Sensitive circulating tumor DNA-based residual disease detection in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is one of the leading causes of cancer-related death in women worldwide, and is characterized by a high rate of recurrence after surgery and chemotherapy. We sought to implement a circulating tumor DNA (ctDNA)-based blood test for more accurate post-operative surveillance of this disease. We analyzed 264 plasma samples collected between June 2016 and September 2021 from 63 EOC patients using tumor-guided plasma cell-free DNA analysis to detect residual disease after treatment. Assay specificity was verified using cross-patient analysis of 1,195 control samples. ctDNA was detected in 51 of 55 (93%) samples at diagnosis, and 18 of 18 (100%) samples at progression. Positive ctDNA in the last on-treatment sample was associated with rapid progression (median 1.02 versus 3.38 yr, HR = 5.63, P < 0.001) and reduced overall survival (median 2.31 versus NR yr, HR = 8.22, P < 0.001) in patients with high-grade serous cancer. In the case of 12 patients, ctDNA assays detected progression earlier than standard surveillance, with a median lead time of 5.9 mo. To approach the physical limits of ctDNA detection, five patients were analyzed using ultra-sensitive assays interrogating 479-1,856 tumor mutations, capable of tracking ctDNA fractions down to 0.0004%. Our results demonstrate that ctDNA assays achieve high sensitivity and specificity in detecting post-operative residual disease in EOC.

Prognostic factors of renal cell cancer in elderly patients: a population-based cohort study.

Mortality in renal cell cancer (RCC) is high in the elderly population. Comorbidities have a greater impact on overall prognosis of RCC among elderly patients than in younger patients. All new RCC cases were collected in people over 74 years of age between 1995 and 2018 from the Finnish cancer registry. The comorbidities were identified from the Care Registry for Healthcare. Charlson Comorbidity Index (CCI) was used to evaluate the risk of death based on comorbidities. The overall risk of death was analyzed using the Cox regression model. The risk for RCC death was analyzed using Fine and Gray regression analysis. Individual prognostic role of CCI components was evaluated by adding each component separately into the multivariable Fine and Gray regression model. Using the most prognostic comorbidities we constructed a nomogram to predict RCC mortality. Statistically significant prognostic factors of RCC death were tumor morphology (clear cell, papillary and chromophobe), sex, operative treatment, age, primary tumor extent and CCI. The strongest prognostic factors for overall mortality were tumor extent, tumor morphology and operative treatment. Among the components of CCI, the most important comorbidities predicting mortality were dementia, heart failure and kidney disease. The limitation of this study is that the comorbidities have only been recorded at inpatient and outpatient hospital contacts, which is why the prevalence of comorbidities is probably underestimated. In addition, physical performance status was not available from registry data, but it significantly affects the treatment decisions. RCC mortality is high in the elderly population. Among comorbidities, dementia and heart failure have the greatest impact on the prognosis. Curative treatment in selected elderly patients is efficient and should be considered in patients who can tolerate it and have only limited comorbidities.

Predictive Biomarkers of Response to Neoadjuvant Therapy in Muscle Invasive Bladder Cancer.

Neoadjuvant cisplatin-based chemotherapy is recommended prior to surgical removal of the bladder for patients with non-metastatic muscle invasive bladder cancer. Despite a survival benefit, approximately half of patients do not respond to chemotherapy and are exposed potentially unnecessarily to substantial toxicity and delay in surgery. Therefore, biomarkers to identify likely responders before initiating chemotherapy would be a helpful clinical tool. Furthermore, biomarkers may be able to identify patients who do not need subsequent surgery after clinical complete response to chemotherapy. To date, there are no clinically approved predictive biomarkers of response to neoadjuvant therapy. Recent advances in the molecular characterization of bladder cancer have shown the potential role for DNA damage repair (DDR) gene alterations and molecular subtypes to guide therapy, but these need validation from prospective clinical trials. This chapter reviews candidate predictive biomarkers of response to neoadjuvant therapy in muscle invasive bladder cancer.

Nationwide analysis of survival after radical cystectomy for bladder cancer in Finland.

BACKGROUND: Population-based survival results after radical cystectomy (RC) are limited. Our objective was to report short and long-term survival results after RC for bladder cancer from Finland in a population-based setting. MATERIALS AND METHODS: The Finnish National Cystectomy Database containing retrospectively collected essential RC data covering the years 2005-2017 was combined with the survival data from the Finnish Cancer Registry. Kaplan-Meier plots were used to estimate survival and the survival graphs were illustrated according to the final pathological staging. Centers were divided according to operational volume, and the results were then compared using Pearsons's Chi-squared test. RESULTS: A total of 2047 patients were included in the study. 30-, and 90-day mortality was 1.3%, and 3.8%, respectively. The OS of the entire RC population at 5- and 10 years was 66% and 55%, and CSS was 74% and 72%, respectively. Center volume did not significantly associate with surgical mortality or long-term survival. The 5- and 10-year OS according to pT-category was 87% and 74% for pT0, 85% and 69% for pTa-pTis-pT1, 70% and 58% for pT2, 50% and 42% for pT3 and 41% and 30% for pT4. The corresponding 5- and 10-year CSS rates were 96% and 93% for pT0, 91% and 90% for pTa-pTis-pT1, 78% and 75% for pT2, 56% and 55% for pT3 and 47% and 44% for pT4. The 5- and 10-year OS rates in patients with no lymph node metastases (pN-) were 74% and 62%, and CSS 82% and 80%, respectively. If lymph nodes were positive (pN+), the corresponding OS rates were 44% and 34% and CSS 49% and 48%, respectively. CONCLUSION: RC survival results have improved in contemporary series and are associated with the pTNM-status. The nationwide results from Finland demonstrate outcome comparable to high volume single-center series.

Plasma soluble urokinase-type plasminogen activator receptor (P-suPAR) in the diagnostics between malignant and non-malignant pancreatic lesions.

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker elevated in several inflammatory conditions and cancers. It has recently been shown to be elevated in pancreatic ductal adenocarcinoma (PDAC). Plasma suPAR (P-suPAR) predicts the severity of the disease in first acute alcohol-induced pancreatitis (AAP) and ten-year mortality after recovery from first AAP. According to our previous results, P-suPAR is not elevated in chronic pancreatitis (CP) and could possibly be used in distinguishing pancreatic cancer (PC) from CP. When imaging creates a suspicion of a pancreatic lesion, the distinction between malignant and non-malignant disease is crucial. Additional tools are needed, and we still lack a sufficiently sensitive and specific biomarker. Our aim was to further investigate whether preoperatively measured P-suPAR is beneficial in distinguishing between malignant and non-malignant pancreatic lesions. METHODS: One hundred and seventy-six patients evaluated in Tampere University Hospital for pancreatic surgery for suspected malignant pancreatic lesion were recruited for the study. The final study group consisted of 113 patients. P-suPAR and other covariates were measured before the planned operation. RESULTS: P-suPAR was significantly higher in patients with pancreatic cancer (PC) [median 4.1 (IQR 3.3-5.1) ng/mL] than in patients with non-malignant [3.3 (2.9-4.4) ng/mL; p = 0.012] histology. ROC curve analysis resulted in an AUC of 0.65 (95% CI 0.55-0.76); p = 0.007 and a cutoff value of 3.2 ng/mL. Crosstabulation yielded sensitivity of 82% and specificity of 43%. A combination of positive P-suPAR and elevated plasma carbohydrate antigen 19-9 (P-CA19-9) tests did not improve sensitivity but elevated specificity up to 86-88%. CONCLUSIONS: Preoperative P-suPAR is elevated in patients with PC compared to patients with a non-malignant pancreatic lesion. Combining P-suPAR with P-CA19-9 may improve diagnostic accuracy.

Plasma suPAR may help to distinguish between chronic pancreatitis and pancreatic cancer.

OBJECTIVES: SuPAR (soluble urokinase-type plasminogen activator receptor) is a biomarker reflecting the inflammatory state of the human body. Earlier studies suggest that urinary suPAR/creatinine ratio levels are elevated in chronic pancreatitis (CP), and that plasma suPAR (P-suPAR) level is elevated in pancreatic cancer (PC). Our aim was to study the levels of P-suPAR in CP in a long-term prospective follow-up setting to explore the possibility of distinguishing between PC and CP. MATERIALS AND METHODS: Two patient groups were compared. The first group included 83 patients who were prospectively followed up after their first acute alcohol-induced pancreatitis (AAP) for median 7.0 (range 0.3-9.8) years. Twelve patients in this group developed CP during follow-up, and two patients were further excluded from the CP cohort. The second group consisted of 25 patients operated on for suspicion of pancreatic malignancy and final pathological diagnosis of PC. P-suPAR levels were measured and compared within and between these groups. RESULTS: P-suPAR levels remained low during follow-up despite the development of CP. P-suPAR was significantly higher in PC patients [median 3.7 (IQR 3.1-4.4) ng/mL] than in CP patients [2.6 (1.8-3.6) ng/mL]; p = .014. A cutoff value of 2.8 ng/mL resulted from a ROC curve with area under curve (AUC) of 0.79 (95% CI 0.61-0.97), p = .009 in differentiation between PC and CP with a sensitivity and a specificity of 88% and 70% respectively. CONCLUSION: P-suPAR is higher in patients with PC than in patients with CP, and it could thus be used in differentiating between PC and CP.

Repetitive Transcranial Magnetic Stimulation for Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Prospective Pilot Study.

PURPOSE: To evaluate the feasibility, efficacy, and safety of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment-resistant chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: Eleven patients with CP/CPPS were enrolled in this prospective clinical study. rTMS was performed for 5 consecutive days in 20-minute sessions. Patients were evaluated at baseline, after treatment, and at 1, 4, 8, and 12 weeks after the last session with questionnaires concerning pain (numerical rating scale [NRS], the National Institutes of Health Chronic Prostatitis Symptom Index [NIH-CPSI], and the Short Form-36 [SF-36]), urinary symptoms (NIH-CPSI, Danish Prostatic Symptom Score [DAN-PSS-1]), quality of life (NIH-CPSI, SF-36), and psychometrics (Beck Depression Index [BDI]). Telephone-based interviews were used to evaluate side effects, subjective response, and changes in drug consumption. RESULTS: All patients completed the planned treatment and follow-up according to protocol. No patients experienced serious side effects or significant pain increase during or after treatment. Mild transient tension headache responsive to oral pain medication was reported by 2 patients. Decreased pain was observed on the NRS after treatment and at 1 and 8 weeks (P=0.019, P=0.006, P=0.042, respectively) and on the NIH-CPSI pain domain at 1 week (P=0.04). Improvement in lower urinary tract symptoms was observed after treatment in the NIH-CPSI urinary domain (P=0.02) but not with the DANPSS-1. No significant changes in the BDI were observed. Nine patients reported a positive overall subjective response (82%) and 6 patients (55%) were able to reduce pain medication. Higher age was associated with lower NRS scores after treatment (R=0.605, P=0.048) and at 8 weeks (R=0.659, P=0.028). CONCLUSION: rTMS for patients with CP/CPPS seemed to be well tolerated, at least moderately effective in pain reduction, and might be of interest in patients with chronic pelvic pain resistant to conventional treatment. These findings remain to be confirmed by a randomized trial.

Repetitive Transcranial Magnetic Stimulation for Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Prospective Pilot Study / 대한배뇨장애요실금학회지

Purpose@#To evaluate the feasibility, efficacy, and safety of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment-resistant chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). @*Methods@#Eleven patients with CP/CPPS were enrolled in this prospective clinical study. rTMS was performed for 5 consecutive days in 20-minute sessions. Patients were evaluated at baseline, after treatment, and at 1, 4, 8, and 12 weeks after the last session with questionnaires concerning pain (numerical rating scale [NRS], the National Institutes of Health Chronic Prostatitis Symptom Index [NIH-CPSI], and the Short Form-36 [SF-36]), urinary symptoms (NIH-CPSI, Danish Prostatic Symptom Score [DAN-PSS-1]), quality of life (NIH-CPSI, SF-36), and psychometrics (Beck Depression Index [BDI]). Telephone-based interviews were used to evaluate side effects, subjective response, and changes in drug consumption. @*Results@#All patients completed the planned treatment and follow-up according to protocol. No patients experienced serious side effects or significant pain increase during or after treatment. Mild transient tension headache responsive to oral pain medication was reported by 2 patients. Decreased pain was observed on the NRS after treatment and at 1 and 8 weeks (P=0.019, P=0.006, P=0.042, respectively) and on the NIH-CPSI pain domain at 1 week (P=0.04). Improvement in lower urinary tract symptoms was observed after treatment in the NIH-CPSI urinary domain (P=0.02) but not with the DANPSS-1. No significant changes in the BDI were observed. Nine patients reported a positive overall subjective response (82%) and 6 patients (55%) were able to reduce pain medication. Higher age was associated with lower NRS scores after treatment (R=0.605, P=0.048) and at 8 weeks (R=0.659, P=0.028). @*Conclusions@#rTMS for patients with CP/CPPS seemed to be well tolerated, at least moderately effective in pain reduction, and might be of interest in patients with chronic pelvic pain resistant to conventional treatment. These findings remain to be confirmed by a randomized trial.

Plasma level of soluble urokinase plasminogen activator receptor (suPAR) predicts long-term mortality after first acute alcohol-induced pancreatitis.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker associated with inflammatory and certain malignancies. Earlier we have shown that plasma suPAR (P-suPAR) predicts severity of acute alcohol-induced pancreatitis (AAP) on admission. Our aim was to investigate whether P-suPAR levels predict AAP recurrences or mortality during long-term follow-up after first AAP. METHODS: Eighty-three patients (median age 47.5, range 25-71 years) suffering their first AAP during 2001-2005 were recruited and followed prospectively for 9 years with a median follow-up time of 7.0 (range 0.3-9.8) years. P-suPAR was measured by enzyme-linked immunosorbent assay (ELISA) from the samples taken at follow-up visits. Survival was registered in November 2014. RESULTS: P-suPAR level on admission or after recovery of the first AAP did not predict the recurrence of AAP. However, higher P-suPAR measured after recovery of first AAP (3.6 vs. 2.9 ng/mL) predicted mortality during follow-up period (hazard ratio 1.48, p = .008). Cut-off value for P-suPAR indicating a higher risk for 10-year mortality resulted a value of ≥3.4 ng/mL. When adjusted for other covariates, P-suPAR above cut-off level retained its statistical significance as an independent factor. CONCLUSIONS: P-suPAR level on admission or after recovery of the first AAP does not predict the recurrence of AAP during long-term follow-up. However, P-suPAR ≥3.4 mg/mL measured after recovery from first AAP is associated with an increased risk of 10-year mortality as an independent factor. This can be used to detect patients with highest risk after AAP, in order to focus the preventive healthcare actions.

The Intensity of Brief Interventions in Patients with Acute Alcoholic Pancreatitis Should be Increased, Especially in Young Patients with Heavy Alcohol Consumption.

AIMS: After the first acute alcoholic pancreatitis (AAP), active repeated brief interventions (BIs) have been shown to protect against recurrent acute pancreatitis (RAP). However, in daily hospital practice the treatment of alcohol problems varies. Our aim was to study BIs performed in the clinic during AAP and whether this prevents from future RAP episodes. METHODS: Data on all patients discharged between 10/2010 and 10/2012 with acute pancreatitis as the primary diagnosis were obtained from the hospital database. Patients with the first attack of AAP were included in the study. Documented BIs during hospitalization for AAP and RAP and the development of RAP and chronic pancreatitis during median (range) follow-up of 4.2 (0.2-6.1) years were analyzed. Patients were also contacted with a mailed questionnaire. RESULTS: A total of 74 patients with first AAP during the study period were included. Of these, 32% developed RAP during follow-up. Of the patients, 72% received a documented BI during initial hospitalization, with no difference between patients who later did or did not develop RAP (71 vs. 72%; ns). Younger age (OR = 0.96, 95% CI = 0.92-1.00) and higher AUDIT points (P = 0.044; OR = 5.6; 95% CI = 1.02-30.9 for ≥20 AUDIT points) were associated with RAP. AUDIT test had 70% sensitivity and 71% specificity at a cut-off value of 20 points for predicting RAP. CONCLUSIONS: Only 72% of the patients received a documented BI during the initial hospitalization for AAP. The in-hospital BI as such did not prevent the development of RAP. Young patients with AUDIT points ≥20 are especially at high risk for developing RAP and should be included in a more intense follow-up care program to maximize prevention. SHORT SUMMARY: During hospitalization for acute alcoholic pancreatitis (AAP), one third of the patients did not receive brief interventions (BIs). The in-hospital BI by itself was not sufficient enough to prevent disease recurrence in follow-up of 4 years. Young age and higher AUDIT-points were significant risk factors for recurrent attacks of AAP.

The Long-term Prospective Follow-up of Pancreatic Function After the First Episode of Acute Alcoholic Pancreatitis: Recurrence Predisposes One to Pancreatic Dysfunction and Pancreatogenic Diabetes.

BACKGROUND: Data on the prevalence of pancreatic dysfunction after an episode of acute pancreatitis are conflicting. Our aim was to evaluate the natural course of endocrine and exocrine pancreatic function in the long-term follow-up after the first episode of acute alcoholic pancreatitis (AAP). METHODS: A total of 77 patients who survived their first episode of AAP between January 2001 and February 2005 were prospectively followed up for a maximum of 13 years. During the follow-up, patients were repeatedly interviewed and monitored for recurrences, new diabetes, and chronic pancreatitis. The pancreatic function was evaluated repeatedly during the follow-up. RESULTS: Of the patients, 35% had ≥1 recurrent acute pancreatitis (RAP) episodes during the follow-up. New pancreatogenic diabetes developed in 19% of the previously nondiabetic patients, but only in patients with RAP (13/26 vs. 0/42; OR=39; 95% CI, 4.6-327.1). In addition, 55% of the patients developed new prediabetes or diabetes, and even this was more frequent in patients with RAP (86% vs. 42%; OR=8.2; 95% CI, 1.2-54.3). Exocrine dysfunction developed in 24% of the patients and was associated with abnormal findings in the endocrine function (P=0.003). Patients with RAP had a higher overall mortality compared with patients without RAP episodes during the follow-up (36% vs. 13%; HR=4.0; 95% CI, 1.4-11.0). CONCLUSIONS: The risk for pancreatic endocrine dysfunction, pancreatogenic diabetes and mortality increases significantly if the patient has recurrent episodes of AAP. The risk of developing pancreatic dysfunction after AAP should be recognized and pancreatic function should be screened routinely during the years after the first episode of AAP.

Pancreatic morphological changes in long-term follow-up after initial episode of acute alcoholic pancreatitis.

OBJECTIVE: The long-term morphological changes induced by a single episode of alcoholic pancreatitis are not known. Our aim was to study these morphological changes in secretin-stimulated magnetic resonance cholangiopancreatography (S-MRCP) after the first episode of alcohol-associated acute pancreatitis and to evaluate the risk factors and possible protective factors potentially associated with later chronic findings. We have previously reported 2-year follow-up results in pancreatic morphology. This study extends the follow-up to 9 years. PATIENTS AND METHODS: In this prospective follow-up study, S-MRCP imaging was performed for 44 (41 M, 3 F; mean age, 46 (25-68) years) patients after their first episode of alcohol-associated pancreatitis. Pancreatic morphology was evaluated at 3 months and at 2, 7, and 9 years after hospitalization. Recurrent attacks of pancreatitis were studied and pancreatic function was monitored by laboratory tests. Patients' alcohol consumption was evaluated with questionnaires, laboratory markers, and self-estimated alcohol consumption via interview. Smoking and body mass index were annually recorded. RESULTS: At 3 months, 32 % of the patients had normal findings in S-MRCP, 52 % had acute, and 16 % had chronic changes. At 7 years, S-MRCP was performed on 36 patients with normal findings in 53 %, the rest (47 %) having chronic findings. Pancreatic cyst was present in 36 %, parenchymal changes in 28 %, and atrophy in 28 % of the cases. There were no new changes in the pancreas in the attending patients between 7 and 9 years (18 patients). Of the patients with only acute findings at 3 months, 60 % resolved to normal in 7 years, but the rest (40 %) showed chronic changes later on. The initial attack was mild in 65 %, moderate in 25 %, and severe in 10 % of the patients. Patients with mild first attack had fewer chronic changes at 7 years compared to patients with moderate or moderate and severe together (p = 0.03, p = 0.01). Of the patients in the seventh year of S-MRCP, 22 % had suffered a recurrent episode of acute pancreatitis (mean, 22 (2-60) months) and 11 % had a clinical diagnosis of chronic pancreatitis. At 7 years, 88 % of the patients with recurrences had chronic findings in S-MRCP versus 36 % with nonrecurrent pancreatitis (p = 0.02). Six (17 %) patients abstained from alcohol throughout follow-up (mean, 8.7 (7-9.1) years), but even one of these developed pancreatic atrophy. Out of the non-abstinent patients who did not suffer recurrences, 4/22 (18 %) had developed new findings during at follow-up S-MRCP (NS). In univariate analysis, heavy smoking showed no correlation with increased chronic changes compared to nonsmoking. CONCLUSIONS: Morphological pancreatic changes increase with recurrent episodes of acute pancreatitis. Patients with mild first attack have fewer chronic changes in the pancreas in the long term. However, even a single episode of acute alcoholic pancreatitis may induce chronic morphological changes in long-term follow-up.

Abstinence after first acute alcohol-associated pancreatitis protects against recurrent pancreatitis and minimizes the risk of pancreatic dysfunction.

AIMS: To determine the recurrence of pancreatitis and subsequent pancreatic function in patients who stop drinking after the first episode of alcohol-associated pancreatitis. METHODS: Of a total of 118 patients suffering from their first alcohol-associated pancreatitis, 18 (all men, age median 47 (27-71) years) met the inclusion criterion for abstinence during follow-up. The criterion for abstinence was alcohol consumption <24 g per 2 months (self-estimated), which is in line with questionnaires eliciting alcohol consumption and dependency (Alcohol Use Disorders Identification Test < 8 and Short Alcohol Dependence Data < 9). Recurrent attacks of acute pancreatitis were studied. Smoking, body mass index and laboratory tests detecting heavy consumption of alcohol were recorded. Blood and faecal tests were studied to assess endocrine and exocrine pancreatic function. RESULTS: During a mean follow-up time of 5.15 (1.83-9.13) years and a total of 92.7 patient-years, there were no recurrent attacks of acute pancreatitis among the 18 abstainers. Two patients had diabetes prior to and one was diagnosed immediately after the first episode of acute pancreatitis. One patient had impaired glucose metabolism at 2 years. Two patients had low insulin secretion in glucagon-C-peptide test, one at 4 years and the other at 5 years. Only one patient (6%) maintained low elastase-1 activity during the abstinence follow-up. Of the 100 non-abstainers, 34% had at least one recurrence during the follow-up. CONCLUSION: Regardless of the mediator mechanisms of acute alcoholic pancreatitis, abstinence after the first episode protects against recurrent attacks. Pancreatic dysfunction is also rare among abstinent patients.