Milada Cvancarova

Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study)

Objective. Cohort studies of unselected and newly diagnosed patients are essential for a better understanding of the prognosis in ulcerative colitis (UC). The aim of this study was to evaluate the course of UC in a population-based inception cohort during the first 10 years, and to identify prognostic risk factors based on information gathered at diagnosis. Material and methods. From 1990 to 1994, a population-based cohort of 843 patients with inflammatory bowel disease was enrolled in South-Eastern Norway. The cohort was systematically followed-up at 1, 5 and 10 years after diagnosis. Results. Of 519 patients with UC, 423 completed the 10-year follow-up, 53 died and 43 were lost to follow-up. The mortality risk was not increased compared with that in the general population. The cumulative colectomy rate after 10 years was 9.8% (95% CI: 7.4–12.4%). Initial presentation with extensive colitis and erythrocyte sedimentation rate (ESR) ≥30 mm/h was associated with an increased hazard ratio (HR) (3.57, 95% CI: 1.60–7.96) and age ≥50 years at diagnosis, with reduced HR (0.28, 95% CI: 0.12–0.65) for subsequent colectomy. Relapsing disease was noted in 83%, but half (48%) of the patients were relapse free during the last 5 years. One-fifth (69/288) of patients with proctitis or left-sided colitis had progressed to extensive colitis. Conclusions. The prognosis for UC during the first 10 years was generally good. The colectomy rate was low, and a large proportion of patients were in remission as time progressed. Patients with initially extensive colitis and elevated ESR could benefit from an early potent medical treatment strategy.

Cisplatin-Induced Long-Term Hearing Impairment Is Associated With Specific Glutathione S-Transferase Genotypes in Testicular Cancer Survivors

PURPOSE Cisplatin, a cornerstone of combination chemotherapy in the treatment of testicular cancer, induces hearing impairment with considerable interindividual variations. These differences might be a result of functional polymorphisms in cisplatin-detoxifying enzymes like glutathione S-transferases (GSTs). PATIENTS AND METHODS We identified 173 cisplatin-treated testicular cancer survivors (TCSs) who had participated in a long-term survey that included audiometric testing and lymphocyte sampling. The hearing decibel thresholds at 4,000 Hz were categorized into leveled scales by normative decibel percentiles. Known functional polymorphisms (positive or negative) in GSTT1 and GSTM1 and codon 105 A/G (Ile/Val) in GSTP1 were analyzed by multiplex polymerase chain reaction, followed by restriction enzyme cutting, and separated by gel electrophoresis. RESULTS The risk of having an inferior audiometric result was more than four times higher in TCSs with 105Ile/105Ile-GSTP1 or 105Val/105Ile-GSTP1 compared with 105Val/105Val-GSTP1 (odds ratio [OR] = 4.21; 95% CI, 1.99 to 8.88; P < .001 when modeled by ordinal logistic regression [OLR]). GSTM1 positivity was detrimental for hearing ability. Two combined genotypes were associated with hearing ability. The presence of pattern 1 (GSTT1 positive, GSTM1 positive, and 105Ile/105Ile-GSTP1) was associated with hearing impairment (OR = 2.76; 95% CI, 1.35 to 5.64; P = .005, OLR). TCSs with pattern 2 (GSTT1 positive, GSTM1 positive, and 105Val/105Val-GSTP1) had better hearing ability than TCSs without this pattern (OR = 5.35; 95% CI, 2.25 to 12.76; P < .001, OLR). CONCLUSION The presence of both alleles of 105Val-GSTP1 offered protection against cisplatin-induced hearing impairment. Two genotype patterns with good and poor protection against cisplatin-induced ototoxicity were identified.

Work disability in inflammatory bowel disease patients 10 years after disease onset: results from the IBSEN Study

Objective To compare the work disability (WD) rate in inflammatory bowel disease (IBD) patients 10 years after disease onset, with the WD rate in the background population,and to assess whether clinical or demographic factors in the early disease course could predict WD after 10 years disease. Design A large, population-based inception cohort (the Inflammatory Bowel in South Eastern Norway cohort) was prospectively followed up at 1, 5 and 10 years after diagnosis. At the 10-year follow-up data on WD were collected. Data on disability pension (DP) in the background population were retrieved from public databases. We calculated overall and age-standardised relative risks (RR) for DP. Logistic regression analysis was used to examine predictive factors. Results A total of 518 patients completed the 10-year follow-up (response rate 83.5%). The overall disability rate in the IBD population was 18.8%, and the RR was 1.8 (95% CI 1.4 to 2.3) for ulcerative colitis (UC) and 2.0 (95% CI 1.4 to 2.7) for Crohns disease (CD). The RR for DP was highest in patients aged below 40 years while patients aged over 60 years had no increased RR. Steroid treatment at the 1-year follow-up predicted WD after 10 years disease in both CD and UC. In UC, increased C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) at diagnosis, early colectomy, and more than two relapses during the first year of the disease also predicted WD. Conclusion Ten years after disease onset IBD patients had an increased RR for DP as compared with the background population. The youngest patients had the highest RR. Markers of severe disease course predicted WD.

Reproduction Rates After Cancer Treatment: Experience From the Norwegian Radium Hospital

PURPOSE Most studies on postcancer reproduction are limited in patient numbers and lack of control group. We have computed 10-year first postdiagnosis cumulative reproduction rates (10-PDRs) and hazard ratios (HRs) avoiding these limitations. PATIENTS AND METHODS Six thousand seventy-one patients with cancer age 15 to 45 years at diagnosis, treated from 1971 to 1997, and 30,355 controls from the general population, all born after 1950, were observed from the true (patients) or assigned (controls) date of diagnosis for a median of 10 years (range, 0 to 35). The primary focus of the study was the 10-PDR before and after 1988+ based on data from the Medical Birth Registry of Norway. Cox proportional hazards regression models were adjusted for age and calendar year at diagnosis, stratified by sex and prediagnosis parenthood. RESULTS Across all cancer types, HRs of females were approximately 50% lower than those of the controls, the comparable percentage for male patients being approximately 30%, with some improvement after 1988+ for selected diagnoses. The highest 10-PDRs were observed in childless patients, with more favorable HRs in male than in female patients. In survivors with at least one child at diagnosis, the post-1988+ HRs improved significantly in patients with testicular and localized cervical cancer compared to pre-1988+ reproduction, with borderline improvement in localized ovarian cancer. CONCLUSION Postcancer reproduction is lower than that of the general population and influenced by sex, age at diagnosis, prediagnosis parenthood, and diagnostic period with more favorable rates in males than in females. Post-1988+ fertility-saving strategies may have improved the reproduction rates for select genital cancers.

Postradiotherapy Morbidity in Long-Term Survivors After Locally Advanced Cervical Cancer: How Well Do Physicians' Assessments Agree With Those of Their Patients?

PURPOSE Descriptions of late morbidity after radiotherapy in cervical cancer survivors (CCSs) are usually based on observations made by physicians, and rarely by patients themselves. We describe and compare physician-assessed morbidity with patient-rated symptoms more than 5 years after pelvic radiotherapy. METHODS AND MATERIALS In 147 CCSs treated between 1994 and 1999 at The Norwegian Radiumhospital, morbidity data were regularly documented by physicians at least for 5 years after radiotherapy. Information on patient-rated symptoms was collected by a questionnaire from 91 (62%) of the 147 survivors after a median follow-up time of 96 months (65-131 months). The results were compared with physician-assessed morbidity scores recorded at 5 years, and to selected normative data using descriptive statistics. Physician-assessed morbidity data were modeled using Kaplan-Meier method. Agreement between physician data and patient data was expressed using weighted kappa statistics. RESULTS The 5-year Kaplan-Meier estimates of physician-assessed intestinal, bladder, and vaginal morbidity Grade 3-4 were 15%, 13%, and 23%, respectively. The prevalence of patient-rated severe symptoms from these organs was much higher (intestines 45%, bladder 23%, and 58% vaginal discomfort among sexually active CCSs). Poor agreement was confirmed by low values of kappa: For bladder the concordance was slight (kappa = 0.16) and for intestine it was fair (kappa = 0.27). Stress incontinence, diarrhea, nausea, and sexual problems were significantly (p < 0.001) more prevalent when compared with a control sample from the general female population. CONCLUSIONS Morbidity is common after pelvic radiotherapy. However, our data indicate that physicians underreport patients symptoms. It is important to incorporate patient-reported outcomes in the evaluation of treatment-related morbidity.

Pregnancy after adolescent and adult cancer: a population-based matched cohort study

Despite fertility‐preserving initiatives, postcancer reproduction is expected to be lower than that of the general population. Using data from the Cancer Registry and the Medical Birth Registry of Norway, postcancer pregnancy rates were analyzed in 27,556 survivors and compared to those from a matched comparison group (“controls”) from the general population. All were born after 1950, diagnosed from 1967 to 2004 at age of 16–45, and had an observation time from the date of diagnosis (assigned date for controls), until pregnancy, death, age 46, or December 31, 2006. Cox regression was used to estimate pregnancy rates, after adjusting for educational level, parity and diagnostic period. Overall, cancer survivors had a lower pregnancy rate than the controls, but the rate for survivors was higher in males than in females [hazard rate (HR) = 0.74 (95% confidence interval (CI) 0.71–0.78) and HR = 0.61 (95% CI 0.58–0.64), respectively]. However, the rates did not differ between controls and survivors of malignant melanoma or thyroid cancer. By contrast, the lowest HRs for pregnancy occurred in survivors of leukemia, cervical or breast cancer. Increased pregnancy rates during the study period were detected for ovarian cancer [HR = 0.2 (95% CI 0.1–0.3) to HR = 0.7 (95% CI 0.5–0.9)], testicular cancer [HR = 0.6 (95% CI 0.4–0.9) to HR = 0.8 (95% CI 0.7–0.8)], and Hodgkin lymphoma diagnosed in men [HR = 0.7 (95% CI 0.5–0.9) to HR = 0.9 (95% CI 0.7–1.0)]. In summary, fertility‐preserving attempts have succeeded in patients with ovarian or testicular cancer and in males with Hodgkin lymphoma. Male survivors initiated pregnancies in a higher degree than female survivors.

Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study

BackgroundTo assess the impact of polymorphisms in Glutathione S-transferase (GST) -P1, -M1, and -T1 on self-reported chemotherapy-induced long-term toxicities in testicular cancer survivors (TCSs).MethodsA total of 238 TCSs, who had received cisplatin-based chemotherapy at median twelve years earlier, had participated in a long-term follow-up survey which assessed the prevalence of self-reported paresthesias in fingers/toes, Raynaud-like phenomena in fingers/toes, tinnitus, and hearing impairment. From all TCSs lymphocyte-derived DNA was analyzed for the functional A→G polymorphism at bp 304 in GSTP1, and deletions in GST-M1 and GST-T1. Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment.ResultsAll six evaluated toxicities were significantly associated with the cumulative dose of cisplatin and/or bleomycin. Compared to TCSs with either GSTP1-AG or GSTP1-AA, the 37 TCSs with the genotype GSTP1-GG, were significantly less bothered by paresthesias in fingers and toes (p = 0.039, OR 0.46 [0.22–0.96] and p = 0.023, OR 0.42 [0.20–0.88], respectively), and tinnitus (p = 0.008, OR 0.33 [0.14–0.74]). Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08–3.03]).ConclusionIn TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in GSTP1 and GSTM1. Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1. Also intracellular inactivation of pro-apoptotic mediators represents a possible explanation of our findings. Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.

Adverse Prognostic Factors for Testicular Cancer-Specific Survival: A Population-Based Study of 27,948 Patients

PURPOSE The prognostic significance of age at testicular cancer (TC) diagnosis, socioeconomic status (SES), race, and marital status on TC-specific mortality is not well-characterized. In a cancer that is so curable, it is important to identify any influence that confers an increased risk of TC-specific mortality. PATIENTS AND METHODS Using multivariate cause-specific Cox regression models that accounted for competing risks, hazard ratios (HRs) were calculated for 10-year TC-specific mortality among 27,948 patients with TC reported to the Surveillance, Epidemiology and End Results program (1978 to 2006). Independent predictors were age at diagnosis, SES, race, marital status, extent of disease (EOD), calendar year of diagnosis, radiotherapy, and retroperitoneal lymph node dissection (RPLND). RESULTS Compared with younger patients, diagnostic age 40+ was associated with increased mortality (seminoma, HR, 2.00, P < .001; nonseminoma, HR, 2.09; P < .001; most evident in metastatic disease, HR, 8.62; P < .001; HR, 6.35; P < .001, respectively). Unmarried men had two-to three-fold excess mortality compared to married men (HR, 2.97; P < .001; HR, 1.54; P < .001, respectively). Among nonseminoma patients, decreasing SES (P trend < .001) and nonwhite race (HR, 2.11; P < .001) increased mortality. Diagnosis after 1987 resulted in reduced mortality compared to earlier calendar years (HR, 0.58; P = .001; HR, 0.74; P = .001, respectively). Lack of RPLND was associated with seven-fold increase in death (P < .001). CONCLUSION TC-specific mortality is doubled among US patients diagnosed with seminoma or nonseminoma after age 40, even when initial treatment and EOD are taken into account. Among men with nonseminoma, nonwhite race and lower SES also significantly increase TC-specific mortality. Additional research is needed, enabling the development of interventional strategies and preventive approaches, as applicable.

Late Patient-Reported Toxicity After Preoperative Radiotherapy or Chemoradiotherapy in Nonresectable Rectal Cancer: Results From a Randomized Phase III Study

PURPOSE Preoperative chemoradiotherapy (CRT) is superior to radiotherapy (RT) in locally advanced rectal cancer, but the survival gain is limited. Late toxicity is, therefore, important. The aim was to compare late bowel, urinary, and sexual functions after CRT or RT. METHODS AND MATERIALS Patients (N = 207) with nonresectable rectal cancer were randomized to preoperative CRT or RT (2 Gy × 25 ± 5-fluorouracil/leucovorin). Extended surgery was often required. Self-reported late toxicity was scored according to the LENT SOMA criteria in a structured telephone interview and with questionnaires European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), International Index of Erectile Function (IIEF), and sexual function-vaginal changes questionnaire (SVQ). RESULTS Of the 105 patients alive in Norway and Sweden after 4 to 12 years of follow-up, 78 (74%) responded. More patients in the CRT group had received a stoma (73% vs. 52%, p = 0.09). Most patients without a stoma (7 of 12 in CRT group and 9 of 16 in RT group) had incontinence for liquid stools or gas. No stoma and good anal function were seen in 5 patients (11%) in the CRT group and in 11 (30%) in the RT group (p = 0.046). Of 44 patients in the CRT group, 12 (28%) had had bowel obstruction compared with 5 of 33 (15%) in the RT group (p = 0.27). One-quarter of the patients reported urinary incontinence. The majority of men had severe erectile dysfunction. Few women reported sexual activity during the previous month. However, the majority did not have concerns about their sex life. CONCLUSIONS Fecal incontinence and erectile dysfunction are frequent after combined treatment for locally advanced rectal cancer. There was a clear tendency for the problems to be more common after CRT than after RT.

Impaired weight gain predicts risk of late death after surgery for congenital heart defects

Objectives: To describe long-term somatic growth in terms of weight for age in children operated on for congenital heart defects who die late (after the first 30 postoperative days) and to study the relationship between postoperative weight gain and survival after surgery for congenital heart defects. Methods: This was a nested case–control study of 80 children born in 1990–2002 who died late after surgery for congenital heart defects at Rikshospitalet, Norway. Weight data were obtained for 74 children, of whom 31 with no extra-cardiac anomalies were defined as cases and 31 surviving children with similar surgical complexity were defined as controls. Results: In the 74 children who died late, mean weight for age converted to z scores at birth, at last operation and at last recorded weight were 0.12, −1.31 and −2.09. In the 31 children defined as cases, the same weight z scores were 0.07, −1.21 and −2.01 compared with 0.05, −1.10 and −0.99 in the 31 matched controls. The odds ratio (OR) for death was 13.5 (95% CI 3.6 to 51.0) if there was a decrease in weight z score of >0.67 after the last operation. Median follow-up time after operation was 5.7 months. Conclusions: A decrease in weight for age during the first months after surgery for congenital heart defects of more than 0.67 z scores, corresponding to a downward percentile crossing through at least one of the displayed percentile lines on standard growth charts, is strongly related to late mortality in children operated on for congenital heart defects.