The cumulative burden of self-reported, clinically relevant outcomes in long-term childhood cancer survivors and implications for survivorship care: A DCCSS LATER study.

BACKGROUND: The aim of this study is to evaluate how cumulative burden of clinically relevant, self-reported outcomes in childhood cancer survivors (CCSs) compares to a sibling control group and to explore how the burden corresponds to levels of care proposed by existing risk stratifications. METHODS: The authors invited 5925 5-year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS LATER) cohort and their 1066 siblings to complete a questionnaire on health outcomes. Health outcomes were validated by self-reported medication use or medical record review. Missing data on clinically relevant outcomes in CCSs for whom no questionnaire data were available were imputed with predictive mean matching. We calculated the mean cumulative count (MCC) for clinically relevant outcomes. Furthermore, we calculated 30-year MCC for groups of CCSs based on primary cancer diagnosis and treatment, ranked 30-year MCC, and compared the ranking to levels of care according to existing risk stratifications. RESULTS: At median 18.5 years after 5-year survival, 46% of CCSs had at least one clinically relevant outcome. CCSs experienced 2.8 times more health conditions than siblings (30-year MCC = 0.79; 95% confidence interval [CI], 0.74-0.85 vs. 30-year MCC = 0.29; 95% CI, 0.25-0.34). CCSs' burden of clinically relevant outcomes consisted mainly of endocrine and vascular conditions and varied by primary cancer type. The ranking of the 30-year MCC often did not correspond with levels of care in existing risk stratifications. CONCLUSIONS: CCSs experience a high cumulative burden of clinically relevant outcomes that was not completely reflected by current risk stratifications. Choices for survivorship care should extend beyond primary tumor and treatment parameters, and should consider also including CCSs' current morbidity.

Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status.

BACKGROUND: Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. METHODS: We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients' outcomes were compared using Cox regression and competing risk models. RESULTS: Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18-3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78-0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9-100%). Conversely, among the 61 patients with gBRCA1m and < 50% sTILs, we observed poor 15-year OS (50.8%; 95% CI, 39.7-65.0%). Furthermore, gBRCA1m was associated with higher (adjusted subdistribution HR, 4.04; 95% CI, 2.29-7.13) and tumor BRCA1-PM with lower (adjusted subdistribution HR, 0.42; 95% CI, 0.19-0.95) incidence of second primary tumors, compared to BRCA1-non-alteration. CONCLUSIONS: Although both gBRCA1m and tumor BRCA1-PM alter BRCA1 gene transcription, they are associated with different outcomes in young, node-negative, chemotherapy-naïve TNBC patients. By combining sTILs and BRCA1 status for risk classification, we were able to identify potential subgroups in this population to intensify and optimize adjuvant treatment.

Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients.

BACKGROUND: The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial. METHODS: Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm. RESULTS: For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08-0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24-1.81) (P-interaction = 0.17). CONCLUSION: Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.

A Phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer.

Preclinical studies have shown synergistic effects when combining PARP1/2 inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. After a formulation change of olaparib from capsules to tablets, we initiated a dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin to prepare comparative studies in this patient group. Patients were included in a 3 + 3 dose-escalation schedule: olaparib 25 mg BID and carboplatin area under the curve (AUC) 3 mg*min/mL d1/d22, olaparib 25 mg BID and carboplatin AUC 4 mg*min/mL d1/d22, followed by increasing dose-levels of olaparib from 50 mg BID, 75 mg BID, to 100 mg BID with carboplatin at AUC 4 mg*min/mL d1/d22. After two cycles, patients continued olaparib 300 mg BID as monotherapy. Primary objective was to assess the maximum tolerable dose (MTD). Twenty-four patients with a confirmed diagnosis of advanced cancer were included. Most common adverse events were nausea (46%), fatigue (33%) and platelet count decrease (33%). Dose-level 3 (olaparib 75 mg BID and carboplatin AUC 4 mg*min/mL; n = 6) was defined as MTD. Fourteen out of 24 patients (56%) had a partial response as best response (RECIST 1.1). Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with olaparib tablet AUC0-12 of 16.3 µg/mL*h at MTD. Polymers of ADP-ribose levels in peripheral blood mononuclear cells were reduced by 98.7% ± 0.14% at Day 8 compared to Day 1 for dose-level 3. Olaparib tablets 75 mg BID and carboplatin AUC 4 mg*min/mL for two cycles preceding olaparib monotherapy 300 mg is a feasible and tolerable treatment schedule for patients with advanced cancer.

Concurrent versus sequential use of trastuzumab and chemotherapy in early HER2+ breast cancer.

PURPOSE: The addition of trastuzumab to adjuvant chemotherapy has improved the outcome of human epidermal growth-factor receptor 2 (HER2)-positive breast cancer. Uncertainty remains about the optimal timing of trastuzumab treatment. Therefore, we compared long-term outcome after concurrent versus sequential treatment, in a population-based setting, using data from the nationwide Netherlands Cancer Registry. METHODS: We identified 1843 women diagnosed in The Netherlands from January 1st 2005 until January 1st 2008 with primary, HER2-positive, T1-4NanyM0 breast cancer who received adjuvant chemotherapy and trastuzumab. Kaplan-Meier survival estimates and Cox regression were used to compare recurrence-free survival (RFS) and overall survival (OS) between women who received trastuzumab concurrently with versus sequentially after chemotherapy. Hazard ratios (HR) were adjusted for age, year of diagnosis, grade, pathological T-stage, number of positive lymph nodes, ER-status, PR-status, socio-economic status, radiotherapy, hormonal therapy, ovarian ablation, and type of chemotherapy. RESULTS: After a median follow-up of 8.2 years, RFS events had occurred in 224 out of 1235 (18.1%) concurrently treated women and 129 out of 608 (21.2%) sequentially treated women (adjusted-HR 0.91; 95% confidence interval (CI) 0.67-1.24; P = 0.580). Deaths occurred in 182/1235 (14.7%) concurrently treated women and 104/608 (17.1%) sequentially treated women (adjusted-HR 0.92; 95% CI 0.65-1.29; P = 0.635). CONCLUSIONS: The results of this population-based study are consistent with earlier randomized trials, demonstrating a non-significant difference in outcome for concurrently treated women compared to those who were treated sequentially, suggesting both options are justified.

Change in cognition before and after non-central nervous system cancer diagnosis: A population-based cohort study.

OBJECTIVE: Clinical studies showing that non-central nervous system cancer patients can develop cognitive impairment have primarily focused on patients with specific cancer types and intensive treatments. To better understand the course of cognitive function in the general population of cancer patients, we assessed cognitive trajectories of patients before and after cancer diagnosis in a population-based setting. METHODS: Between 1989 and 2014, 2211 participants from the population-based Rotterdam study had been diagnosed with cancer of whom 718 (32.5%) had undergone ≥1 cognitive assessment before and after diagnosis. Cognition was measured every 3 to 6 years using a neuropsychological battery. Linear mixed models were used to compare cognitive trajectories of patients before and after diagnosis with those of age-matched cancer-free controls (1:3). RESULTS: Median age at cancer diagnosis was 70.3 years and 47.1% were women. Most patients (68.1%) had received local treatment only. Cognitive trajectories of patients before and after cancer diagnosis were largely similar to those of controls. After diagnosis, the largest difference was found on a memory test (patients declined with 0.14 units per year on the Word Learning Test: delayed recall [95% CI = -0.35; 0.07] and controls with 0.09 units [95% CI = -0.18;-0.00], p for difference = .59). CONCLUSIONS: In this longitudinal cohort, cancer did not appear to alter the trajectory of change in cognitive test results over time from that seen in similar individuals without cancer, although most cancer patients did not receive systemic therapies. Future studies should focus on identifying subgroups of patients who are at high risk for developing cognitive impairment.

The CXCR5 T follicular helper cell compartment in children with antibody deficiencies-in search of a prognostic marker of childhood hypogammaglobulinemia.

BACKGROUND: Novel immunodiagnostic markers are required in order to discriminate between mild hypogammaglobulinemia and severe humoral primary immune deficiencies in children. The efficacy of an antibody response to infections and vaccines is underpinned by T follicular helper (Tfh) cells, activating an immunoglobulin class switch recombination, somatic hypermutations, and affinity maturation. OBJECTIVE: To determine the formation of the Tfh cells in antibody deficient children and to define their importance as prognostic markers helpful in defining the severity of hypogammaglobulinemia. METHODS: We retrospectively reviewed medical records of 200 children aged from 2 months to 10 years, in whom hypogammaglobulinemia was assessed, from January to December 2019. In all the children studied, a flow cytometric analysis of the Tfh cell compartment was performed. RESULTS: In young infants aged from 2 to 9 months, the mean relative frequency of the Tfh population was lower than in the control population. Concomitantly, the relative values of Tfh cells, corresponding with the 95th percentile, were below the reference values in all age groups. CONCLUSIONS: A deficiency of Tfh cells in young infants mirrors the immaturity of the humoral immune response, whereas in older children Tfh cells are proposed as a prognostic marker facilitating to distinguish between mild hypogammaglobulinemia and the developing common variable immunodeficiency.

Hearing loss among elderly people and access to hearing aids: a cross-sectional study from a rural area in Germany.

PURPOSE: Hearing loss is common and associated with reduced quality of life, particularly among elderly people. However, many patients do not use hearing aids. We evaluated the use of hearing aids among people with hearing loss by health services availability near their residence in a rural area in the state of Brandenburg, Germany. METHODS: Audiometry was performed in a convenience sample of subjects in ten towns and hearing loss was determined, defined as a threshold of ≥ 30 dB in at least one ear and at least one of the frequencies 0.5, 1.0, 2.0 and 4.0 kHz. For each participant, age and gender were collected and whether or not hearing aids were available. RESULTS: Among 186 persons with an average age of 74 years (interquartile range 71-81), 97% had hearing loss [95% confidence interval (CI) 95-100]. Among 121 patients with hearing loss who reported whether or not they have a hearing aid, 93 had no hearing aid (77%, 95% CI 69-84). The proportion of hearing-impaired persons who do not have a hearing aid significantly increased with the absence of a hearing aid specialist or ear nose throat (ENT) physician or both in the town where the tests were performed (p trend = 0.001). CONCLUSION: Hearing loss is common among elderly people in the study area and many people in rural areas in Germany may not be properly supplied with hearing aids due to lack of hearing aid specialists and/or ENT physicians close to their residence. Interventions to improve this situation are urgently required.

Platinum exposure and cause-specific mortality among patients with testicular cancer.

BACKGROUND: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. METHODS: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. RESULTS: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m2 platinum dose administered (Ptrend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. CONCLUSIONS: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.

Lymphovascular invasion and presence of embryonal carcinoma as risk factors for occult metastatic disease in clinical stage I nonseminomatous germ cell tumour: a systematic review and meta-analysis.

OBJECTIVE: To systematically review the literature on the prognostic value of lymphovascular invasion (LVI) and embryonal carcinoma (EC) for occult metastatic disease in clinical stage I nonseminomatous germ cell tumour (CS I NSGCT). MATERIALS AND METHODS: The PubMed, Embase (OVID) and SCOPUS databases were searched up to March 2019. Studies reporting on the association between LVI and/or EC and occult metastatic disease were considered for inclusion. The quality and risk of bias were evaluated by the Quality in Prognosis Studies tool. RESULTS: We screened 5287 abstracts and 207 full-text articles. We included 35 studies in the narrative synthesis and 24 studies in a meta-analysis. LVI showed the strongest effect. Pooled rates of occult metastasis were 47.5% and 16.9% for LVI-positive and LVI-negative patients, respectively (odds ratio [OR] 4.33, 95% confidence interval [CI] 3.55-5.30; P < 0.001). Pooled rates of occult metastasis were 33.2% for EC presence and 16.2% for EC absence (OR 2.49, 95% CI 1.64-3.77; P < 0.001). Pooled rates of occult metastasis were 40.0% for EC >50% and 20.0% for EC <50% (OR 2.62, 95% CI 1.93-3.56; P < 0.001). CONCLUSIONS: LVI is the strongest risk factor for relapse. The prognostic value of EC is high, but there is no common agreement on how to define this risk factor. Both EC presence and EC >50% have similar ORs for occult metastasis. This shows that the assessment of EC presence is sufficient for the classification of EC.

Biocontrol ability and volatile organic compounds production as a putative mode of action of yeast strains isolated from organic grapes and rye grains.

The inhibiting activity of three yeast strains belonging to Pichia kudriavzevii, Pichia occidentalis, and Meyerozyma quilliermondii/Meyerozyma caribbica genera against common plant pathogens representing Mucor spp., Penicillium chrysogenum, Penicillium expansum, Aspergillus flavus, Fusarium cereals, Fusarium poae, as well as Botrytis cinerea genera was investigated. The yeast strains tested had a positive impact on growth inhibition of all target plant pathogens. The degree of inhibition was more than 50% and varied depending on both the yeast antagonist and the mold. Ethyl esters of medium-chain fatty acids, phenylethyl alcohol, and its acetate ester prevailed among the analyzed volatile organic compounds (VOCs) emitted by yeasts in the presence of the target plant pathogens. Due to the method used, assuming no contact between the antagonist and the pathogen, the antagonistic activity of the yeast strains studied resulted mainly from the production of biologically active VOCs. Moreover, the antagonistic activity was not only restricted to a single plant pathogen but effective towards molds of different genera, making the yeast strains studied very useful for potential application in biological control.

Cutaneous and systemic granulomatosis in ataxia-telangiectasia: a clinico-pathological study.

INTRODUCTION: The development of granulomas is a well-recognized manifestation of immunodeficiency in ataxia-telangiectasia (A-T), resulting from lymphocyte developmental abnormalities, impaired immunosurveillance, and inappropriate innate immune response-driven inflammation. AIM: To better understand pathological and immunological phenomena involved in development of cutaneous and visceral granulomatosis observable in patients with ataxia-telangiectasia. MATERIAL AND METHODS: We retrospectively reviewed medical records of eight A-T children, aged from 2 to 13 years, with regard to clinical, immunological and histopathological features of cutaneous and visceral granulomatosis. RESULTS: In four out of eight A-T patients studied, cutaneous granulomas clinically presented as skin nodules and ulcerated erythematous plaques disseminated on the face, and on trauma-prone areas of upper and lower extremities. Visceral granulomatosis had a severe clinical course and involved the lungs, the spleen, the liver and the larynx. Histologically, cutaneous and laryngeal granulomas showed extensive cellular infiltrations containing T lymphocytes with predominating CD8+ phenotype and with CD68+ histiocytes. The immunological profile with the hyper-IgM phenotype, markedly reduced numbers of B and naive CD4+ and CD8+ T cells with predominating IgM-only memory B cells and skewed repertoire of a T cell receptor was observable in patients with skin and visceral granulomatosis. CONCLUSIONS: In the setting of combined immunodeficiency in A-T, cutaneous and systemic granulomatosis reflects a granulomatous reaction pattern, as a result of inappropriate immune regulation.

Integrated versus separate reading of F-18 FDG-PET/CT and MRI for abdominal malignancies - effect on staging outcomes and diagnostic confidence.

OBJECTIVE: Abdominal cancer patients increasingly undergo multimodality imaging. This study evaluates effects of integrated reading of PET/CT and abdominal MRI on staging outcomes and diagnostic confidence compared to "routine" separate reading. METHODS: In total, N = 201 patients who underwent abdominal MRI and whole-body F-18 FDG-PET/CT within 14 days were retrospectively analyzed. Original MRI and PET/CT reports were retrieved and reported findings translated into a 5-point confidence score (1 = definitely benign to 5 = definitely malignant) for 7 standardized regions (primary tumor/regional lymph nodes/distant lymph nodes/liver/lung/bone/peritoneum) per patient. Two-reader teams (radiologist + nuclear medicine physician) then performed integrated reading of the images using the same scoring system. RESULTS: Integrated reading led to discrepant findings in 59 of 201 (29%) of patients, with potential clinical impact in 25 of 201 (12%). Equivocal scores decreased from 5.7% (PET/CT) and 5.4% (MRI) to 3.2% (p = 0.05 and p = 0.14). Compared to the original PET/CT reports, integrated reading led to increased diagnostic confidence in 8.9% versus decreased confidence in 6.6% (p = 0.26). Compared with the original MRI reports, an increase in confidence occurred in 9.6% versus a decrease in 6.9% (p = 0.18). The effect on diagnostic confidence was most pronounced in lymph nodes (p = 0.08 vs. MRI), cervical cancer (p = 0.03 vs. MRI), and recurrent disease staging (p = 0.06 vs. PET/CT). CONCLUSIONS: Integrated PET/CT+MRI reading alters staging outcomes in a substantial proportion of cases with potential clinical impact in ± 1 out of 9 patients. It can also have a small positive effect on diagnostic confidence, particularly in lymph nodes and cervical cancer, and in post-treatment settings. These findings support further collaboration between radiology and nuclear medicine disciplines. KEY POINTS: • Increasing numbers of patients undergo multimodality imaging consisting of both MRI and PET/CT for staging of abdominal malignancies. • Integrated reading of FDG-PET/CT and abdominal MR images by a team, consisting of a radiologist and a nuclear medicine physician, can alter staging outcomes compared to separate reporting of the exams in a substantial proportion of cases and with potential clinical impact in ± 1 out of 9 patients. • Integrated PET/CT+MRI reading can have a small positive effect on diagnostic confidence.

Salvage surgery for advanced stage head and neck squamous cell carcinoma following radiotherapy or chemoradiation.

PURPOSE: Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma (HNSCC) is known to result in poor prognosis. As there are only small and heterogeneous studies available with wide variety in outcome measures, our purpose was to select and pool literature according to specific criteria. METHODS: Systematic review and meta-analysis of clinical outcome after salvage surgery for recurrent advanced stage HNSCC following primary radiotherapy or chemoradiation. RESULTS: 16 of 3956 screened studies were included for analysis (729 patients). Pooled 5-year OS was 37% (95% CI 30-45%, 12 studies, 17 outcome measurements, 540 patients). Outcome was presented for larynx (6 studies, 397 patients), hypopharynx (2 studies, 47 patients), larynx and hypopharynx combined (3 studies, 69 patients) or separately (1 study, 134 patients), oral cavity (1 study, 11 patients), oropharynx (1 study, 34 patients) and multiple subsites combined (2 studies, 37 patients). There was no significant difference in survival outcome between subsites (pheterogeneity = 0.8116). The pooled tumor-positive resection margin rate was 32% and pooled re-operation rate 17%. Complication rates from the pooled data were: fistulas 33%, wound infections 24% and flap failure 3%. Treatment-related mortality rate was 1% and mean hospital stay was 23 days. CONCLUSIONS: Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma after primary (chemo)radiotherapy is a good last resort curative treatment option, resulting in 37% overall survival at 5 years. As data from advanced stage non-laryngeal tumors were sparse, no solid conclusions can be drawn with regard to outcome differences between tumor subsites.

Current concepts on epilepsy management in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors.

This corrects the article DOI: 10.1038/bjc.2017.85.

Breast-specific factors determine cosmetic outcome and patient satisfaction after breast-conserving therapy: Results from the randomized COBALT study.

BACKGROUND AND OBJECTIVES: To identify breast-specific factors and the role of tumor, treatment, and patient-related items in influencing patient opinion on cosmesis and satisfaction after breast-conserving therapy (BCT). METHODS: Data from the randomized COBALT study was used. At 3, 12, and 36 months, 128 patients with T1-T2 breast cancer completed a questionnaire on breast-specific factors and overall cosmetic outcome and patient satisfaction, using a 4-point Likert scale. RESULTS: There was a strong positive correlation between breast-specific factors, overall cosmetic outcome,and satisfaction at all time-points. Excellent/good cosmetic outcomes and satisfaction decreased during follow-up. A shift was noted in the degree of influence of the various breast-specific factors. At 3 years, symmetry factors such as size, shape, and nipple position largely determined a patient's opinion on the final cosmesis, followed by firmness. The risk of an unacceptable outcome was associated with young age and large excision volumes. CONCLUSION: A questionnaire including breast-specific questions provides important information on final cosmetic results and satisfaction after BCT. These outcomes can also be of great value as quality indicators and pre-operative counseling. The major influence of breast-specific factors on asymmetry underlines the importance of achieving an optimal excision volume at the initial procedure.

Optimized yeast-based in vitro bioassay for determination of estrogenic and androgenic activity of hydroxylated / methoxylated metabolites of BDEs / CBs and related lipophilic organic pollutants.

Persistent organic pollutants (POPs) are known to show endocrine disrupting (ED) activity, including interactions with hormone receptors. The aim of this work was to develop a bioassay applicable for evaluation of ED potency of highly lipophilic metabolites of POPs. To that end, a yeast-based bio-assay protocol was used. Estrogenic / androgenic activity of some native brominated biphenyl ethers (BDEs) / chlorinated biphenyls (CBs), and their hydroxylated / methoxylated metabolites was assessed. Since data (including potency compared to reference native hormones) obtained using different protocols vary, the possibility that yeast transforms POPs into some more potent compounds was first checked; it seems that no such transformation is important from the test applicability standpoint. The developed method was sensitive with EC50 values 6.5*10-11 M and 4.5*10-9 M calculated for E2 and DHT, respectively. Both CBs and BDEs show weak estrogenic activity negatively correlated with the degree of their halogenation, but their metabolites are significantly more potent xenohormones. 4-OH-2,2',4',6'-TeCB was the most potent estrogen receptor (ER) agonist among all tested compounds; its activity was only 1,000 times lower than that of native E2.

Isolated Limb Perfusion for Melanoma is Safe and Effective in Elderly Patients.

BACKGROUND: Data on isolated limb perfusion (ILP) in elderly melanoma patients are scarce. We aimed to evaluate the efficacy and safety of ILP in our institutional cohort of melanoma patients. METHODS: We performed retrospective analysis of stage IIIB/C melanoma patients who underwent ILP for melanoma in-transit metastases (ITMs) in our institution between 2000 and 2016. Normothermic ILP was performed with either melphalan or melphalan and tumor necrosis factor. Baseline and treatment characteristics, locoregional progression-free survival (LPFS) and melanoma-specific survival (MSS) were assessed and prognostic factors for response, recurrence, and survival were analyzed using univariable and multivariable analysis. RESULTS: Overall, 91 patients were included in this study. Based on the median age of 70 years, we split patients into younger and elderly groups. No differences in response rates were observed between age groups, with an overall response rate of 81% and complete response (CR) rate of 47%. LPFS did not differ between age groups, and median LPFS was 16 months for patients with a CR. Median MSS was 38 months and differed between younger (45 months) and elderly patients (18 months). Toxicity was generally mild and did not differ between age groups. Two patients (2.2%) suffered Wieberdink IV toxicity, while no patients required amputation because of severe toxicity. CR was prognostic for improved LPFS and MSS, while patients >70 years of age and patients with stage IIIC disease had a higher risk of melanoma-specific death. CONCLUSIONS: Because of its safety profile and high CR rates, ILP is a viable option for patients with bulky or multiple melanoma ITMs, including elderly (>70 years of age) patients.

Colorectal cancer surveillance in Hodgkin lymphoma survivors at increased risk of therapy-related colorectal cancer: study design.

BACKGROUND: Second primary malignancies are a major cause of excess morbidity and mortality in cancer survivors. Hodgkin lymphoma survivors who were treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine have an increased risk to develop colorectal cancer. Colonoscopy surveillance plays an important role in colorectal cancer prevention by removal of the precursor lesions (adenomas) and early detection of cancer, resulting in improved survival rates. Therefore, Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine could benefit from colonoscopy, or other surveillance modalities, which are expected to reduce colorectal cancer incidence and mortality. Current knowledge on clinicopathological and molecular characteristics of therapy-related colorectal cancer is limited. The pathogenesis of such colorectal cancers might be different from the pathogenesis in the general population and therefore these patients might require a different clinical approach. We designed a study with the primary aim to assess the diagnostic yield of a first surveillance colonoscopy among Hodgkin lymphoma survivors at increased risk of colorectal cancer and to compare these results with different screening modalities in the general population. Secondary aims include assessment of the test characteristics of stool tests and evaluation of burden, acceptance and satisfaction of CRC surveillance through two questionnaires. METHODS/DESIGN: This prospective multicenter cohort study will include Hodgkin lymphoma survivors who survived ≥8 years after treatment with infradiaphragmatic radiotherapy and/or procarbazine (planned inclusion of 259 participants). Study procedures will consist of a surveillance colonoscopy with removal of precursor lesions (adenomas) and 6-8 normal colonic tissue biopsies, a fecal immunochemical test and a stool DNA test. All neoplastic lesions encountered will be classified using relevant histomorphological, immunohistochemical and molecular analyses in order to obtain more insight into colorectal carcinogenesis in Hodgkin lymphoma survivors. The Miscan-model will be used for cost-effectiveness analyses. DISCUSSION: Evaluation of the diagnostic performance, patient acceptance and burden of colorectal cancer surveillance is necessary for future implementation of an individualized colorectal cancer surveillance program for Hodgkin lymphoma survivors. In addition, more insight into treatment-induced colorectal carcinogenesis will provide the first step towards prevention and personalized treatment. This information may be extrapolated to other groups of cancer survivors. TRIAL REGISTRATION: Registered at the Dutch Trial Registry (NTR): NTR4961 .