgrading in univariate and multivariate analysis. 3D TRUS-guidance with biopsy core pre-embedding did not improve Gleason concordance. Improved detection techniques are needed for recognition of low-grade disease upgrading.

Toward Personalised Liquid Biopsies for Urothelial Carcinoma: Characterisation of ddPCR and Urinary cfDNA for the Detection of the TERT 228 G>A/T Mutation.

Background:TERT promotor mutations are present in >75% of bladder tumours; these mutations are also detectable in urine. Previous studies have used urinary pellet DNA, and semi-quantitative methods unsuitable for detecting very low mutant allele frequencies.Objective:In this proof-of-principle study we use ddPCR to count the DNA molecules with wt and mutant TERT sequences in urinary cfDNA from patients whose bladder cancers harbour TERT mutations.Methods:Urinary cfDNA prepared from the urine from 104 bladder cancer patients was analysed. We determined the mutant allele frequency across stages and grades of disease, analysed concordance between cfDNA and tumour DNA, compared cfDNA with pellet DNA, and analysed the quantity and size distribution of cfDNA.Results:In 71 of 77 patients with a 228 G>A/T mutant tumour, the mutation was also detected in urinary cfDNA by ddPCR; all 6 “false negatives” were low grade pTa tumours. Overall concordance between tissue and cfDNA mutation status was 92%, and 100% was achieved for high grade disease. Median mutant allele frequencies in urinary cfDNA were 3.4, 13.4 and 32.1% in grade 1, 2 and 3 disease. The 228 G>A/T mutation was not detected in urinary cfDNA in 26 out of 27 mutation-negative patients (96% specificity).Conclusions:Concordance between tumour DNA and urinary cfDNA is high, and TERT 228 G>A/T ddPCR may prove useful for monitoring patients that harbour this mutation. Mutant allele frequencies in cfDNA are often high, but assays capable of detecting very low mutant allele frequencies will be required to achieve high sensitivity in low grade disease.

Role of CD44 in Regulating TLR2 Activation of Human Macrophages and Downstream Expression of Proinflammatory Cytokines.

Osteoarthritis (OA) is a low-grade chronic inflammatory joint disease. Innate immunity contributes to OA progression, mediated by TLR2 and TLR4. We evaluated the role of cluster determinant 44 (CD44), a transmembrane glycoprotein, in regulating TLR2-linked macrophage activation and resultant proinflammatory responses. TLR2 stimulation was performed on differentiated THP-1 macrophages in the presence or absence of a CD44-specific Ab or hyaluronan (HA). NF-κB nuclear translocation, IL-1 β and TNF-α gene expression, and protein concentrations were determined. Anti-CD44 Ab and HA treatments reduced NF-κB translocation, IL-1β and TNF-α expression, and production (p < 0.001). Inhibition of proinflammatory response in macrophages by HA was mediated by CD44. Protein phosphatase 2A mediated the reduction in NF-κB translocation by HA. CD44 knockdown reduced NF-κB nuclear translocation and downstream IL-1β and TNF-α protein production following TLR2 receptor stimulation (p < 0.001). CD44+/+ murine bone marrow-derived macrophages produced higher TNF-α compared with CD44-/- macrophages following TLR2 stimulation (p < 0.01). HA dose-dependently inhibited TLR2-induced TNF-α production by murine bone marrow-derived macrophages (p < 0.001). OA synovial fluids (SF) stimulated TLR2 and TLR4 receptors and induced NF-κB translocation in THP-1 macrophages. Anti-CD44 Ab treatment significantly reduced macrophage activation by OA SF (p < 0.01). CD44 regulated TLR2 responses in human macrophages, whereby a reduction in CD44 levels or engagement of CD44 by its ligand (HA) or a CD44-specific Ab reduced NF-κB translocation and downstream proinflammatory cytokine production. A CD44-specific Ab reduced macrophage activation by OA SF, and CD44 is a potentially novel target in OA treatment.

Mucoepidermoid Carcinoma: A 23-Year Experience with Emphasis on Low-Grade Tumors with Close/Positive Margins.

Objective Describe outcomes for mucoepidermoid carcinoma by histologic grade and evaluate outcomes for patients with low-grade tumors with close/positive margins after initial surgical resection. Study Design Cohort study. Setting Kaiser Permanente Southern California Medical Group from 1993 to 2016. Subjects and Methods Retrospective review of 154 patients with major and minor salivary gland mucoepidermoid carcinoma of the head and neck. Disease-specific and recurrence-free survival were stratified by tumor grade. Subgroup analysis of recurrence-free survival in patients with low-grade disease with close or positive margins was also performed. Results Five-year recurrence-free and disease-specific survival were excellent for both low- and intermediate-grade tumors, while there was there was a high rate of recurrence and mortality among patients with high-grade tumors. Patients with low-grade tumors with close or positive margins who were observed had no difference in recurrence-free survival compared to those who underwent revision surgery and/or adjuvant radiotherapy. Conclusions High-grade mucoepidermoid carcinoma has poor outcomes despite aggressive treatment. Among patients with low-grade tumors with close or positive margins on initial resection, additional treatment had no impact on survival or recurrence. Observation may be a reasonable alternative to additional treatment in this select group of patients.

Functional Defects of Regulatory T Cell Through Interleukin 10 Mediated Mechanism in the Induction of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a metabolic and low-grade inflammatory disease most commonly found in pregnant women with high body mass index and non-Caucasian ethnicities; however, not all women of high-risk groups develop GDM. We hypothesized that regulatory T cells (Tregs) might present a role in suppressing GDM development. To this end, 55 high-risk women at early pregnancy (first trimester) were recruited, and 21 of them developed GDM while the other 34 did not. Compared to those subjects who did not develop GDM (non-GDM), the patients who developed GDM presented reduced levels of Tregs and elevated levels of serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). The Tregs in the GDM group also presented reduced levels of transforming growth factor beta and IL-10, compared with the non-GDM group. The frequency of circulating Tregs and serum TNF-alpha level were inversely correlated. In addition, addition of Tregs from non-GDM patients, but not those from GDM patients, significantly suppressed the interferon gamma and TNF-alpha production by effector T cells through IL-10-mediated mechanisms, suggesting a functional defect in Tregs from GDM subjects. Together, these data indicated that the presence of functional Tregs could protect the pregnant women from GDM development by suppressing pro-inflammatory responses and that the dysregulation of Tregs early in pregnancy elevated the risk of GDM.

Characterization and outcomes of local treatment for primary bladder lymphoma: A population-based cohort analysis.

Introduction:Primary bladder lymphoma (PBL) is rare, representing 0.2% of extranodal lymphoma and less than 1% of all tumors originating in the bladder. Since the initial description of the disease, low-grade mucosa-associated lymphoid tissue (MALT) lymphoma has been reported as the most common subtype while high-grade disease was thought to represent only 20% of the reported cases.Materials and Methods:One hundred and ninety five patients with PBL from the Surveillance, Epidemiology, and End Results (SEER) registry from 1998-2010 were reviewed. Tumors were classified as high or low grade based on histologic subtype of lymphoma based on revised European-American Lymphoma classification system. Socio-demographic and clinical variables were reported, as well as survival outcome analyses using the Kaplan-Meier method and log-rank test. Cox proportional hazard analysis was used to generate hazard ratios for risk factors associated with mortality.Results:Eighty-three patients (42.6%) with low-grade and 112 patients (57.4%) with high-grade bladder lymphoma were studied. There were no differences between the low and high-grade groups for socio-demographic or clinical variables. Median overall survival or patients with low-grade disease was 38 months versus 15 months for patients with high-grade disease (p< 0.001). Analysis demonstrated worse survival outcomes for patients with high-grade disease compared to low-grade disease (p< 0.001). On multivariable analysis, increasing age and high-grade disease were associated with worse disease specific mortality (p< 0.001).Conclusion:Patient with high-grade primary bladder lymphoma had worse survival outcomes compared to those with low-grade disease. While transurethral resection provides tissue for diagnosis, immunotherapy/chemotherapy remains the mainstay of treatment for bladder lymphoma. Consolidation chemotherapy has been recommended in young patients not achieving complete remission with immunotherapy/chemotherapy.

Human Papillomavirus in Urothelial Carcinoma of Bladder: An Indian study.

Objectives:To study the role of high-risk human papillomavirus (HPV-16 and HPV-18) types in the causation of urothelial carcinoma of the urinary bladder in Indian population.Methods:50 patients with Urothelial carcinoma of the urinary bladder were included in the study. Another 10 age-matched subjects who were hospitalized for transurethral resection of prostate for benign prostatic hyperplasia and/or ureterorenoscopy for ureteric stone disease were enrolled as controls. The tissue samples were analyzed for the presence of HPV-16 and HPV-18 DNA by polymerase chain reaction (PCR). The histopathology of the tumor tissue was carried out to assess the grade of the tumor.Results:The mean age of the patients was 54.1 years. A total of 28 (56%) patients had high-grade tumors and 22 (44%) had low-grade disease. T2 or higher stage disease was observed in 18 (36%) patients. All cancerous specimens and control specimens were found to be negative by PCR for the presence of HPV DNA.Conclusion:HPV prevalence in the urothelium is very low irrespective of the stage and grade of the disease, and hence, it is unlikely to be the causative agent for urothelial carcinoma of the urinary bladder in Indian population. However, the role of other HPV types in the etiology of this tumor needs to be clarified.

Outcome of Mainz II Pouch Urinary Diversion after Radical Cystectomy in Patients with Muscle-invasive Bladder Cancer: Our Experience.

Introduction:Mainz II pouch urinary diversion in patients with muscle-invasive bladder cancer is one of the options of continent urinary diversion following radical cystectomy (RC). We aim to report our experience and the outcome of our patients who had this procedure.Patients and Methods:Patients who had RC and Mainz II pouch urinary diversion for muscle-invasive bladder cancer in our institution from 2007 to 2016 were evaluated. Variables analyzed included age, gender, stage of the disease, pathological grade and tumor types, complications, and survival status.Results:There were 11 patients who had Mainz II pouch urinary diversion after RC for bladder cancer over a 10-year period. Four (36%) were male and 7 (64%) were female. The mean age of the patients was 58.6 (range, 52–65) years. The diseases were pT2, pT3, and pT4 in 2 (18%), 7 (64%), and 2 (18%) patients, respectively. Four (36%) had pelvic nodal metastasis. Nine (82%) had a histological diagnosis of transitional cell carcinoma, and two (18%) were squamous cell carcinoma (SCC). Ten (91%) patients had high-grade disease, whereas only 1 (9%) patient had low-grade disease. Short-term morbidities were electrolytes derangement, hypokalemia, and acidosis in 2 (18%) patients and pyelonephritis in 2 (18%) patient. The two patients with invasive SCC had recurrence and death within 12 months of surgery. At present, four of the patients are alive, and seven are dead. Survival till date ranged from 8 to 120 months (mean survival time was 48 months). All patients achieved day and night time continence, and there was no significant long-term morbidity from the method of urinary diversion.Conclusion:Mainz II pouch urinary diversion is safe and acceptable to most of our patients with good long-term results.

Magnesium deficiency and increased inflammation: current perspectives.

Animal studies have shown that magnesium deficiency induces an inflammatory response that results in leukocyte and macrophage activation, release of inflammatory cytokines and acute-phase proteins, and excessive production of free radicals. Animal and in vitro studies indicate that the primary mechanism through which magnesium deficiency has this effect is through increasing cellular Ca2+, which is the signal that results in the priming of cells to give the inflammatory response. Primary pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-1; the messenger cytokine IL-6; cytokine responders E-selectin, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1; and acute-phase reactants C-reactive protein and fibrinogen have been determined to associate magnesium deficiency with chronic low-grade inflammation (inflammatory stress). When magnesium dietary intake, supplementation, and/or serum concentration suggest/s the presence of magnesium deficiency, it often is associated with low-grade inflammation and/or with pathological conditions for which inflammatory stress is considered a risk factor. When magnesium intake, supplementation, and/or serum concentration suggest/s an adequate status, magnesium generally has not been found to significantly affect markers of chronic low-grade inflammation or chronic disease. The consistency of these findings can be modified by other nutritional and metabolic factors that affect inflammatory and oxidative stress. In spite of this, findings to date provide convincing evidence that magnesium deficiency is a significant contributor to chronic low-grade inflammation that is a risk factor for a variety of pathological conditions such as cardiovascular disease, hypertension, and diabetes. Because magnesium deficiency commonly occurs in countries where foods rich in magnesium are not consumed in recommended amounts, magnesium should be considered an element of significant nutritional concern for health and well-being in these countries.

Persistent hematuria in patients with antineutrophil cytoplasmic antibody-associated vasculitis during clinical remission: chronic glomerular lesion or low-grade active renal vasculitis?

BackgroundWhether persistent hematuria in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) during clinical remission reflects active disease or chronic glomerular injury is uncertain. This study aimed to investigate the significance of persistent hematuria during clinical remission in a large cohort of AAV patients.MethodsA cohort of 219 AAV patients in complete clinical remission after induction therapy at our center was retrospectively studied, and their clinical and laboratory data as well as long-term outcomes were analyzed.ResultsA total of 80 out of 219 patients had persistent hematuria during clinical remission of AAV. Compared with patients without hematuria during remission, the slope of eGFR decline in patients with persistent hematuria was significantly higher during the long-term follow-up [3.6 (IQR 1.2, 7.2) vs. 1.5 (IQR 0.2, 4.0) mL/min/1.73 m2/year, P < 0.001]. Among the 80 patients with persistent hematuria during remission, there was little difference between those with fast and slow decline of eGFR, as divided by either median or interquartile range of the slope of eGFR decline. We also compared patients without hematuria who had a slope of eGFR decline that was lower than the median level of the slope of eGFR decline with those with persistent hematuria, and found that patients with hematuria had significantly lower levels of CRP and ESR at baseline and higher levels of ANCA at remission.ConclusionsAmong the AAV patients who achieved clinical remission after immunosuppressive therapy, those with persistent hematuria are not rare and may reflect either chronic renal damage or low-grade active renal disease.

Diagnostic performance of 68Gallium-PSMA-11 PET/CT to detect significant prostate cancer and comparison with 18FEC PET/CT.

BackgroundRadiolabeled prostate-specific membrane antigen (PSMA) has proven to be a highly accurate method to detect recurrence and metastases of prostate cancer, but only sparse data is available about its performance in the diagnosis of clinically significant primary prostate cancer.MethodsWe compared 68Ga-PSMA-11 PET/CT in 25 patients with 18FEC PET/CT in 40 patients with suspected prostate carcinoma based on an increased PSA level.The PET/CT results were compared with the histopathologic Gleason Score (GS) of biopsies.ResultsThe 68Ga-PSMA-11 PET/CT revealed highly suspect prostatic lesions (maximum standardized uptake value/SUVmax >2.5) in 21/25 patients (84%), associated with GS≥6 (low-grade/high-grade carcinoma). Two histopathologic non-malignancy-relevant cases (GS<6) had PSMA-SUVmax ≤2.5; all histopathologic high-grade cases (GS≥7b) showed PSMA-SUVmax >12.0 which further increased with rising GS. There were 2 false positives and no false negative findings for high-grade prostate cancer using a cut off-level for SUVmax of 2.5.In contrast, the 18FEC PET/CT showed suspected malignant lesions in 38/40 patients (95%), which included 3 lesions with GS<6. The mean SUVmax values did not differ with different GS. There were 11 false positives and 1 false negative for detection of high-grade prostate cancer (cut off 2.5).By means of ROC analysis a SUVmax of 5.4 was found to be an optimal cut off-level to distinguish between low- and high-grade carcinoma in 68Ga-PSMA-11 PET/CT (AUC=0.9692; 95% CI 0.9086;1.0000;SD(AUC)=0.0309)). Choosing a cut off-level of SUVmax5.4, 68Ga-PSMA-11 PET/CT was able to distinguish between GS ≤7a/≥7b with a sensitivity of 84%, a specificity of 100%, a negative predictive value (NPV) of 67%, and an efficiency of 88% (p<0.001).The ROC analysis revealed a SUVmax 6.5 as an optimal cut off-level to distinguish between low- and high-grade carcinoma in 18FEC PET/CT (AUC=0.7470; 95% CI 0.5919;0.9020;SD(AUC)=0.0791) with a sensitivity of 61% and a specificity of 92%; but the efficiency was only 70% and the NPV 50% (p=0.01).Conclusion68Ga-PSMA-11 PET/CT guided biopsy of the prostate increases diagnostic precision and is likely to help to reduce overtreatment of low-grade malignant disease as well as detect the foci of the highest Gleason pattern. Both methods (68Ga-PSMA-11,18FEC) were suitable to detect primary prostate cancer, but the excellent image quality, the higher specificity and the good correlation of positive scans with GS are advantages of 68Ga-PSMA-11.

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

BackgroundThe administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)–positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment.MethodsIn this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan–Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients’ outcomes during the period from 5 to 20 years.ResultsBreast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1–3), and 34% with four to nine nodes involved (T1N4–9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1–3, and 41% with T2N4–9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively.ConclusionsAfter 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.)