High-grade Disease Research Articles

Long-Term Follow-up of Patients with Indolent Lymphoma after First Line Therapy with Rituximab As Single Agent or in Combination with Interferon-α2a

Background:For patients with indolent lymphoma, the optimal timing, sequence and choice of therapeutic regimens remain matters of debate. The Nordic Lymphoma Group performed two randomized trials (the phase II M39035 accrual 1998-1999 and the phase III ML16865 accrual 2002-2008) including a total of 439 (126+313) patients with symptomatic indolent CD20+ lymphoma (Kimby et al. 2008, 2015) with rituximab monotherapy or rituximab in combination with interferon(IFN)-α2a as initial treatment. In the first trial responding patients (CR, PR or MR) after 4 weekly infusions of single rituximab were randomized to 4 additional infusions + IFN-α2a MIU/day subcutaneously week 1, followed by 4.5 MIU/day weeks 2-5. In the second trial randomization was performed already at inclusion. Most were previously untreated but patients with late relapse after a previous response to chlorambucil, local radiation or both were also eligible. The trial rationales were to delay chemotherapy and associated acute and long-term side effects by initial immunotherapy and investigate whether priming with IFN-α2a in addition to rituximab improves progression-free survival. Yet, some concerns have been raised regarding the risk of undertreatment without chemotherapy and possibly a higher incidence of transformation to high-grade lymphoma and premature death.Aim/ Purpose:To evaluate the long-term effect and safety of mere biologic therapy, consisting of rituximab 375 mg/m2, 2 x 4 weeks with or without IFN-α2a, by assessing overall survival (OS), late toxicities and need of additional treatment in patients with indolent CD20+ lymphoma.Methods:Eligible were all Danish, Norwegian and Swedish patients from the previous trials with the exclusion of patients with mantle cell lymphoma (MCL), with immunocytoma, with chronic lymphocytic lymphoma phenotype and those whose biopsy reviews rendered diagnoses of any high-grade lymphoma, leaving in total 395 patients (84% with follicular lymphoma) eligible for follow-up. Those who still alive were asked for participation including permission of extensive medical file reviews. Diseased patients were included under the presumption of consent as they all had approved the former clinical trials. 31 patients who had data available only from the original trials were censored at their individual follow-up time point of 3-5 years. The study was approved of by the Regional Ethical Committees in each country. Treating physicians at the participating centers collected data on patients' therapies after the end of trial, any evidence of transformation to high-grade disease, infectious complications and second cancers.Results:After a median follow-up time of 9,4 (0,1 -18,1) years from randomization, 286 patients were still alive (fig. 1) more women than men (p < 0,05). Median follow-up for living patients was 10,5 years. Cause of death was for 62 patients progression of disease or therapy complications whereas 30 had died of non-lymphoma related causes. After protocol induction therapy, 107 patients (27%) had not required any additional treatment. Median time to new therapy was 2,1 (0,01-17,5) years. At a median follow-up of 8,7 (0,1-17,8) years from randomization 82 patients with indolent disease had transformed to diffuse large B cell lymphoma (DLBCL), a rate of 2,3% per year. Two patients transformed to Hodgkins lymphoma and one to MCL after 1, 6,5 years and 2 years (fig. 2). At least one second malignancy was diagnosed in 39 patients, whereof 7 were acute myeloid leukemia/myelodysplastic syndrome, one was a T cell lymphoproliferative disease and one was chronic myeloid leukemia (table 2). Infections were most likely somewhat under reported (not shown).Conclusion:Most low-grade lymphoma patients included in the M39035 or ML16865 trial are alive at a median follow-up of more than 10 years, providing an opportunity to achieve long-term data on relapse, transformation, late toxicity and survival. We found that the overall survival and rate of transformation after initial treatment with biological agents was comparable to trials with immunochemotherapy. A subgroup of patients show longstanding remission, suggesting initial therapy with only biological agents may well be considered. Close ahead is an extension of this follow-up project with comparative analyses including a matched group of indolent lymphoma patients treated with standard immunochemotherapy as first-line therapy. [Display omitted] DisclosuresHolte:Nordic Nanovector: Consultancy; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Oslo University Hospital: Employment. Kimby:Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.

Does margin width impact breast cancer recurrence rates in women with breast conserving surgery for ductal carcinoma in situ?

Controversy remains regarding the optimal margin width for patients with ductal carcinoma in situ (DCIS) who undergo breast conserving surgery (BCS). Women with a primary DCIS diagnosis were enrolled in a statewide population-based cohort from 1997 to 2006. Patients were surveyed every two years with follow-up data available through 2016. Surgical pathology reports were collected for 559 participants following breast conserving surgery. Multivariable Cox proportional hazard models evaluated relationships between locoregional recurrence (LRR) and margin width in the presence or absence of adjuvant radiation therapy while controlling for age, menopausal status and duration of endocrine therapy use. The majority of women in this study were over 50yo (74%), 34% had high grade disease, and 77% underwent radiation. The overall LRR rate was 12%. A LRR occurred in 46 women who had radiation (11%) and 23 women who did not undergo radiation (19%). Univariate analysis identified smaller margin width, younger age, premenopausal status, no radiotherapy, and shorter endocrine therapy use associated with LRR. Multivariable models demonstrated that close margins (< 2mm) were associated with an increased risk of recurrence when compared to margins ≥ 2mm in width whether women received radiation (HR 1.98 CI 0.87-4.54) or not (HR 1.32 CI 0.27-6.49), but confidence intervals were wide. In this study, patients with DCIS and close margins were less likely to experience recurrence after routine re-excision to margins greater than 2mm.

High-risk HPV positivity is a long-term risk factor for recurrence after cervical excision procedure in women living with HIV.

ObjectiveTo evaluate the risk factors for recurrence of high‐grade disease after cervical excision in women living with HIV (WLWH), with a specific interest in the role of high‐risk (HR‐) HPV positivity.MethodsMulticentric retrospective study conducted on WLWH who underwent cervical excision between January 1987 and June 2017 in six Italian institutions. The rate of high‐grade recurrence was determined. Risk factors for recurrence and HR‐HPV positivity were determined with the Log‐rank test and Cox proportional hazards regression models.ResultsA total of 271 WLWH were included in the final analysis. A high‐grade recurrence was found in 58 (21.4%) patients. Age 41 years or more at inclusion and HR‐HPV positivity during follow up were independently associated with a higher risk of disease recurrence with relative risks of 4.15 (95% confidence interval [CI] 2.01–8.58, P < 0.001) and 5.18 (95% CI 2.12–12.67, P < 0.01), respectively. Age 41 years or more (relative risk 1.75, 95% CI 1.01–3.04, P = 0.047) resulted as a risk factor for HR‐HPV positivity during follow up.ConclusionHR‐HPV positivity is a risk factor for recurrence after cervical excision in WLWH. Women older than 41 years may benefit from a long‐term yearly follow up. Future studies regarding HPV vaccination after treatment in WLWH may be useful, considering the protective role of the higher probability of HPV negativity in vaccinated women.

Seminal plasma metabolomics reveals lysine and serine dysregulation as unique features distinguishing between prostate cancer tumors of Gleason grades 6 and 7.

Prostate cancer (PCa) is a metabolic disease. Most men are diagnosed with low grade indolent disease and differentiating these men from those who have life threatening cancer is a challenging but important clinical dilemma. There are currently limited biomarkers that can distinguish between the indolent Gleason grade 6 and higher-grade disease. Moreover, some individuals initially diagnosed with low grade disease progress to higher grade disease. Currently prostate biopsies are the only reliable methods of stratifying risk, but biopsies can cause significant morbidity, sample only a small portion of the gland and are costly. Therefore, biomarkers distinguishing between indolent and aggressive patterns of PCa are urgently required to minimize biopsy-associated morbidity, prevent over-treatment of indolent PCa and to better stratify patients for appropriate treatment. Seminal fluid samples were collected from normal individuals (n = 13) Before infertility treatment and histologically confirmed PCa patients (n = 51). 1 H Nuclear magnetic resonance spectroscopy and orthogonal partial least square discriminant analysis were used to compare the populations. Alterations in amino acids levels, specifically lysine and serine and changes in glycolytic intermediates were the most significant metabolic features associated with differences between healthy controls andPCa and between Gleason grade 6 (GS6) and Gleason grade 7 (GS7) samples. Orthogonal partial least square plots discriminated healthy controls from PCa samples (R 2 = 0.54, Q 2 = 0.31; area under the receiver operating characteristics curve [AUC] = 0.96), and GS6 from GS7 samples (R 2 = 0.62, Q 2 = 0.49; AUC = 0.98) based on lysine and serine content. This study suggests that seminal plasma metabolomics profiling of seminal fluid is a promising means of differentiating indolent from aggressive disease. Particularly, lysine and serine levels may be able to differentiate GS6 from GS7 disease.

Evaluation of Collagen Alterations in Early Precursor Lesions of High Grade Serous Ovarian Cancer by Second Harmonic Generation Microscopy and Mass Spectrometry.

Simple SummaryThe collagen architecture in the extracellular matrix (ECM) is highly remodeled in high grade serous ovarian cancer (HGSOC). Many of these tumors begin in the fallopian tubes (FT) before metastasizing to the ovaries and it is important to study ECM alterations in carcinogenesis. Here, we used Second Harmonic Generation (SHG) microscopy to classify changes in the collagen fiber morphology in normal FT, and precursor pure p53 signatures and serous tubal intraepithelial carcinoma (STICs) in tissues with no HGSOC. Using a machine learning approach based on image features, we were able to discriminate the tissue groups with good classification accuracy. We additionally performed mass spectrometry analysis of normal and HGSOC tissues to associate the differential expression of collagen isoforms with fiber morphology alterations. This work provides new insights into ECM remodeling in early stage HGSOC and suggests the combined use of SHG microscopy and mass spectrometry as a new diagnostic/prognostic approach.Background: The collagen architecture in high grade serous ovarian cancer (HGSOC) is highly remodeled compared to the normal ovary and the fallopian tubes (FT). We previously used Second Harmonic Generation (SHG) microscopy and machine learning to classify the changes in collagen fiber morphology occurring in serous tubal intraepithelial carcinoma (STIC) lesions that are concurrent with HGSOC. We now extend these studies to examine collagen remodeling in pure p53 signatures, STICs and normal regions in tissues that have no concurrent HGSOC. This is an important distinction as high-grade disease can result in distant collagen changes through a field effect mechanism. Methods: We trained a linear discriminant model based on SHG texture and image features as a classifier to discriminate the tissue groups. We additionally performed mass spectrometry analysis of normal and HGSOC tissues to associate the differential expression of collagen isoforms with collagen fiber morphology alterations. Results: We quantified the differences in the collagen architecture between normal tissue and the precursors with good classification accuracy. Through proteomic analysis, we identified the downregulation of single α-chains including those for Col I and III, where these results are consistent with our previous SHG-based supramolecular analyses. Conclusion: This work provides new insights into ECM remodeling in early ovarian cancer and suggests the combined use of SHG microscopy and mass spectrometry as a new diagnostic/prognostic approach.

Selected Articles from This Issue

Emerging data indicates genetic polymorphisms may affect the efficacy of aspirin for chemoprevention of colorectal cancer and may be used as a tool to improve risk assessment and identify individuals that are likely to benefit. Biltaji and colleagues created a decision analytical model to assess the potential benefit of a genotype-guided aspirin strategy for colorectal cancer chemoprevention in an average risk population. The authors concluded the approach was cost-effective and improved clinical outcomes. This model establishes a framework and the potential clinical utility for a precision medicine approach to targeted chemoprevention of colorectal cancer.Examining excess mortality among cancer survivors relative to the general population can inform planning for surveillance and follow-up after cancer treatment. Anderson and colleagues examined patterns of excess mortality among women with endometrial cancer identified in the Surveillance, Epidemiology and End Results (SEER) database. Overall, endometrial cancer survivors had little excess mortality compared to the general population beyond 4 years post-diagnosis. However, excess mortality was greater for Black survivors and those with more advanced stage or higher-grade disease. Strategies to mitigate long-term mortality disparities among endometrial cancer survivors are needed.Type 2 diabetes (T2DM) has been associated with an increased risk of developing several common cancers, but it is unclear whether this association is causal. Pearson-Stuttard and colleagues aimed to summarize the evidence on T2DM and cancer and evaluate the validity of associations from both observational and Mendelian randomization (MR) studies. This study provides a comprehensive update of the observational evidence linking type 2 diabetes and cancer risk across 21 different sites and is substantially enhanced by the inclusion of MR studies which address potential causation and mechanisms. The most robust observational evidence was detected for T2DM and increased risk of colorectal, breast, endometrial, gallbladder, hepatocellular and pancreatic cancer, while MR studies supported a causal association between genetically predicted T2DM and/or fasting insulin concentrations and risk of endometrial, breast and pancreatic cancer, as well as with lung, kidney and cervical cancer.Accelerated breast tissue aging is thought to contribute to an elevated incidence of breast cancer in younger women. Estrogen stimulation and cell cycling are thought to underlie this accelerated aging process. Sehl and colleagues investigated methylation-based estimates of biologic aging in normal breast tissue of healthy women donors, focusing analysis on Grim age, an epigenetic age measure whose acceleration in peripheral blood is associated with time to cancer. The study found that earlier age at menarche and higher body mass index are associated with acceleration in Grim age in breast tissue, supporting the hypothesis that lifetime estrogen exposure drives epigenetic aging in healthy female breast tissue.

Novel FAP ligands enable improved imaging contrast in sarcoma patients due to FAPI-PET/CT

PurposeA high expression of fibroblast activation protein (FAP) was observed in multiple sarcomas, indicating an enormous potential for PET/CT using 68Ga-radiolabeled inhibitors of FAP (FAPI). Therefore, this retrospective study aimed to evaluate the role of the novel hybrid imaging probe for sarcomas as a first clinical evaluation.MethodsA cohort of 15 patients underwent 68Ga-FAPI-PET/CT for staging or restaging. The acquisition of PET scans was performed 60 min after administration of 127 to 308 MBq of the tracer. The uptake of 68Ga-FAPI in malignant tissue as well as in healthy organs was quantified by standardized uptake values SUVmean and SUVmax.ResultsExcellent tumor-to-background ratios (> 7) could be achieved due to low background activity and high SUVmax in primary tumors (median 7.16), local relapses (median 11.47), and metastases (median 6.29). The highest uptake was found for liposarcomas and high-grade disease (range 18.86–33.61). A high SUVmax (> 10) was observed for clinically more aggressive disease.ConclusionThese preliminary findings suggest a high potential for the clinical use of 68Ga-FAPI-PET/CT for patients diagnosed with sarcoma.

The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice.

Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, the Ataxia-telangiectasia mutated (ATM) gene, is involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some variants of ATM are associated with an increased risk of BC development and a worse prognosis. Thus, many patients harboring ATM mutations develop intermediate- and high-grade disease, and there is a higher rate of lymph node metastatic involvement. The evidence concerning a correlation of ATM gene mutations and the efficacy of therapeutic strategies in BC management are controversial. In fact, ATM mutations may sensitize cancer cells to platinum-derived drugs, as BRCA1/2 mutations do, whereas their implications in objective responses to hormonal therapy or target-based agents are not well defined. Herein, we conducted a review of the role of ATM gene mutations in BC development, prognosis, and different treatment strategies.

Prospective validation of the Kaiser Permanente prostate cancer risk calculator in a contemporary, racially diverse, referral population

PurposeTo prospectively validate a new prostate cancer risk calculator in a racially diverse population. Materials and MethodsWe recently developed, internally validated and published the Kaiser Permanente Prostate Cancer Risk Calculator. This study is a prospective validation of the calculator in a separate, referral population over a 21-month period. All patients were tested with a uniform PSA assay and a standardized systematic, ultrasound-guided biopsy scheme. We report on 3 calculator models: Model 1 included age, race, PSA, prior biopsy status, body mass index, and family history of prostate cancer; Model 2 added digital rectal exam to Model 1 variables; Model 3 added prostate volume to Model 2 variables. We considered three outcomes: high-grade disease (Gleason score ≥7), low-grade disease (Gleason score=6), and no cancer. Predictive discrimination and calibration were calculated. How each model might alter biopsy frequency and outcomes at various thresholds of risk was assessed. We compared the performance of our calculator with two other calculators. ResultsIn 4178 patients (16.2% Asian, 11.3% African American, 13.5% Hispanic), cancer was found in 53%; 62% were Gleason score ≥7. Using a high-grade risk threshold for biopsy of ≥10%, Model 2 predictions would result in 9% of men avoiding a biopsy, while only missing 2% of high-grade cancers. At the same threshold, Model 3 predictions would result in 26% of men avoiding a biopsy, while only missing 5% of high-grade cancers. The c-statistics for Models 1, 2, and 3 to predict high-grade disease vs. low-grade or no cancer were 0.76, 0.79 and 0.85, respectively. The c-statistics for Models 1, 2, and 3 to predict any prostate cancer vs. no cancer were 0.70, 0.72 and 0.80, respectively. All models were well calibrated for all outcomes. Our Model 3 calculator had superior discrimination for high grade disease (c-statistic=0.85, 0.84-0.86) and any cancer (0.80, 0.79-0.82) compared to the PBCG calculator [(0.79, 0.78-0.80); 0.72 (0.70-0.73)] and the PCPT calculator [(0.75, 0.74-0.77); 0.69 (0.67-0.70)], respectively. In the high-grade cancer predicted risk range of 0-30%, our Model 2 was better calibrated than the PCPT and PBCG calculators. ConclusionsThis validation of our calculator showed excellent performance characteristics.

Intraoperative radiotherapy boost as part of breast-conservation therapy for breast cancer: a single-institution retrospective analysis

BackgroundThere are currently no data from randomized controlled trials on the use of intraoperative radiotherapy (IORT) as a tumor bed boost as part of a breast-conservation approach for breast cancer. This study retrospectively reviewed the safety and efficacy of IORT as a boost treatment at a tertiary cancer center.MethodsFrom 2015 to 2019, patients underwent breast-conserving surgery with axillary lymph node staging and a single dose of 20 Gy IORT with 50-kV photons, followed by whole-breast irradiation (WBI) and adjuvant systemic therapy (if applicable). Patients were followed for assessment of acute and late toxicities (using the Common Terminology Criteria for Adverse Events version 5.0) at 3–6-month intervals. Outcomes included ipsilateral (IBTR) and contralateral breast progression-free survival (CBE), distant metastasis-free survival (DMFS), and overall survival (OS).ResultsMedian follow-up for the 214 patients was 28 (range 2–59) months. Most patients had T1 disease (n = 124) and were clinically node negative. Only few patients had high-grade and/or triple-negative disease. The vast majority of patients underwent sentinel node biopsy, and 32 (15%) required re-resection for initially positive margins. Finally, all tumor bed margins were clear. Nine (4.2%) and 48 (22.4%) patients underwent neoadjuvant and adjuvant chemotherapy, respectively. WBI was predominantly performed as conventionally fractionated WBI (n = 187, 87.4%), and the median time from BCS to WBI was 54.5 days. IORT was delivered with a single dose of 20 Gy. The median WBI dose was 50 Gy (range 29.4–50.4 Gy). No patients experienced grade 4 events; acute grade 3 toxicities were limited to 17 (8%) cases of radiation dermatitis. Postoperative toxicities were mild. After WBI only one case of late grade ≥ 2 events was reported. There were two recurrences in the tumor bed and one contralateral breast event.ConclusionThis investigation provides additional preliminary data supporting the using of IORT in the boost setting and corroborates the existing literature. These encouraging results should be prospectively validated by the eventual publication of randomized studies such as TARGIT‑B.

Treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy.

Pseudomyxoma peritonei is a disease caused by the widespread distribution of mucinous tumor into the peritoneal space from a perforated appendiceal neoplasm. All patients in this study had cytoreductive surgery with total gastrectomy plus perioperative intraperitoneal chemotherapy. A high diverting jejunostomy was used on all patients. Patient characteristics, adverse events, and survival were accumulated prospectively. Fifty-eight patients were available for long-term follow-up. In the univariate analysis, features associated with a less favorable outcome included female gender (p = 0.0127), intestinal obstruction before treatment (p = 0.00791), and prior surgical score (PSS) (p = 0.0054). In the multivariate analysis, the two significant variables were grade (p = 0.0458) and PSS (p = 0.0041). Median survival was 12 years with a 5-, 10-, and 20-year survival of 76%, 58%, and 37%, respectively. There were two postoperative deaths (3.4%) and Grades 3 and 4 adverse events in 20 (34.5%) patients. A 10-year survival after cytoreductive surgery, total gastrectomy with temporary high diverting jejunostomy, and perioperative chemotherapy occurred in 58% of these patients with advanced pseudomyxoma peritonei. High-grade disease and extensive prior surgery with a high PSS were associated with reduced benefit.

Clinicopathological Characteristics and Prognostic Prediction in Pseudomyxoma Peritonei Originating From Mucinous Ovarian Cancer.

ObjectiveTo describe the clinicopathological characteristics of mucinous ovarian cancer (MOC)-derived pseudomyxoma peritonei (PMP) and identify prognostic factors for survival.MethodsMedical records from patients with MOC-derived PMP who attended the Aerospace Center Hospital, Beijing, China between January 2009, and December 2019 were retrospectively reviewed. Survival analysis was performed with the Kaplan-Meier method, the log-rank test, and a Cox proportional hazards model.ResultsCytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for PMP originating from MOC were performed on 22 patients, who had a median age of 52 years at the time of surgery. At the last follow-up in June 2020, 9 (41%) patients were still alive. Median OS was 12 months (range, 1 to 102 months), and the 2-, 3-, and 5-year survival rates were 23, 9, and 5%, respectively.ConclusionHistopathologic subtype and PCI may be applied as predictors of prognosis in patients with MOC-derived PMP. Patients with high-grade disease could benefit from completeness of cytoreduction (CCR) 0/1.

Triage of human papillomavirus infected women by methylation analysis in first-void urine

Host cell DNA methylation analysis in urine provides promising triage markers for women diagnosed with a high-risk (HR) human papillomavirus (HPV) infection. In this study, we have investigated a panel of six host cell methylation markers (GHSR, SST, ZIC1, ASCL1, LHX8, ST6GALNAC5) in cervicovaginal secretions collected within the first part of the urine void (FVU) from a referral population. Cytology, histology, and HPV DNA genotyping results on paired FVU and cervical samples were available. Urinary median methylation levels from HR-HPV (n = 93) positive women were found to increase for all markers with severity of underlying disease. Significantly elevated levels were observed for GHSR and LHX8 in relation to high-grade cervical intraepithelial neoplasia (CIN2 +; n = 33), with area under de curve values of 0.80 (95% Confidence Interval (CI) 0.59–0.92) and 0.76 (95% CI 0.58–0.89), respectively. These findings are the first to support the assertion that methylation analysis of host cell genes is feasible in FVU and holds promise as molecular, triage strategy to discern low- from high-grade cervical disease in HR-HPV positive women. Molecular testing on FVU may serve to increase cervical cancer screening attendance in hard-to-reach populations whilst reducing loss to follow-up and await further optimization and validation studies.

Misanian Men, are or aren't a Prostatic Adenocarcinoma?

It is an observational study in Al-Shafaa Oncology Center in Misan province about male patients with prostatic carcinoma to make an idea about the prevalence of this malignancy. This study was carried out during the period from July 2018 to March 2019 in Al-Shafaa Oncology Center in Al-Sadder teaching hospital in Misan province in which 53 male patients were involved. In our study we found that that the disease reaching a peak among patients between (70-80) years, (66.03%) of patients are a smoker (13.2%), had a family history of different type of cancer, (100%) of the patients had adenocarcinoma, (56.6%) that had high-grade cancer (Gleason score ˃8), (77.35%) of the patient had PSA level &gt;100 ng/ml. The prostate cancer in Misan appears to be more likely to occur in the presence of particular risk factor like age, hypertension, family history, and less likely in the presence of diabetes mellitus. It is more likely to be presented with high grade and metastatic disease, and this may be primarily explained by the absence of the screening program.

Five-year follow-up after cervical cytology and histology discordance: A retrospective cohort study.

Cervical smear cytology and colposcopic biopsy histology are prone to error at both collection and interpretation stages, leading to a large number of discordant cases. Investigation of five-year outcomes for women who have cervical cytology that is discordant and higher grade than histology results. A retrospective cohort study was carried out for 111 women with cervical cytology discordant and higher grade than histology, after cytopathological review, over a three-year period. Five-year follow-up data were reviewed to identify the highest level of pathology seen within five years from the discordance. Women with atypical squamous cells with possible high-grade change (ASC-H) cytology and negative biopsy (n=28) had a 46% chance of high-grade histological disease within 5years; with cervical intraepithelial neoplasia grade 1 (CIN1) histology (n=20), this was reduced to 30%. With high-grade cytology and negative histology (n=23), 48% had high-grade disease within five years, including one case of invasive disease; with CIN1 histology 50% had high-grade disease within five years. This study demonstrates a 30-50% chance of high-grade disease within five years, in the setting of ASC-H or high-grade cytology with a negative or low-grade colposcopic biopsy. This highlights that in the setting of cytology and histology discordance, at least one of the tests indicating high-grade pathology warrants the need for treatment or close ongoing surveillance.

Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas.

Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications. We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes. Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM. TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.

Association Between Antibiotic Treatment and the Efficacy of Intravesical BCG Therapy in Patients With High-Risk Non-Muscle Invasive Bladder Cancer.

ObjectiveTo investigate the association between antibiotic therapy and the efficacy of intravesical BCG therapy in patients with high-risk non-muscle invasive bladder cancer (NMIBC).MethodsThis study involved the retrospective review of medical records of patients who underwent transurethral resection of bladder tumors for high-risk NMIBC followed by intravesical BCG therapy between 2008 and 2017. Patients were categorized as none, short- (2-6 days), and long-course use (≥7 days) based on the duration of antibiotic treatment concurrent with or initiated ≤30 days before BCG therapy. Oncologic outcomes, including recurrence-free survival and progression-free survival, were analyzed.ResultsOf the 276 patients enrolled in the study, 162 (58.7%) had pathologic T1 disease and 206 (80.2%) had high-grade disease. Concurrently with or prior to BCG therapy, 114 patients had (41.3%) received short-course antibiotic therapy, and 96 (34.8%) patients had received long-course antibiotics. The 5-year recurrence-free survival (62.2% vs 26.9%; log rank, p <0.001) and progression-free survival (79.6% vs. 53.3%; log rank, p=0.001) rates were significantly higher in patients who did not receive antibiotic therapy than in those treated with long-course antibiotics. Multivariable analysis revealed that antibiotic treatment for more than 7 days was independently associated with increased risks of recurrence (hazard ratio [HR], 2.45; 95% confidence interval [CI], 1.49-4.05; p < 0.001) and progression (HR, 3.68; 95% CI, 1.65-8.22 p = 0.001).ConclusionLong-course antibiotic treatment concurrently with or prior to intravesical BCG adversely influenced disease recurrence and progression outcomes in patients with high-risk NMIBC. Careful use of antibiotics may be required to enhance the efficacy of intravesical BCG therapy. Further mechanistic and prospective studies are warranted.

The Impact of COVID-19 Disease on Urology Practice.

The diagnosis and timely treatment of cancer patients should not be compromised during an infectious disease pandemic. The pandemic of coronavirus disease 2019 (COVID-19) has serious implications on urology practice and raises particular questions for urologists about the management of different conditions. It was recommended to cancel most of the elective urological surgeries. Urological cancers surgeries that should be prioritized are radical cystectomy for selective tumors, orchiectomy for suspected testicular tumors, nephrectomy for c T3 + , nephroureterectomy for high-grade disease, and radical adrenalectomy for tumors >6 cm or adrenal carcinoma. Most prostatectomies can be delayed without compromising the survival rate of patients. Urological emergencies should be treated adequately even during this pandemic. There is a potential risk of coronavirus diffusion during minimally invasive procedures performed. It is crucial to use specific precautions when urologists performed those type of surgeries. It was also recommended to suspend the kidney transplantation program during the COVID-19 pandemic except for specific cases. In this review, we discussed the triage of urological surgeries, the risk of minimally invasive urological procedure, the kidney transplantation challenges, the systemic therapies, intravesical instillation of Bacillus Calmette-Guérin (BCG), endourology, teleconferencing, and telemedicine application in urology during the COVID-19 pandemic.

High-risk human papillomavirus testing in women with ASCUS cytology: results from The ATHENA HPV study

This study evaluated the clinical performance of the cobas 4800 HPV Test (Roche Molecular Systems, Pleasanton, CA, USA) for high-risk human papillomavirus (HR-HPV) testing with individual HPV-16/HPV-18 genotyping in women 21 years or older with atypical squamous cells of undetermined significance (ASCUS). Women (N = 47,208) were recruited in the United States during routine screening, and liquid-based cytology and HPV testing were performed. The ASCUS prevalence was 4.1% (1,923/47,208), and 1,578 women underwent colposcopy with valid results. The cobas 4800 HPV Test demonstrated performance comparable to the Hybrid Capture 2 test (QIAGEN, Gaithersburg, MD, USA) for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse and grade 3 or worse. HPV-16/HPV-18+ women had a greater absolute risk of CIN 2 or worse compared with pooled HR-HPV+ and HR-HPV- women (24.4%, 14.0%, and 0.8%, respectively).The cobas 4800 HPV Test is clinically validated for ASCUS triage. HPV-16/HPV-18 genotyping can identify women at highest risk for high-grade cervical disease, and this additional risk stratification may be used in formulating patient management decisions.

An Updated Systematic Review of Human Papillomavirus Genotype Distribution by Cervical Disease Grade in Women Living With Human Immunodeficiency Virus Highlights Limited Findings From Latin America.

Cervical cancer is 5 times more likely among women living with human immunodeficiency virus (WHIV), likely due to higher prevalence of human papillomavirus (HPV). Despite evidence of higher rates with multiple HPV genotypes in WHIV, there are no recommendations for triage by HPV genotyping specific to WHIV. In Latin America/Caribbean rates are high and vary significantly. To guide optimization of HPV-based cervical cancer screening among WHIV in Latin America/Caribbean, review of current literature was completed to assess HPV genotype distribution by cervical disease grade in WHIV in this region; and further expanded globally for comparison across regions.A systematic review of the literature from June 2016 to January 2020 revealed 15 studies reporting human papillomavirus (HPV) genotype distribution by cervical disease state (normal, low-grade disease, high-grade disease, and invasive cervical cancer) across different global regions.Across all studies, there were 6928 WHIV from 4 global regions, 3952 of whom were HPV-positive. Three studies from Latin America/Caribbean (LAC) countries were reviewed, with 1 providing enough detail to describe HPV genotypes by cervical disease grade and identified types 31 and 35 in high-grade cervical lesions. Of the studies included, 4 from Africa and Europe/North America each, and 1 from Asia included data that were able to be summarized.Latin America, a region which experiences high rates of HPV, human immunodeficiency virus (HIV), and cervical disease, had few published studies reporting HPV genotypes by cervical disease grade, with 1 reporting individual HPV genotype and specific cervical disease grade. Identifying HPV types associated with CIN2+ in WHIV in this region has the potential to improve screening and treatment for cervical cancer prevention and should be the focus of future research.