Population-based Series Of Patients Research Articles

Genetic Characterization of Kidney Failure of Unknown Etiology in Spain: Findings From the GENSEN Study

Chronic kidney disease (CKD) of unknown etiology (CKDUE) is one of the main global causes of kidney failure. While genetic studies may identify an etiology in these patients, few studies have implemented genetic testing of CKDUE in population-based series of patients which was the focus of the GENSEN. Case series. 818 patients aged ≤45 years at 51 Spanish centers with CKDUE, and either an estimated GFR <15 mL/min/1.73 m2 or treatment with maintenance dialysis or transplantation. Genetic testing for 529 genes associated to inherited nephropathies using high-throughput sequencing (HTS). Pathogenic and/or likely pathogenic (P/LP) gene variants concordant with the inheritance pattern were detected in 203 (24.8%) patients. Variants in type IV collagen genes were the most frequent (COL4A5, COL4A4, COL4A3; 35% of total gene variants), followed by NPHP1, PAX2, UMOD, MUC1 and INF2 (7.3%, 5.9%, 2.5%, 2.5% and 2.5% respectively). Overall, 87 novel variants classified as P/LP were identified. The top 5 most common previously undiagnosed diseases were Alport syndrome spectrum (35% of total positive reports), genetic podocytopathies (19%), nephronophthisis (11%), autosomal dominant tubulointerstitial kidney disease (7%) and congenital anomalies of the kidney and urinary tract (CAKUT: 5%). Family history of kidney disease was reported by 191 (23.3 %) participants and by 65/203 (32.0%) patients with P/LP variants. Missing data. Selection bias resulting from voluntary enrollment. Genomic testing with HTS identified a genetic cause of kidney disease in approximately one quarter of young patients with CKDUE and advanced kidney disease. These findings suggest that genetic studies are a potentially useful tool for the evaluation of people with CKDUE.

Epilepsy surgery in patients with hypothalamic hamartomas - Population-based two-year and long-term outcomes.

Hypothalamic hamartomas are benign lesions associated with drug resistant epilepsy. Surgical treatment has become an increasingly utilised approach with promising results. This study aims to evaluate seizure outcome and complications after surgery in a population-based series of patients with intractable epilepsy and hypothalamic hamartoma. All patients with hypothalamic hamartoma treated with epilepsy surgery in Sweden since 1995 with at least two years of follow-up were included. Preoperative, two-, five- and ten-year prospective longitudinal data were collected from The Swedish National Epilepsy Surgery Register. Data included seizure types and frequency, duration of epilepsy, clinical characteristics, neurological deficits, cognitive level and complications. In a subgroup from Gothenburg, we also analysed data not included in the register such as classification of hamartomas, surgical procedures and gelastic seizures. Eighteen patients were operated on during the period 1995-2020. The median age at epilepsy onset was 6 months and age at surgery 13 years. Four were seizure free and another four had ≥75% reduction in seizure frequency at the two-year follow-up. Two of the 13 patients with a long-term follow-up (five or ten years) were seizure-free and four had ≥75% reduction in seizure frequency. Three had an increased seizure frequency. No major complications were seen. Five had minor complications. In the Gothenburg subgroup all had open pterional disconnection or intraventricular endoscopic disconnection. Six of 12 were free from gelastic seizures at the two-year follow-up and six of eight at the long-term follow-up. This study supports surgical treatment of hypothalamic hamartomas as a safe method with a low risk of permanent complications. The seizure reduction seems to be persistent over time.

Compliance to adjuvant endocrine therapy and survival in breast cancer patients.

BackgroundData on compliance to adjuvant endocrine treatment (ET) is mainly reported from prospective clinical trials or from smaller retrospective cohorts without correlation to outcome. AimsTo determine compliance to adjuvant ET and the impact on survival in a population-based series of patients with early breast cancer (BC) advised ET. Patients and methods1090 consecutive patients with hormone receptor positive (HR+) stage I-III BC diagnosed from 1 January 1997 to 31 December 2003 from one health care region of Sweden were included. Data on tumour, type of ET, compliance, reason for termination and outcome were collected. Statistical analyses were calculated with patients in three groups. Results72 patients were excluded leaving 1018 patients with a HR+ stage I to III BC for analyses. The most common ET was tamoxifen (n = 751, 73.8%). At the last follow up (31 Dec 2019) with a median follow-up of 18 years (interquartile range 16–22) 228 (22.4%) patients had a relapse. 71.1% of the included patients were compliant to endocrine therapy. Older patients ≥74 years had lower compliance, 61% compared with 75% in the other age groups (≤50 years and 51–73 years) (p < 0001), other parameters including type of ET were not associated with compliance. Low compliance remained as an independent risk factor in multivariate analyses for lower relapse-free survival, HR=1.83, 95% Confidence Interval (CI) 1.52–2.19, p < 0.001 and for time to BC death, HR=2.69, 95%CI 1.82–3.98, p < 0.001. ConclusionsPatients compliant to adjuvant ET have an improved survival.

Regional spreading of symptoms at diagnosis as a prognostic marker in amyotrophic lateral sclerosis: a population-based study

ObjectiveThe lack of prognostic biomarkers in patients with amyotrophic lateral sclerosis (ALS) induced researchers to develop clinical evaluation tools for stratification and survival prediction. We assessed the correlation between patterns...

Heterogeneous radiological response to neoadjuvant therapy is associated with poor prognosis after resection of colorectal liver metastases

IntroductionSurgery combined with perioperative chemotherapy has become standard of care in patients with resectable colorectal liver metastases. However, poor outcome is expected for a significant subgroup. The clinical implications of inter-metastatic heterogeneity remain largely unknown. In a prospective, population-based series of patients undergoing resection of multiple colorectal liver metastases, the aim was to investigate the prevalence and prognostic impact of heterogeneous response to neoadjuvant chemotherapy. Materials and MethodsRadiological response to treatment was evaluated in a lesion-specific manner in 2–5 metastases per patient. Change of lesion diameter was evaluated and response/progression was classified according to three different size thresholds; 3, 4 and 5 mm. A heterogeneous response was defined as progression and response of different metastases in the same patient. ResultsIn total, 142 patients with 585 liver metastases were examined with the same radiological method (MRI or CT) before and after neoadjuvant treatment. Heterogeneous response to treatment was seen in 16 patients (11%) using the 3 mm size change threshold, and this group had a 5-year cancer-specific survival of 19% compared to 49% for patients with response in all lesions (p = 0.003). Cut-off values of 4–5 mm were less sensitive for detecting a heterogeneous response, but the survival difference was similar and significant. ConclusionA subgroup of patients with multiple colorectal liver metastases had heterogeneous radiological response to neoadjuvant chemotherapy and poor prognosis. The evaluation of response pattern is easy to perform, feasible in clinical practice and, if validated, a promising biomarker for treatment decisions.

PB2224 POLYCYTHEMIA VERA: A DIAGNOSTIC CHALLENGE

Background:In patients referred to hematology for investigating the etiology of the increased hemoglobin concentration and/or hematocrit, the first step is to find out whether there is a secondary cause of the polycythemia. Serum erythropoietin levels and JAK‐2 mutation screening are recommended after it is decided that polycythemia is not caused by a secondary cause. World Health Organization International Agency for Research on Cancer (WHO/IARC) has made major changes in 2016 on the diagnostic criteria for polycythemia vera. One of the major changes is lowered treshold hemoglobin/hematocrit levels. These values are use not only as diagnostic criteria, but also as the initiation of screening diagnostic tests for polycythemia. Thus, there has been a significant increase in the number of patients admitted to outpatient hematology clinics.Aims:Which patients should be investigated? Are there any preliminary characteristics or should all the patients be requested to JAK‐2 mutation or erythtropoetin leves ? 2‐ Which test should be requested first: serum erytropoetin level test or JAK mutation test? 3‐ When compared to WHO 2008, do the new diagnostic hb/htc criteria allow more patients to be diagnosed as polycthemia vera?Methods:243 Patients who applied to our clinic between 2016 and 2018 years, for high hemoglobin and/or hematocrit values according to WHO 2016 criteria, were analyzed retrospectively. All patients were tested for serum EPO levels and JAK‐2 exon 14 mutation status, and evaluated for the secondary causes of polycytemia. Normal values of lab for serum EPO levels are 3,5‐16,4 UI/L. All statistical analysis was made by SPSS version 22. Categorical variables were compared using χ2 or Fishers exact test.Results:243 patients were included in the study. Demographic data and laboratory results of the patients are summarized in Table‐1. 24 of 243 patients (%9,8) had positive JAK‐2 exon 14 mutation and diagnosed polycytemia vera. 30 of 243 (%12,3) had low serum Epo levels. (≤3,5 UI/L). 18 of 24 JAK‐2 positive patients had low EPO levels so there was a significant correlation between low serum EPO levels and JAK‐2 mutation status (p&lt;0,001). There was no relationship between leukocytosis, thrombocytosis and JAK‐2 status. (p = 0,34). Age was another major factor related to JAK‐2 status. 20 of 24 JAK positive patients’ ages were 50 and above (p&lt;0,001). 12 of these 20 patiens had a low Epo level, while 8 of them had a normal serum EPO values. (p&lt;0,001). 4 of 24 JAK positive patients whose age was younger than 50 years, had a low EPO levels (p&lt;0,001). Therefore, all of patentse diagnosed P.Vera below 50 years had a supressed EPO levels. When compared to P.Vera diagnosed patients who met the previous WHO‐2008 criteria (Hb ≥ 18,5‐Htc ≥ %55) (8/39, %20,5) and patients who had Hb values between 16,5‐18,4 g/dl (according to WHO‐2016 criteria)(16/196, %8,1), no significant difference was observed (p = 0,09) between two groups.Summary/Conclusion:This analysis concluded that in patients younger than 50 years old, the investigation of polycythemia must start with EPO levels. If EPO levels are suppresed, then JAK mutation testing can be performed. After the age of 50, both tests should be performed at the same time. If we had examined the patients according to WHO 2008, we couldn’t have diagnosed P.Vera for 16 patients whom hb levels were under 18,5 g/dl. On the other hand, we wouldn’t have tested 196 patients. Therefore, in population based patient series, the preliminary characteristics for further investigation to polyctemia must be established for cost effectiveness and labor.image

Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1.

The current study was designed to determine the risk of cancer in patients with neurofibromatosis type 1 (NF1) by cancer type, age, and sex with unprecedented accuracy to be achieved by combining two total population-based registers. A population-based series of patients with NF1 (N = 1,404; 19,076 person-years) was linked to incident cancers recorded in the Finnish Cancer Registry and deaths recorded in the national Population Register Centre between 1987 and 2012. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated for selected cancer types. Survival of the patients with cancer with and without NF1 was compared. In malignant peripheral nerve sheath tumors and CNS tumors, the cancers traditionally associated with NF1, we observed SIRs of 2,056 (95% CI, 1,561 to 2,658), and 37.5 (95% CI, 30.2 to 46.0), respectively, and SMRs of 2,301 (95% CI, 1,652 to 3,122) and 30.2 (95% CI, 19.1 to 45.2), respectively. We found an unequivocally increased risk for breast cancer. In particular, SIR was 11.1 (95% CI, 5.56 to 19.5) for breast cancer in women with NF1 age < 40 years; the overall SMR for breast cancer was 5.20 (95% CI, 2.38 to 9.88). Particularly high overall SIRs were observed in patients with NF1 age < 15 years: women, 87.6 (95% CI, 58.6 to 125); men, 45.6 (95% CI, 28.4 to 68.5). An estimated lifetime cancer risk for patients with NF1 was 59.6%. The 5-year survival of patients with cancer and NF1, excluding nervous tissue cancers, was worse than that of comparable patients with cancers without NF1 (54.0% v 67.5%; P = .01). Our results emphasize the general cancer proclivity of patients with NF1. These findings should translate to clinical practices to determine clinical interventions and focused follow-up of patients with NF1.

KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence.

Mutated KIT and platelet-derived growth factor alpha gene (PDGFRA) drive GI stromal tumor (GIST) oncogenesis, but the clinical significance of their single mutations is known incompletely. We identified 11 population-based series of patients with GIST through a literature search and pooled individual data from 3,067 patients treated with macroscopically complete tumor excision. Mutation analysis was done from 1,505 tumors. We analyzed associations between KIT and PDGFRA mutations and recurrence-free survival (RFS) in the subsets in which patients were treated with surgery alone. We identified 301 different single mutations in KIT and 33 in PDGFRA. Patients with PDGFRA mutations had more favorable RFS than those with KIT mutations (hazard ratio, 0.34; P = .004). Only one of the 35 GISTs with KIT exon 11 duplication mutations recurred. Patients with deletions of only one codon of KIT exon 11 had better RFS than those with another deletion type, and some KIT exon 11 substitution mutations (Trp557Arg, Val559Ala, and Leu576Pro) were also associated with favorable RFS. Patients with an identical mutation had greatly variable outcomes depending on the standard prognostic factors, notably, mitotic count. Commonly used risk stratification schemes tended to overestimate the risk for recurrence in subgroups with prognostically favorable mutations. GISTs with an identical KIT or PDGFRA mutation may have widely varying risks for recurrence. Most of the patients with PDGFRA mutations and those with KIT exon 11 duplication mutation or deletion of one codon have favorable RFS with surgery alone and are usually not candidates for adjuvant therapy.

Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study.

There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) progression for clinical practice and pharmacological trials. To correlate several hematological markers evaluated at diagnosis with ALS outcome in a population-based series of patients (discovery cohort) and replicate the findings in an independent validation cohort from an ALS tertiary center. The discovery cohort included 712 patients with ALS from the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis from January 1, 2007, to December 31, 2011. The validation cohort comprised 122 patients with ALS at different stages of disease consecutively seen at an ALS tertiary center between January 1, 2007, and January 1, 2009. The following hematological factors were investigated and correlated with survival: total leukocytes, neutrophils, lymphocytes, monocytes, glucose, creatinine, uric acid, albumin, bilirubin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatine kinase, thyroid-stimulating hormones, and erythrocyte sedimentation rate; all analyses were performed separately by sex. The patient of the validation cohort also underwent bioelectrical impedance analysis for the calculation of fat-free mass. Of the 712 patients in the examined period in Piemonte and Valle d'Aosta, 638 (89.6%) were included in the study. Only serum albumin (men: ≤ 4.3 vs >4.3 mg/dL, P < .001; women: ≤ 4.3 vs >4.3 mg/dL, P < .001) and creatinine levels (men: ≤ 0.82 vs >0.82 mg/dL, P = .004; women: ≤ 0.65 vs >0.05 mg/dL, P = .004) and lymphocyte count (men: ≤ 1700 vs >1700/μL, P = .04; women: ≤ 1700 vs >1700/μL, P = .02) were significantly associated with ALS outcome in both sexes with a dose-response effect (better survival with increasing levels). These findings were confirmed in the validation cohort. Multivariable analysis showed that serum albumin (men: hazard ratio [HR], 1.39; 95% CI, 1.05-1.90; P = .02; women: HR, 1.73; 95 % CI, 1.35-2.39; P = .001) and creatinine (men: HR, 1.47; 95% CI, 1.11-1.95; P = .007; women: HR, 1.49; 95% CI, 1.07-2.05; P = .02) were independent predictors of survival in both sexes; no other hematological factor was retained in the model. In patients with ALS, serum albumin was correlated with markers of inflammatory state while serum creatinine was correlated with fat-free mass, which is a marker of muscle mass. In ALS, serum albumin and creatinine are independent markers of outcome in both sexes. Creatinine reflects the muscle waste whereas albumin is connected with inflammatory state. Both creatinine and albumin are reliable markers of the severity of clinical status in patients with ALS and can be used in defining prognosis at the time of diagnosis.

The effect of smoking and timing of smoking cessation on clinical outcome in non–muscle-invasive bladder cancer

ObjectivesCigarette smoking is the most important risk factor for urinary bladder cancer. The prognostic effect of cigarette smoking on disease recurrence and progression in patients with non–muscle-invasive bladder cancer (NMIBC), however, is still unclear. We evaluated the effect of smoking status and intensity, and timing of smoking cessation, on NMIBC prognosis. Methods and materialsA population-based series of patients diagnosed with NMIBC from 1995 until 2010 was identified through the Netherlands Cancer Registry. Self-reported smoking history was obtained by a postal lifestyle questionnaire at study inclusion. Detailed clinical data concerning diagnosis, treatment, and disease course were collected retrospectively through a medical file survey. The association of smoking variables with recurrence- and progression-free survival of 963 patients with primary NMIBC was studied using cumulative incidence curves and competing risk regression analyses. ResultsThe study population comprised 181 never smokers (18.8%), 490 former smokers (50.9%), and 292 current smokers (30.3%) at the time of diagnosis. No statistically significant difference or trend in risk of recurrence (Ptrend = 0.47) or progression (Ptrend = 0.23) across the 3 smoking status categories was found. Moreover, no dose-response association was observed across categories of smoking quantity, duration, or cumulative exposure in relation to NMIBC prognosis. The timing of smoking cessation (i.e., ceased smoking≥10y before diagnosis,<10y before diagnosis, vs. current smoker at diagnosis) did not significantly affect the risk of recurrence (Ptrend = 0.31) and progression (Ptrend = 0.19). ConclusionsBased on our study, smoking status, smoking intensity, or cessation at any time before diagnosis does not seem to alter the risks of recurrence and progression among patients with NMIBC. Patients’ smoking history is not useful for the guidance of clinical management decisions. Patients should nevertheless be advised to quit considering the known beneficial effects on other non-NMIBC–related end points such as cardiovascular disease and second primary cancers.

Effects of age and comorbidity on treatment and survival of patients with muscle‐invasive bladder cancer

Our study assessed whether rising age, socioeconomic status (SES) and the presence of serious comorbidity affected treatment choice and survival in a population-based series of patients with muscle-invasive bladder cancer (MIBC) in The Netherlands. Therefore, a consecutive series was studied, including all patients diagnosed with MIBC between 1995 and 2009 in the Eindhoven Cancer Registry, preceding centralization of cystectomy. The independent effects of age, SES and serious comorbidity on therapy choice and their effects on overall survival were estimated by multivariate logistic regression and multivariate Cox proportional hazard analyses, respectively. Out of the 2,445 patients, 38% were aged ≥ 75 years at diagnosis and 63% had at least one serious comorbid condition. Higher age and serious comorbidity were independent predictors for abstaining from cystectomy, where SES was not (61-74 vs. ≤ 60: odds ratio [OR], 0.8; 95% confidence interval [CI], 0.6-1.0; ≥ 75 vs. ≤ 60: OR, 0.1; 95% CI,0.1-0.2; one comorbid condition vs. none: OR, 0.7; 95% CI, 0.5-0.9; two vs. none: OR, 0.6; 95% CI, 0.5-0.8). Patients undergoing cystectomy, external beam radiotherapy or interstitial radiotherapy survived longer independent of age, SES and serious comorbidity (hazard ratio [HR]: 0.4; 95% CI: 0.4-0.5; HR: 0.8; 95% CI: 0.7-0.9; HR: 0.4; 95% CI: 0.3-0.5, respectively). Consequently, preceding centralization of cystectomy, higher age and serious comorbidity were independent predictors for abstaining from cystectomy owing to an expected high rate of short-term medical problems. As cystectomy is associated with a better survival, independently of age, SES and serious comorbidity, it can be questioned whether cystectomy has been underutilised in elderly and in patients with serious comorbidity. Centralization might be a solution for this suggested underutilisation.

A comparison of published rates of resection margin involvement and intra‐operative perforation between standard and ‘cylindrical’ abdominoperineal excision for low rectal cancer

The study aimed to compare recent reports on standard and alternative methods of abdominoperineal excision for low rectal cancer regarding the rates of circumferential resection margin involvement and intra-operative bowel perforation. Data on rates of margin involvement and perforation were obtained from eight recently published reports and also from a prospective registry of resections at Concord Hospital. Rates of these outcomes and their 95% confidence intervals were evaluated. There was no evidence that extralevator abdominoperineal excision yielded significantly lower rates of resection margin involvement or intra-operative bowel perforation compared with standard abdominoperineal excision in six independent hospital- and population-based patient series. Abdominosacral resection of the rectum, on the other hand, did show significantly lower rates of these endpoints, albeit in selected patients. The role of extralevator abdominoperineal excision and abdominosacral resection of the rectum should be investigated further in randomized controlled trials.

Prevalence of germline TP53 mutations and history of Li–Fraumeni syndrome in families with childhood adrenocortical tumors, choroid plexus tumors, and rhabdomyosarcoma: A population‐based survey

Whether childhood adrenocortical tumors (ACTs), choroid plexus tumors (CPTs), and rhabdomyosarcoma (RMS) are early manifestation of Li-Fraumeni syndrome (LFS) is uncertain. In this study, we evaluated the frequency of germline TP53 mutations and family history in a population-based series of patients. We identified children (≤18 years) diagnosed between 1958 and 2008 with ACT (n = 3) or CPT (n = 7), or children ≤5 years with RMS (n = 29). Registry-based pedigree expansion was performed. No patients had a family history of classic LFS but 17 fulfilled Chompret or Eeles criteria. TP53 mutations were found in 1/3 ACT patients and 1/18 RMS patients; both were novel mutations. Of five tested CPT patients none had a detectable mutation. No excess of LFS associated tumors was observed, except for breast cancer in families of CPT patients. An overall increased cancer incidence was observed in families of patients with CPT [standardized incidence ratio (SIR) = 2.0; 95% CI: 1.1-3.5] due to excess of breast and female kidney cancer and in families of patients with RMS (SIR = 1.2; 95% CI: 0.9-1.7), due to excess of early-onset melanoma and male stomach cancer. Relatives of patients with childhood ACTs, CPTs, and RMSs showed no increased risk of LFS associated tumors. However, TP53 mutations could be found in these children irrespective of family history. Absence of LFS associated tumors may suggest the presence of other cancer syndromes. Improved knowledge about relatives' cancer risks could be helpful in counseling family members of children with cancer.

FLT3mutation incidence and timing of origin in a population case series of pediatric leukemia

BackgroundMutations in FLT3 result in activated tyrosine kinase activity, cell growth stimulation, and a poor prognosis among various subtypes of leukemia. The causes and timing of the mutations are not currently known. We evaluated the prevalence and timing of origin of FLT3 mutations in a population series of childhood leukemia patients from Northern California.MethodsWe screened and sequenced FLT3 mutations (point mutations and internal tandem duplications, ITDs) among 517 childhood leukemia patients, and assessed whether these mutations occurred before or after birth using sensitive "backtracking" methods.ResultsWe determined a mutation prevalence of 9 of 73 acute myeloid leukemias (AMLs, 12%) and 9 of 441 acute lymphocytic leukemias (ALLs, 2%). Among AMLs, FLT3 mutations were more common in older patients, and among ALLs, FLT3 mutations were more common in patients with high hyperdiploidy (3.7%) than those without this cytogenetic feature (1.4%). Five FLT3 ITDs, one deletion mutation, and 3 point mutations were assessed for their presence in neonatal Guthrie spots using sensitive real-time PCR techniques, and no patients were found to harbor FLT3 mutations at birth.ConclusionsFLT3 mutations were not common in our population-based patient series in California, and patients who harbor FLT3 mutations most likely acquire them after they are born.

Pediatric follicular lymphoma - a clinico-pathological study of a population-based series of patients treated within the Non-Hodgkin's Lymphoma - Berlin-Frankfurt-Munster (NHL-BFM) multicenter trials

Background Pediatric follicular lymphoma has recently been recognized as a novel variant of follicular lymphoma in the World Health Organization classification of lymphomas. Given the rarity of the disease, histopathological and genetic data on this type of lymphoma are still scarce. We analyzed 25 cases of pediatric follicular lymphoma (patients aged <or=18 years) by morphology, immunohistochemistry and interphase fluorescence in situ hybridization. All patients analyzed were treated within Non-Hodgkin's Lymphoma--Berlin-Frankfurt-Münster (NHL-BFM) multicenter trials, and the cohort was representative of the German population. The genetic hallmark of adult follicular lymphoma, t(14;18)(q32;q21), was not detectable in any of the pediatric cases, although BCL2 protein was expressed in 55% of the latter cases. No correlation was found between BCL2 protein expression and outcome. Chromosomal breaks in the immunoglobulin heavy chain gene (IGH) and the BCL6 locus were detected in 5 of 17 and 1 of 18 cases, respectively. Patients with pediatric follicular lymphoma had long event-free survival and, in contrast to adult follicular lymphoma, the clinical course was not dominated by relapses. A simultaneous diffuse large B-cell lymphoma was frequently detected at initial diagnosis in children but did not indicate an aggressive clinical course. Conclusions Our data suggest that pediatric follicular lymphoma is a disease that differs from its adult counterpart both genetically and clinically.

Population-Based Analysis of Incidence and Outcome of Transformed Non-Hodgkin's Lymphoma

To assess the incidence and predictive factors for development of transformed lymphoma in a population-based series of patients with follicular lymphoma (FL). The Lymphoid Cancer Database was used to identify patients with FL diagnosed and treated in the province of British Columbia, Canada. Transformed lymphoma was defined as the development of aggressive non-Hodgkin's lymphoma (NHL) in patients with FL. Factors present at the time of initial diagnosis of indolent NHL and at transformation were analyzed for their impact on risk of transformation and subsequent outcome. Between 1986 and 2001, 600 patients with newly diagnosed FL met the inclusion criteria. With a median follow-up of 109 months (range, 10 to 244), 170 (28%) developed transformation, 107 (63%) based on biopsy confirmation. The annual risk of transformation was 3% continuously through 15 years. A multivariate analysis of clinical factors at diagnosis identified advanced stage as the only predictor of future transformation. The median post-transformation survival was 1.7 years. The 5-year survival was superior for patients with limited extent transformation compared with those with advanced cases (66% v 19%, P < .0001). Patients with transformation based on clinical versus histological criteria had an identical median survival of 1.8 years (P = .2). The annual risk of transformation of FL is 3% continuing without plateau beyond 15 years. Advanced stage at diagnosis is predictive of future transformation. Clinically diagnosed transformation has an equal impact on outcome as biopsy proven transformation.

Missense Polymorphisms in the Adenomatous Polyposis Coli Gene and Colorectal Cancer Risk

Whereas truncating germline mutations of the adenomatous polyposis coli (APC) gene give rise to familial adenomatous polyposis, missense polymorphisms of APC may confer a weaker risk for colorectal cancer. We sequenced the entire open reading frame of the APC gene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas. Missense adenomatous polyposis coli alterations identified in this colorectal cancer multiple-polyp population were analyzed in a population-based series of patients with colorectal cancer and healthy control subjects. Germline APC or mutY human homologue (MYH) alterations were identified in 16 of 39 colorectal cancer-multiple polyp patients. Four missense APC gene alterations (S130G, E1317Q, D1822V, G2502S) were observed in 13 individuals and 3 additional patients carried presumed pathogenic (APC Y94X, biallelic MYH Y165C and heterozygous MYH G382D) mutations. When independently assessed in 971 patients with colorectal cancer and 954 healthy control subjects, none of the identified missense APC alterations conferred a significantly increased risk for colorectal cancer, odds ratio (95 percent confidence intervals): S130G = 3.1 (0.29-32.25), E1317Q = 1.08 (0.59-2.74), G2502S = 1 (0.65-1.63), D1822V (heterozygous) = 0.79 (0.64-0.98), D1822V (homozygous) = 0.82 (0.63-1.27). Germline missense APC alterations observed in 33 percent of patients with multiple colorectal neoplasms seemed to play a limited role in colorectal cancer risk when independently assessed by a population-based, case-control analysis.

No improvement in renal cell carcinoma survival: A population-based study in the Netherlands

BackgroundThe increased finding of kidney ‘incidentalomas’ and more frequent surgery in patients with renal cell cancer (RCC) metastases may have improved survival from the disease. However, recent data on survival of unselected population-based series of patients with RCC are sparse. MethodsWe collected the follow-up data for all the patients registered with RCC in the population-based cancer registry held by the Comprehensive Cancer Centre East, the Netherlands. ResultsPatients (1504) diagnosed with RCC between 1989 and 2002 were included. Eighty-three percent of all tumours were histologically confirmed; 17% of all diagnoses were based on clinical examination only. The latter group was older, had a worse stage distribution, often did not receive any kind of therapy and showed a 5-year relative survival of 8%. Five-year relative survival for patients with a histologically confirmed RCC was 60% and did not improve over the last 15 years. A low resection rate in patients with metastasis was observed, most pronounced in elderly, without a tendency of increase in more recent years. ConclusionThe relative survival of RCC did not improve over the years. The resection rate in patients with metastasised disease did not increase over time, despite current knowledge concerning its benefit on tumour complications, time to progression and response to immunotherapy.

Low BMI-1 expression is associated with an activated BMI-1-driven signature, vascular invasion, and hormone receptor loss in endometrial carcinoma

We studied the expression of polycomb group (PcG) protein BMI-1 in a large population-based patient series of endometrial carcinomas in relation to clinical and molecular phenotype. Also, 57 fresh frozen endometrial carcinomas were studied for the relationship between BMI-1 protein expression, BMI-1 mRNA level, and activation of an 11-gene signature reported to represent a BMI-1-driven pathway. BMI-1 protein expression was significantly weaker in tumours with vascular invasion (P<0.0001), deep myometrial infiltration (P=0.004), and loss of oestrogen receptor (ER) (P<0.0001) and progesterone receptors (PR) (P=0.03). Low BMI-1 protein expression was highly associated with low BMI-1 mRNA expression (P=0.002), and similarly low BMI-1 mRNA expression correlated significantly with vascular invasion, ER and PR loss, and histologic grade 3. In contrast, activation of the reported 11-gene signature, supposed to represent a BMI-1-driven pathway, correlated with low mRNA expression of BMI-1 (P<0.001), hormone receptor loss, presence of vascular invasion, and poor prognosis. We conclude that BMI-1 protein and mRNA expression are significantly correlated and that BMI-1 expression is inversely associated with activation of the 11-gene signature. Loss of BMI-1 seems to be associated with an aggressive phenotype in endometrial carcinomas.

Frequency of Muir–Torre Syndrome in the Lynch Syndrome

A syndrome that increases the risk of some skin cancers may be a component of another syndrome that increases the risk of colorectal cancer, according to a February 20th report in the Journal of the National Cancer Institute.Some individuals with Lynch syndrome—an inherited predisposition to develop colorectal and other specific types of cancers—also have a tendency to develop certain kinds of skin tumors (ie, Muir–Torre syndrome). Cancerous lesions associated with both syndromes are characterized by inherited mutations in DNA mismatch repair (MMR) genes, including MSH2.The cohort study by Dr Albert de la Chapelle and colleagues at The Ohio State University examined the frequency of Muir–Torre syndrome–related skin tumors among 50 Lynch syndrome families (confirmed by MMR gene mutation analysis) who were ascertained from a population-based series of patients newly diagnosed with colorectal or endometrial cancer. Histories of Muir–Torre syndrome–associated skin tumors were documented during counseling of family members.Muir–Torre syndrome was observed in 28% of the 50 families and in 9.2% of the 152 individuals with Lynch syndrome. The frequency of Muir–Torre syndrome was 75% among families who carried a specific mutation in the MSH2 gene versus 25% among families who carried other mutations in this gene. There was a preponderance of the Muir–Torre syndrome–associated deleterious MSH2 gene mutation in the study cohort, the authors note. However, they point out that histories of skin lesions may have been subject to recall bias.“On the basis of our results, we suggest that Muir–Torre syndrome be defined as a variant of Lynch syndrome that is characterized by mutations in all [mismatch repair] genes. We propose that Muir–Torre syndrome-associated skin lesions be included as a component tumor of the Lynch syndrome and screened for accordingly,” the authors write.See, “The Frequency of Muir–Torre Syndrome Among Lynch Syndrome Families,” J Natl Cancer Inst 2008;100:277–281. A syndrome that increases the risk of some skin cancers may be a component of another syndrome that increases the risk of colorectal cancer, according to a February 20th report in the Journal of the National Cancer Institute. Some individuals with Lynch syndrome—an inherited predisposition to develop colorectal and other specific types of cancers—also have a tendency to develop certain kinds of skin tumors (ie, Muir–Torre syndrome). Cancerous lesions associated with both syndromes are characterized by inherited mutations in DNA mismatch repair (MMR) genes, including MSH2. The cohort study by Dr Albert de la Chapelle and colleagues at The Ohio State University examined the frequency of Muir–Torre syndrome–related skin tumors among 50 Lynch syndrome families (confirmed by MMR gene mutation analysis) who were ascertained from a population-based series of patients newly diagnosed with colorectal or endometrial cancer. Histories of Muir–Torre syndrome–associated skin tumors were documented during counseling of family members. Muir–Torre syndrome was observed in 28% of the 50 families and in 9.2% of the 152 individuals with Lynch syndrome. The frequency of Muir–Torre syndrome was 75% among families who carried a specific mutation in the MSH2 gene versus 25% among families who carried other mutations in this gene. There was a preponderance of the Muir–Torre syndrome–associated deleterious MSH2 gene mutation in the study cohort, the authors note. However, they point out that histories of skin lesions may have been subject to recall bias. “On the basis of our results, we suggest that Muir–Torre syndrome be defined as a variant of Lynch syndrome that is characterized by mutations in all [mismatch repair] genes. We propose that Muir–Torre syndrome-associated skin lesions be included as a component tumor of the Lynch syndrome and screened for accordingly,” the authors write. See, “The Frequency of Muir–Torre Syndrome Among Lynch Syndrome Families,” J Natl Cancer Inst 2008;100:277–281.