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Supplementary Data from Clonal Evolution in t(14;18)-Positive Follicular Lymphoma, Evidence for Multiple Common Pathways, and Frequent Parallel Clonal Evolution

Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome.Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed.Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances.Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.

Background 18F-Flourodeoxyglucose positron emission combined with computed tomography (FDG-PET/CT) has been proposed to improve preoperative staging in patients with bladder cancer subjected to radical cystectomy (RC). Objective Our aim was to assess the accuracy of FDG-PET/CT for lymph node staging compared to lymph node status in the surgical lymphadenectomy specimen obtained at RC, and to explore potential factors associated with false positive FDG-PET/CT results. Design, setting and participants Consecutive patients with bladder cancer undergoing RC with extended lymph node dissection between 2011 and 2019 without preoperative chemotherapy in a tertial referral cystectomy unit were included in the study. Outcome measurements and statistical analyses Sensitivity, specificity, positive and negative predictive values, and likelihood ratios were calculated. Potential factors investigated for association with false positive FDG-PET/CT were; bacteriuria within four weeks prior to FDG-PET/CT, Bacillus Calmette-Guerin (BCG) treatment within 12 months prior to FDG-PET/CT and transurethral resection of bladder tumor (TURB) within four weeks prior to FDG-PET/CT. Results Among 159 patients included for analysis, 46 (29%) were clinically node positive according to FDG-PET/CT. The sensitivity and specificity for detection of lymph node metastasis were 50% and 82%, respectively, and the corresponding positive predictive and negative predictive values were 59% and 76%. Positive and negative likelihood ratios were 2.8 and 0.6, respectively. No association were found between bacteriuria, previous BCG treatment or TURB within 28 days and false positive FDG-PET/CT results. Conclusions Preoperative FDG-PET/CT prior to RC had a clinically meaningful high specificity (82%) but lower sensitivity (50%) for detection of lymph node metastases compared to lymph node status in an extended pelvic lymphadenectomy template. We could not identify any factors associated with false positive FDG-PET/CT outcomes.

We constructed Bladder Cancer Data Base Sweden (BladderBaSe) 2.0 to expand studies in BladderBaSe on incidence, treatment outcomes, side effects, survival and health economic aspects of men and women with cancer in the urinary bladder, upper tract urothelial carcinoma (UTUC) (renal pelvis and ureter) and urethral carcinoma.BladderBaSe 2.0 includes 53 298 patients with cancer in the urinary bladder, diagnosed from 1 January 1997 to 31 December 2019, and 961 patients with UTUC in the renal pelvis and 792 in the ureter, and 146 patients with urethral urothelial carcinoma, diagnosed from 1 January 2015 to 31 December 2019, and in total 275 816 participants in reference groups, free of cancer in the urinary tract, matched 1:5 on sex, age and county.To date, 18 published studies based on data from the BladderBaSe have investigated calendar time trends in survival; impact of gender, socioeconomic factors, tumour aggressiveness and hospital volume for radical cystectomy on prognosis; survival after radical cystectomy compared with radical radiotherapy; risk factors for complications and side effects after radical cystectomy such as thromboembolism, strictures of ureteroenterostomies and incisional hernia.The BladderBaSe initiators are currently investigating gender-dependent detection delays due to urinary tract infections; survival after non-muscle invasive bladder cancer with respect to the number of transurethral resections; short-term outcomes comparing open and robot-assisted radical cystectomy; studies on risk for intravesical recurrence after different diagnostic measures in UTUC, and suicide risk after bladder cancer diagnosis. The BladderBaSe project group is open for collaborations with national and international colleagues.

Introduction: We aimed to compare short term outcomes after robot assisted radical cystectomy (RARC) and open radical cystectomy (ORC) for urinary bladder cancer in a large population. Materials and methods: We included all patients without distant metastases who underwent either RARC or ORC with ileal conduit between 2011 and 2019 registered in the Bladder cancer data Base Sweden (BladderBaSe) 2.0. Primary outcome was unplanned readmissions within 90 days, and secondary out-comes within 90 days of surgery were reoperations, Clavien 3-5 complications, total days alive and out of hospital, and mortality. The analysis was carried out using multivariate regression models. Results: Out of 2905 patients, 832 were operated with RARC and 2073 with ORC. Robotic procedures were to a larger extent performed during later years, at high volume centers (47% vs 17%), more often for organ-confined disease (82% vs. 72%) and more frequently in patients with high socioeconomic status (26% vs. 21%). Patients operated with RARC were more commonly readmitted (29% vs. 25%). In multi -variable analysis RARC was associated with decreased risk of Clavien 3-5 complications (OR 0.58, 95% CI 0.47-0.72), reoperations (OR 0.53, 95% CI 0.39-0.71) and had more days alive and out of hospital (mean difference 3.7 days, 95% CI 2.4-5.0). Conclusion: This study illustrates the "real-world" effects of a gradual and nation-wide introduction of RARC. Patients operated with RARC had fewer major complications and reoperations but were more frequently readmitted compared to ORC. The observed differences were largely due to more wound related complications among patients treated with ORC.

OBJECTIVE: Papillary urothelial neoplasm of low malignant potential (PUNLMP) and stage TaG1 non-muscle invasive bladder cancer (NMIBC) represent separate categories in current WHO 1999 grade definitions. Similarly, PUNLMP and Ta low-grade are separate entities in the WHO 2004/2016 grading system. However, this classification is currently questioned by reports showing a similar risk of recurrence and progression for both categories. PATIENTS AND METHODS: In this population-based study, risk estimates were evaluated in patients diagnosed with PUNLMP (n = 135) or stage TaG1 (n = 2176) NMIBC 2004-2008 with 5-year follow-up registration in the nation-wide Bladder Cancer Data Base Sweden (BladderBaSe). The risk of recurrence was assessed using multivariable Cox regression with adjustment for multiple confounders (age, gender, marital status, comorbidity, educational level, and health care region). RESULTS: At five years, 28/135 (21%) patients with PUNLMP and 922/2176 (42%) with TaG1 had local recurrence. The corresponding progression rates were 0.7% (1/135) and 4.0% (86/2176), respectively. A higher relative risk of recurrence was detected in patients with TaG1 tumours compared to PUNLMP (Hazard Ratio 1.6, 95% CI 1.2-2.0) at 5-year follow-up, while progression events were too few to compare. CONCLUSIONS: The difference in risk of recurrence between primary stage TaG1 and PUNLMP stands in contrast to the recently adapted notion that treatment and follow-up strategies can be merged into one low-risk group of NMIBC.

Objective: The incidence of benign ureteroenteric strictures following radical cystectomy (RC) for urinary bladder cancer (UBC) is investigated mainly in single-centre studies from high-volume centres. The aim of this study was to evaluate the cumulative incidence of strictures and risk factors in a population-based cohort. Patients and methods: Data was collected from Bladder Cancer Data Base Sweden (BladderBaSe). The primary endpoint was stricture with intervention. Secondary endpoint included hydronephrosis both with/without intervention. Results: In total, 5,816 patients were registered as having had RC due to UBC between 1997 and 2014. After a median follow-up of 23.5 months (IQR = 9.0–63.1 months; range = 0.0–214.0 months), we found that 515 (8.9%) patients underwent intervention for stricture. Seven hundred and sixty-one (13.1%) patients were diagnosed with hydronephrosis without intervention. The cumulative incidence of strictures with intervention was 19.7% (95% CI = 16.7–23.1%) during the 17 years of follow-up. In the first year, the cumulative incidence of strictures was 5.6% (95% CI = 5.0–6.2%), and in the first 2 years 8.4% (95% CI = 7.6–9.3%). For the secondary endpoint, the cumulative incidence was 30.4% (95% CI = 26.7–33.1%) after 17 years. Only the year of RC was associated with stricture incidence in Cox regression analysis, whereas hospital cystectomy volume, patient age and patient sex were not. Conclusion: Ureteroenteric strictures requiring intervention may be more common than previously reported, affecting nearly one fifth of patients who have undergone RC for UBC. The annual incidence was highest in the first 2 years after surgery but the cumulative incidence increased continuously during 17 years of follow-up.

Background Intravesical recurrence (IVR) after surgery for upper tract urothelial carcinoma (UTUC) is a clinical problem. We investigated if preoperative invasive diagnostic modalities (IDM) such as antegrade/retrograde uretero-pyelography and/or selective urine cytology/barbotage, and URS with or without concomitant biopsy are associated with IVR after radical surgery for UTUC. Risk of death from urothelial cancer and all causes was investigated as secondary outcomes. Methods We investigated a population-based cohort of 1038 consecutive patients subjected to radical surgery for UTUC 2015–2019 in Sweden, using the Bladder Cancer Data Base Sweden (BladderBaSe 2.0), comprising all patients in the Swedish National Registry of Urinary Bladder Cancer. Risk estimates of IVR, death from urothelial cancer, and all causes was assessed using multivariable Cox regression models. Results The study included 536 cases with and 502 without preoperative IDM. IDM was associated with increased risk of IVR (HR 1.24, 95% CI 1.03–1.52) and risk of urothelial cancer death (HR 1.56, CI 1.12–2.18), compared to no IDM after a median follow-up of 1.3 yrs. Stratified analysis for tumor location showed that IDM was associated with risk of IVR in ureteric cancer (HR 1.66, 95% CI 1.21–2.28) but not in renal pelvic cancer (HR 1.07, 95% CI 0.81–1.41). Limitations included the observational setting and the lack of variables such as tumour grade, multifocality and preoperative hydronephrosis. Conclusions Worse outcomes for patients subjected to preoperative IDM highlight the need for carefully considering diagnostic decisions for UTUC patients, specifically in tumours located in the ureter.

Background Parastomal hernia (PSH) after urinary diversion with ileal conduit is frequently a clinical problem. Objective To investigate whether a prophylactic lightweight mesh in the sublay position can reduce the cumulative incidence of PSH after open cystectomy with ileal conduit. Design, setting, and participants From 2012 to 2017, we randomised 242 patients 1:1 to conventional stoma construction (n = 124) or prophylactic mesh (n = 118) at three Swedish hospitals (ISRCTN 95093825). Outcome measurements and statistical analysis The primary endpoint was clinical PSH, and secondary endpoints were radiological PSH assessed in prone position with the stoma in the centre of a ring, parastomal bulging, and complications from the mesh. Results and limitations Within 24 mo, 20/89 (23%) patients in the control arm and 10/92 (11%) in the intervention arm had developed a clinical PSH (p = 0.06) after a median follow-up of 3 yr, corresponding to a hazard ratio of 0.45 (confidence interval 0.24–0.86, p = 0.02) in the intervention arm. The proportions of radiological PSHs within 24 mo were 22/89 (25%) and 17/92 (19%) in the two study arms. During follow-up, five patients in the control arm and two in the intervention arm were operated for PSH. The median operating time was 50 min longer in patients receiving a mesh. No differences were noted in proportions of Clavien-Dindo complications at 90 d postoperatively or in complications related to the mesh during follow-up. Conclusions Prophylactic implantation of a lightweight mesh in the sublay position decreases the risk of PSH when constructing an ileal conduit without increasing the risk of complications related to the mesh. The median surgical time is prolonged by mesh implantation. Patient summary In this randomised report, we looked at the risk of parastomal hernia after cystectomy and urinary diversion with ileal conduit with or without the use of a prophylactic mesh. We conclude that such a prophylactic measure decreased the occurrence of parastomal hernias, with only a slight increase in operating time and no added risk of complications related to the mesh.

PURPOSE: To study how patients with urinary bladder cancer (UBC) with previous or concomitant other primary cancers (OPC) were treated, and to investigate their prognosis.METHODS: Using nationwide ...

Late mortality of European five-year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends in cause-specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five-year survivors of cancer diagnosed before age 21 between 1940 to 2008 followed for an average age of 21 years and a total of 1.27 million person-years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow-up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval [95%CI] 9.69-10.09), AER 6.47 per 1000 person-years, (95%CI 6.32-6.62). At 60-68 years of attained age all-cause mortality was still higher than expected (SMR = 2.41, 95%CI 1.90-3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95%CI 16.5-20.4) to 7.3% (95%CI 6.7-8.0) over the observation period. Compared to the diagnosis period 1960-69, the mortality hazard ratio declined for first neoplasms (p for trend

INTRODUCTION AND OBJECTIVES: Bladder cancer is primarily a disease of older age and little is known about the differences between patients diagnosed with bladder cancer at a younger versus older age. Our objectives were to compare bladder cancer specific survival in patients aged

Purpose: To investigate the clinical management and outcome of patients with muscle-invasive bladder cancer with clinical lymph node involvement, using longitudinal nationwide population-based data ...

Background Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. Patients and methods Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. Results Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. Conclusion Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting., Highlights • Pazopanib given in metastatic or locally advanced GIST in third line is beneficial for about half of the patients. • The results indicate a similar progression-free survival as regorafenib in third line with a favourable tolerance. • Plasma concentration of pazopanib correlates weakly with disease control rate.

Objective To assess the value of second-look resection (SLR) in stage T1 bladder cancer (BCa) with respect to progression-free survival (PFS), and also the secondary outcomes recurrence-free survival (RFS), bladder-cancer-specific survival (CSS), and cystectomy-free survival (CFS). Patients and methods The study included 2456 patients diagnosed with stage T1 BCa 2004-2009 with 5-yr follow-up registration in the nationwide Bladder Cancer Data Base Sweden (BladderBaSe). PFS, RFS, CSS, and CFS were evaluated in stage T1 BCa patients with or without routine SLR, using univariate and multivariable Cox regression with adjustment for multiple confounders (age, gender, tumour grade, intravesical treatment, hospital volume, comorbidity, and educational level). Results SLR was performed in 642 (26%) individuals, and more frequently on patients who were aged < 75 yr, had grade 3 tumours, and had less comorbidity. There was no association between SLR and PFS (hazard ratio [HR] 1.1, confidence interval [CI] 0.85-1.3), RFS (HR 1.0, CI 0.90-1.2), CFS (HR 1.2, CI 0.95-1.5) or CSS (HR 1.1, CI 0.89-1.4). Conclusions We found similar survival outcomes in patients with and patients without SLR, but our study is likely affected by selection mechanisms. A randomised study defining the role of SLR in stage T1 BCa would be highly relevant to guide current praxis. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [CAN 2019/62, CAN 2017/278]; Lund Medical Faculty (ALF); Skane University Hospital Research Funds; Gyllenstierna Krapperups Foundation; Cancer Research Fund at Malmo General Hospital; Stiftelsen Sigurd och Elsa Goljes Minne; Bergqvist Foundation; Skane County Councils Research and Development Foundation [REGSKANE622351]; Gosta Jonsson Research Foundation; Foundation of Urological Research; Hillevi Fries Research Foundation

BACKGROUND: Routine VTE prophylaxis within 30 days of radical cystectomy (RC) for urinary bladder cancer (UBC) is used to protect from venous thromboembolism (VTE). However, randomized studies and nationwide population-based studies are lacking. OBJECTIVE: To study VTE and risk factors for VTE in muscle-invasive UBC in a nationwide population-based series, with a focus on the association with RC with and without chemotherapy. MATERIALS AND METHODS: We studied all patients with clinical stage T2-T4 UBC diagnosed 1997 to 2014 in the Bladder Cancer Data Base Sweden (BladderBaSe). Previous VTE events and risk factors for VTE were registered from 1987. Cox regression analyses and Kaplan-Meier curves were performed to study risk factors for VTE and cumulative incidence of VTE. RESULTS: In 9720 patients (71% males) with a median age of 74 years 546 (5.6%) had VTE after diagnosis. In Cox analyses controlling for patients and tumour characteristics, and risk factors for VTE, VTE after diagnosis and first treatment date were associated with chemotherapy with or without RC. Cumulative incidence of VTE increased during 24 months after diagnosis and first treatment date. VTE were less common in patients with previous cardiovascular disease. CONCLUSION: VTE was commonly observed after 30 days from diagnosis and from first treatment date in patients with T2-T4 UBC, particularly after chemotherapy. The findings suggest that long-term intervention studies of benefit and possible harms of VTE prophylaxis after UBC should be undertaken. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [CAN 2016/470, CAN 2017/278]

Objective For patients undergoing radical cystectomy for bladder cancer, a procedure requiring complex urinary tract reconstruction prone to major postoperative complications, the timing and quality of the surgery have been associated with outcomes. Patients and methods This study investigated if radical cystectomy for bladder cancer performed during holiday periods had worse disease-specific (DSS) and overall survival (OS), higher 90-day mortality and risk of readmissions. All patients operated on with radical cystectomy for primary bladder cancer during 1997-2014 with holiday periods as exposure (with one narrow (7 weeks) and one wider (14 weeks) definition) in the Swedish population-based bladder cancer research-database (BladderBaSe) were studied. DSS and OS after radical cystectomy during holiday periods were analysed with Cox regression models adjusted for sex, age, comorbidity, marital status, T-stage and nodal metastases, neoadjuvant chemotherapy, hospital volume and year of cystectomy. Results Surgery during the holiday periods (narrow and wide definitions) were not associated with DSS (Hazard ratio [HR] = 1.05, 95% confidence interval [95% CI] = 0.90-1.21 and HR = 1.04, 95% CI = 0.91-1.17), respectively. HRs for OS were similar, and no associations between radical cystectomy during any of the holiday period definitions and 90-day mortality and readmission were found. Conclusion Survival after radical cystectomy in Sweden is similar during holiday and non-holiday periods. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [CAN 2019/62, CAN 2017/278]; Lund Medical Faculty (ALF); Skane University Hospital Research Funds; Gyllenstierna Krapperup s Foundation; Skane County Councils Research and Development Foundation [REGSKANE-622351]; Gosta Jonsson Research Foundation; Foundation of Urological Research; Hillevi Fries Research Foundation

To study how patients with urinary bladder cancer (UBC) with previous or concomitant other primary cancers (OPCs) were treated, and to investigate their prognosis.Using nationwide population-based data in the Bladder Cancer Data Base Sweden (BladderBaSe), we analysed the probability of treatment with curative intent, and UBC-specific and overall survival (OS) in patients with UBC diagnosed in the period 1997-2014 with or without OPC. The analyses considered the patient's characteristics, UBC tumour stage at diagnosis, and site of OPC.There were 38 689 patients, of which 9804 (25%) had OPCs. Those with synchronous OPCs more often had T2 and T3 tumours and clinically distant disease at diagnosis than those with UBC only. Patients with synchronous prostate cancer, female genital cancer and lower gastro-intestinal cancer were more often treated with curative intent than patients with UBC only. When models of survival were adjusted for age at diagnosis, marital status, education, year of diagnosis, Charlson Comorbidity Index and T-stage, UBC-specific survival was similar to patients with UBC only, but OS was lower for patients with synchronous OPC, explained mainly by deaths in OPC primaries with a bad prognosis.OPC is common in patients with UBC. Treatment for UBC, after or in conjunction with an OPC, should not be neglected and carries just as high a probability of success as treatment in patients with UBC only. The needs of patients with UBC and OPC, and optimisation of their treatment considering their complicated disease trajectory are important areas of research.

Purpose To investigate the outcome following adjuvant doxorubicin and ifosfamide in a prospective non-randomised study based on a soft tissue sarcoma (STS) patient subgroup defined by specific morphological characteristics previously shown to be at a high-risk of metastatic relapse. The expected 5-year cumulative incidence of metastases in patients with this risk profile has previously been reported to be about 50% without adjuvant chemotherapy. Methods High-risk STS was defined as high-grade morphology (according to the Federation Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade II–III) and either vascular invasion or at least two of the following criteria: tumour size ≥8.0 cm, infiltrative growth and necrosis. Six cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2) were given. Postoperative accelerated radiotherapy was applied and scheduled between cycles 3 and 4. Results For the 150 eligible patients, median follow-up time for metastases-free survival was 3.9 years (range 0.2–8.7). Five-year metastases-free survival (MFS) was 70.4% (95% confidence interval [CI]: 63.1–78.4) with a local recurrence rate of 14.0% (95% CI: 7.8–20.2). For overall survival (OS), the median follow-up time was 4.4 years (range: 0.2–8.7). The five-year OS was 76.1% (95% CI: 68.8–84.2). Tumour size, deep location and reduced dose intensity ( Conclusions A benefit of adjuvant chemotherapy, compared to similar historical control groups, was demonstrated in STS patients with defined poor prognostic factors. Vascular invasion, tumour size, growth pattern and necrosis may identify patients in need of adjuvant chemotherapy.

Standard treatment of localized squamous cell carcinoma of the anus (SCCA) is radiotherapy (RT) combined with chemotherapy, that is, chemoradiation (CRT). Primary surgery has a limited role, but is a recommended treatment for small well differentiated SCCA localized in the anal margin, with re-excision or postoperative RT/CRT in case of involved surgical margins. The evidence supporting these strategies is limited.To study the recurrence patterns and survival outcomes in patients treated with surgery alone compared with surgery followed by postoperative RT/CRT.From a large Nordic database we identified 93 patients with stage TxT1-2N0M0 SCCA treated with surgery alone (n = 59) or surgery followed by RT/CRT (n = 34). Surgery consisted of local excision in 86 patients and abdominoperineal resection in seven patients, all of them in the surgery alone group. In 38 (41%) of the patients, the tumor was localized merely in the anal margin and in all remaining cases the anal canal was involved. Median RT dose to the tumor bed was 54 (range 46-66) Gy. Adjuvant RT to lymph nodes was given in 75% of the patients. Half of the patients received concomitant chemotherapy, usually 5-fluorouracil and mitomycin C.The locoregional recurrence (LRR) rate was significantly higher after surgery alone compared to surgery followed by adjuvant RT/CRT (36% vs. 9%, p = .006). The 3-year recurrence free survival (RFS) and overall survival (OS) were significantly better in patients who received postoperative RT/CRT than in patients who did not (3-year RFS 84.2% vs. 52.7%, p .001 and 3-year OS 87.2% vs. 70%, p = .026).Surgery alone of SCCA was associated with a high LRR rate and poor survival. The addition of postoperative RT/CRT lead to significantly improved locoregional control and survival.

Childhood cancer survivors face risks from a variety of late effects, including cardiac events, second cancers, and late mortality. The aim of the pan-European PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) Consortium was to collect data on incidence and risk factors for these late effects among childhood cancer survivors in Europe. This paper describes the methodology of the data collection for the overall PanCareSurFup cohort and the outcome-related cohorts. In PanCareSurFup 13 data providers from 12 countries delivered data to the data centre in Mainz. Data providers used a single variable list that covered all three outcomes. After validity and plausibility checks data was provided to the outcome-specific working groups. In total, we collected data on 115,596 patients diagnosed with cancer from 1940 to 2011, of whom 83,333 had survived 5 years or more. Due to the eligibility criteria and other requirements different numbers of survivors were eligible for the analysis of each of the outcomes. Thus, 1014 patients with at least one cardiac event were identified from a cohort of 39,152 5-year survivors; for second cancers 3995 survivors developed at least one second cancer from a cohort of 71,494 individuals, and from the late mortality cohort of 79,441 who had survived at least 5 years, 9247 died subsequently. Through the close cooperation of many European countries and the establishment of one central data collection and harmonising centre, the project succeeded in generating the largest cohort of children with cancer to date.

Background We recently reported outcomes from a Scandinavian Sarcoma Group adjuvant study (SSG XX group A) conducted on localized and operable high risk soft tissue sarcoma (STS) of the extremities and trunk wall. SSG XX, group B, comprised of patients in a defined cohort with locally advanced STS considered at high risk for intralesional surgery. These patients received preoperative accelerated radiotherapy, together with neoadjuvant and adjuvant chemotherapy. Herein we report the results of this group B. Methods Twenty patients with high-grade, locally advanced and deep STS located in lower extremities (n = 12), upper extremities (5) or trunk wall (3) were included. The median age was 59 years and 14 patients were males. The treatment regimen consisted of 6 cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2), with three cycles given neoadjuvantly, and preoperative radiotherapy (1, 8 Gyx2/daily to 36 Gy) between cycles 2 and 3. After a repeated MRI surgery was then conducted, and the remaining 3 chemotherapy cycles were given postoperatively at 3 weeks intervals. Survival data, local control, toxicity of chemotherapy and postoperative complications are presented. Results Median follow-up time for metastasis-free survival (MFS) was 2.8 years (range 0.3–10.4). The 5-year MFS was 49.5% (95% confidence interval [CI] 31.7–77.4). The median follow-up time was 5.4 years (range 0.3–10.4) for overall survival (OS). The 5-year OS was 64.0% (95% CI 45.8–89.4). The median tumour size was 13 cm, with undifferentiated pleomorphic sarcoma (n = 10) and synovial sarcoma (n = 6) diagnosed most frequently. All patients completed surgery. Resection margins were R0 in 19 patients and R1 in 1 patient. No patients had evidence of disease progression preoperatively. Three patients experienced a local recurrence, in 2 after lung metastases had already been diagnosed. Eleven patients (55%) had postoperative wound problems (temporary in 8 and persistent in 3). Conclusions Preoperative chemotherapy and radiotherapy were associated with temporary wound-healing problems. Survival outcomes, local control and toxicities were deemed satisfactory when considering the locally advanced sarcoma disease status at primary diagnosis. Trial registration This study was registered at ClinicalTrials.gov Identifier NCT00790244 and with European Union Drug Regulating Authorities Clinical Trials No. EUDRACT 2007-001152-39

Improved survival of men 50 to 75 years old with acute myeloid leukemia over a 20-year period

To investigate the association between hospital volume and overall survival (OS), cancer-specific survival (CSS), and quality of care of patients with bladder cancer who undergo radical cystectomy (RC), defined as the use of extended lymphadenectomy (eLND), continent reconstruction, neoadjuvant chemotherapy (NAC), and treatment delay of3 months.We used the Bladder Cancer Data Base Sweden (BladderBaSe) to study survival and indicators of perioperative quality of care in all 3172 patients who underwent RC for primary invasive bladder cancer stage T1-T3 in Sweden between 1997 and 2014. The period-specific mean annual hospital volume (PSMAV) during the 3 years preceding surgery was applied as an exposure and analysed using univariate and multivariate mixed models, adjusting for tumour and nodal stage, age, gender, comorbidity, educational level, and NAC. PSMAV was either categorised in tertiles, dichotomised (at ≥25 RCs annually), or used as a continuous variable for every increase of 10 RCs annually.PSMAV in the highest tertile (≥25 RCs annually) was associated with improved OS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.75-1.0), whereas the corresponding HR for CSS was 0.87 (95% CI 0.73-1.04). With PSMAV as a continuous variable, OS was improved for every increase of 10 RCs annually (HR 0.95, 95% CI 0.90-0.99). Moreover, higher PSMAV was associated with increased use of eLND, continent reconstruction and NAC, but also more frequently with a treatment delay of3 months after diagnosis.The current study supports centralisation of RC for bladder cancer, but also underpins the need for monitoring treatment delays associated with referral.

Background: The delay between onset of macroscopic haematuria and diagnosis of bladder cancer is often long. Methods: We evaluated timely diagnosis and health-care costs for patients with macroscopic haematuria given fast-track access to diagnostics. During a 15-month period, a telephone hotline for fast-track diagnostics was provided in nine Swedish municipalities for patients aged ⩾50 years with macroscopic haematuria. The control group comprised 101 patients diagnosed with bladder cancer in the same catchment area with macroscopic haematuria who underwent regular diagnostic process. Results: In all 275 patients who called ‘the Red Phone' hotline were investigated, and 47 of them (17%) were diagnosed with cancer and 36 of those had bladder cancer. Median time from patient-reported haematuria to diagnosis was 29 (interquartile range (IQR) 14−104) days and 50 (IQR 27−165) days in the intervention and the control group, respectively (P=0.03). The median health-care costs were lower in the intervention group (655 (IQR 655−655) EUR) than in the control group (767 (IQR 490−1096) EUR) (P=0.002). Conclusions: Direct access to urologic expertise and fast-track diagnostics is motivated for patients with macroscopic haematuria to reduce diagnostic intervals and lower health-care expenditures.

OBJECTIVE: The incidence of urinary bladder cancer (UBC) has increased in Sweden despite decreased smoking, indicating that other factors might be associated. The increased use of statin medication for elevated blood lipids might be one such influencing factor. The aim of the present study was to assess whether statins are afflicted with an increased incidence of UBC. MATERIAL AND METHODS: Data from the Swedish National Register of Urinary Bladder Cancer, National Population Register, and Swedish Prescribed Drug Register were extracted. There were 22,936 patients with new diagnosed UBC between 2005 and 2014. Statin prescription was defined as any medication prescribed with the Anatomical Therapeutic Classification code C10A. For each patient, 10 control individuals were matched by age, gender, and living area, comprising 229,326 individuals. The Cochran-Mantel-Haenszel test was used to evaluate the hazards ratios. RESULTS: Statins were more frequently used in patients with UBC (33.8%) than in controls (29.8%, p

Objective: This study assessed a national healthcare intervention launched in Sweden in 2015 to reduce the time between macroscopic haematuria, diagnosis and treatment of urinary tract cancer. Methods: The outcome of the first 11 months was evaluated in 1697 individuals referred to a standardized care pathway for urinary tract cancer compared with 174 patients with conventionally diagnosed urothelial carcinoma. Results: Among the referred individuals, 317 (19%) were diagnosed with cancer, 1034 (61%) had a benign diagnosis and 345 (20%) had a negative evaluation. Bladder cancer was the most common malignant diagnosis [262/317 (83%)]. Cancers were diagnosed in 23% of males and 13% of females, and showed a strong correlation with age: cancer diagnosis in 2% aged

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF. Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public. Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case–control studies of subsequent malignancies and cardiac disease in 5-year survivors. Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health.

Purpose To monitor the quality of bladder cancer care, the Swedish National Register of Urinary Bladder Cancer (SNRUBC) was initiated in 1997. During 2015, in order to study trends in incidence, effects of treatment and survival of men and women with bladder cancer, we linked the SNRUBC to other national healthcare and demographic registers and constructed the Bladder Cancer Data Base Sweden (BladderBaSe). Participants The SNRUBC is a nationwide register with detailed information on 97% of bladder cancer cases in Sweden as compared with the Swedish Cancer Register. Participants in the SNRUBC have registered data on tumour characteristics at diagnosis, and for 98% of these treatment data have been captured. From 2009, the SNRUBC holds data on 88% of eligible participants for follow-up 5 years after diagnosis of non-muscle invasive bladder cancer, and from 2011, data on surgery details and complications for 85% of participants treated with radical cystectomy. The BladderBaSe includes all data in the SNRUBC from 1997 to 2014, and additional covariates and follow-up data from linked national register sources on comorbidity, socioeconomic factors, detailed information on readmissions and treatment side effects, and causes of death. Findings to date Studies based on data in the SNRUBC have shown inequalities in survival and treatment indication by gender, regions and hospital volume. The BladderBaSe includes 38 658 participants registered in SNRUBC with bladder cancer diagnosed from 1 January 1997 to 31 December 2014. The BladderBaSe initiators are currently in collaboration with researchers from the SNRUBC investigating different aspects of bladder cancer survival. Future plans The SNRUBC and the BladderBaSe project are open for collaborations with national and international research teams. Collaborators can submit proposals for studies and study files can be uploaded to servers for remote access and analysis. For more information, please contact the corresponding author.

Objective. Cystectomy combined with pelvic lymph-node dissection and urinary diversion entails high morbidity and mortality. Improvements are needed, and a first step is to collect information on the current situation. In 2011, this group took the initiative to start a population-based database in Sweden (population 9.5 million in 2011) with prospective registration of patients and complications until 90 days after cystectomy. This article reports findings from the first year of registration. Material and methods. Participation was voluntary, and data were reported by local urologists or research nurses. Perioperative parameters and early complications classified according to the modified Clavien system were registered, and selected variables of possible importance for complications were analysed by univariate and multivariate logistic regression. Results. During 2011, 285 (65%) of 435 cystectomies performed in Sweden were registered in the database, the majority reported by the seven academic centres. Median blood loss was 1000 ml, operating time 318 min, and length of hospital stay 15 days. Any complications were registered for 103 patients (36%). Clavien grades 1-2 and 3-5 were noted in 19% and 15%, respectively. Thirty-seven patients (13%) were reoperated on at least once. In logistic regression analysis elevated risk of complications was significantly associated with operating time exceeding 318 min in both univariate and multivariate analysis, and with age 76-89 years only in multivariate analysis. Conclusions. It was feasible to start a national population-based registry of radical cystectomies for bladder cancer. The evaluation of the first year shows an increased risk of complications in patients with longer operating time and higher age. The results agree with some previously published series but should be interpreted with caution considering the relatively low coverage, which is expected to be higher in the future.

BackgroundStandard treatment of adult Burkitt lymphoma is not defined due to the lack of randomised trials. In this situation, population-based data may represent a useful contribution in order to identify an optimal treatment strategy.Patients and methodsThe aims of this study were to investigate the outcome for adult HIV-negative BL with different chemotherapy regimens, and to assess possible improvement within the time frame of the study. The study population was identified through the Swedish and Danish lymphoma registries 2000-2009.ResultsA total of 258 patients were identified. Since 2000, overall survival (OS) improved significantly only for younger patients (

The aim of this investigation was to describe tumour characteristics, treatments and survival in patients with urinary bladder cancer (UBC) in a national population-based cohort, with special reference to gender-related differences.All primary UBC patients with urothelial pathology reported to the Swedish National Registry of Urinary Bladder Cancer (SNRUBC) from 1997 to 2011 were included in the study. Groups were compared regarding tumour, node, metastasis classification, primary treatment and survival.In total, 30,310 patients (74.9% male, 25.1% female) with UBC were analysed. A larger proportion of women than men had stage T2-T4 (p 0.001), and women also had more G1 tumours (p 0.001). However, compared to women, a larger proportion of men with carcinoma in situ or T1G3 received intravesical treatment with bacillus Calmette-Guérin or intravesical chemotherapy, and a larger proportion of men with stage T2-T4 underwent radical cystectomy (38% men vs 33% women, p 0.0001). The cancer-specific survival at 5 years was 77% for men and 72% for women (p 0.001), and the relative survival at 5 years was 72% for men and 69% for women (p 0.001).In this population-based cohort comprising virtually all patients diagnosed with UBC in Sweden between 1997 and 2011, female gender was associated with inferior cancer-specific and relative survival. Although women had a higher rate of aggressive tumours, a smaller proportion of women than men received optimal treatment.

Background/Purpose: Alternatives to corticosteroids in the treatment of irritant contact dermatitis (ICD) are needed and may include glycerol and topical immunomodulators like tacrolimus. Because the efficacy of different treatments in experimentally induced ICD may vary depending on the irritant applied, we tested the efficacy of four anti-irritant compounds using the two different irritants sodium lauryl sulfate (SLS) and nonanoic acid (NON). Methods: In a randomized, double-blind, controlled trial, healthy volunteers were exposed to 5% SLS and 50% NON (the right and the left forearm, respectively) in a cumulative wash test. Induction of ICD was obtained by three daily washings for 7 days, followed by a maintenance phase with two daily washings for 12 days. Treatment (triamcinolone acetonide, clobetasol propionate, tacrolimus and glycerol ointment) was started at day 7 and applied immediately after washing. Vehicle and no treatment served as the control. Reactions were evaluated clinically and instrumentally. Results: No treatments were significantly better than the other treatments and controls. There was a tendency toward a dose-dependent response to corticoid treatment, and a trend toward worsened irritancy by tacrolimus on SLS-irritated skin. Explained variance in the experiment by anova revealed a very small effect of treatments compared with an immense and significant subject effect. Conclusion: No claims of effective anti-irritant properties for any of the ointments can be maintained. Application of the present wash test as a tool for anti-irritant efficacy testing may be complicated by the small observed variance explained by treatment.

Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome. Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed. Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances. Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.

Objective Comparison of provider performance is commonly used to inform health care decision-making. Little attention has been paid to how data presentations influence decisions. This study analyzes differences in suggested actions by decision-makers informed by league tables or funnel plots. Design Decision-makers were invited to a survey and randomized to compare hospital performance using either league tables or funnel plots for four different measures within the area of cancer care. For each measure, decision-makers were asked to suggest actions towards 12–16 hospitals (no action, ask for more information, intervene) and provide feedback related to whether the information provided had been useful. Setting Swedish health care. Participants Two hundred and twenty-one decision-makers at administrative and clinical levels. Intervention Data presentations in the form of league tables or funnel plots. Main outcome measures Number of actions suggested by participants. Proportion of appropriate actions. Results For all four measures, decision-makers tended to suggest more actions based on the information provided in league tables compared to funnel plots (44% vs. 21%, P