Cancer incidence among Finnish seafarers, 1967–92

A cohort of 30,940 male and 11,529 female seafarers registered in the files of Seafarers' Pension Fund in Finland was followed up through the Finnish Cancer Registry for cancer in 1967–92. Among male seafarers, there were 1,199 cases of cancer, which corresponds to the average cancer incidence in Finnish men. There was a statistically significant excess of non-melanoma skin cancer (standardized incidence ratio [SIR]=1.8, 95 percent confidence interval [CI]=1.2–2.5) and mesothelioma (SIR=2.9, CI=1.2–5.6) in the follow-up category of 20 or more years since the first employment. Alcohol-related cancers were increased among seafarers (SIR for cancer of the mouth and pharynx = 1.; esophagus = 1.4; and liver = 1.5; combined CI=1.1–1.9). Deck crews had a significantly high risk of cancer of the pancreas (SIR=2.0) and also prostate after 10 years since first employment (SIR=1.6). Occupational asbestos exposure among seafarers is likely strong enough to cause excess cases of mesothelioma but not of lung cancer. Occupational exposures also may be associated with increased risk of cancers of the kidney, pancreas, prostate and old-age brain cancer in some of the main occupational categories. Cumulative ultraviolet radiation likely doubles the risk of nonmelanoma skin cancer among older men and repeated sunburns that of skin melanoma in ages below 30 (SIR among deck and engine crew = 4.6, CI=3.1–6.5). Female ship personnel had a significantly elevated total cancer risk (observed number of cases = 732) which increased over follow-up time (SIR in the category 20 years since the first employment was 1.3, CI=1.1–1.5). This excess was attributable primarily to lung cancer (SIR=2.6, CI=2.0–3.3). Also cancers of the cervix uteri, vulva, and vagina showed significant excess after 10 to 20 years since first employment aboard.Address correspondence to Dr Pukkala, Finnish Cancer Registry, Litsankatu 21 B, FIN-00170 Helsinki, Finland. The Finnish Work Environment Fund financially supported this project.Dr Pukkala is with the Finnish Cancer Registry, Helsinki, Finland. Dr Saarni is with the Regional Institute of Occupational Health, Turku, Finland.     

Prospective randomized comparison of endonasal endoscopic dacryocystorhinostomy and external dacryocystorhinostomy

Objectives and Study Design: The advent of the rigid endonasal endoscope and the development of functional endoscopic sinus surgery (FESS) technique have awakened interest in an endonasal endoscopic dacryocystorhinostomy (EESC-DCR) in treating nasolacrimal obstruction. This prospective, randomized study compares EESC-DCR with traditional external dacryocystorhinostomy (EXT-DCR) for their success rates, surgical duration, and postoperative symptoms. Patients and Methods: Sixty-four cases in 60 patients with primary acquired nasolacrimal sac or duct obstruction were divided into two subgroups by symptoms (simple epiphora/ chronic dacryocystitis). These patients were randomized within both subgroups into two operation groups. Altogether 32 EESC-DCRs and 32 EXT-DCRs were performed. The final follow-up visit was at 1 year. The patency of the lacrimal passage was investigated by irrigation and patients were questioned about their symptoms. Results: The success rate at 1 year after surgery was 75% for EESC-DCR and 91% for EXT-DCR after primary surgery. The difference was not statistically significant (P = .18). The success rate after secondary surgery with a follow-up time of 1 year was 97% in both study groups. The average duration for EESC-DCR was 38 minutes, and 78 minutes for EXT-DCR, (P < .001). Conclusions: EXT-DCR, when compared with EESC-DCR, appears to give a higher, although not statistically significant, primary success rate, but the secondary success rates are equal, indicating that these two different DCR techniques are acceptable alternatives.     

The effect of tightened hearing protection regulations on military noise-induced tinnitus

The objective of this study was to investigate the effect of tightened hearing protection regulations on tinnitus in the Finnish Defence Forces. The initial study group comprised 252 officers and non-commissioned officers (NCOs), of which 229 were included in the final study group. Subjective symptoms of tinnitus and audiometric test results for these officers and NCOs examined before retirement, from 1984 to 1986 (Period I), and 2003 to 2005 (Period II), were reviewed. Changes in tinnitus reports between the two time periods, during which regulations had been revised, were investigated. Prevalence of tinnitus showed a decline both in officers (from 68% to 63%) and in NCOs (from 76% to 72%) between the two study periods, in accordance with tightened hearing protection regulations. The Cox regression analysis showed a significantly decreased hazard ratio for constant or disturbing tinnitus for Period II. Tinnitus prevalence, especially constant or disturbing tinnitus, in the Finnish Defence Forces was diminished by tightened hearing protection regulations. Tinnitus might be more persistent than hearing loss and does not necessarily improve in direct relation to hearing loss after protective measures.     

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.Subject terms: Breast cancer, Translational research, Predictive markers, Breast cancer     

First trimester combined screening biochemistry in detection of congenital heart defects

Objective: To evaluate the performance of first trimester biochemical markers, pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (fβ-hCG), and nuchal translucency (NT) in detection of severe congenital heart defects (CHDs).

Methods: During the study period from 1 January 2008 to 31 December 2011, biochemical markers and NT were measured in 31,144 women as part of voluntary first trimester screening program for Down’s syndrome in Northern Finland. Data for 71 severe CHD cases and 762 controls were obtained from the hospital records and from the National Medical Birth Register, which records the birth of all liveborn and stillborn infants, and from the National Register of Congenital Malformations that receives information about all the CHD cases diagnosed in Finland.

Results: Both PAPP-A and fβ-hCG multiple of median (MoM) values were decreased in all severe CHDs: 0.71 and 0.69 in ventricular septal defects (VSDs), 0.58 and 0.88 in tetralogy of Fallot cases (TOFs), 0.82 and 0.89 in hypoplastic left heart syndromes (HLHSs), and 0.88 and 0.96 in multiple defects, respectively. NT was increased in all study groups except of VSD group. ROC AUC was 0.72 for VSD when combining prior risk with PAPP-A and fβ-hCG. Adding NT did not improve the detection rate. With normal NT but decreased (<0.5 MoM) PAPP-A and fβ-hCG odds ratios for VSD and HLHS were 19.5 and 25.6, respectively.

Conclusions: Maternal serum biochemistry improves the detection of CHDs compared to NT measurement only. In cases with normal NT measurement but low concentrations of both PAPP-A and fβ-hCG, an alert for possible CHD, especially VSD, could be given with thorough examination of fetal heart in later ultrasound scans.     

Trastuzumab emtansine: mechanisms of action and drug resistance

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within the target cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The effect of T-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1.     

Cardiac arrest and left ventricular fibrosis in a Finnish family with the lamin A/C mutation

Introduction: We screened the candidate genes from a Finnish family in which the mother was resuscitated from ventricular fibrillation and the daughter died suddenly without any prior cardiac symptoms.
Methods and Results: In addition to screening of potential structural gene mutations, phenotyping of the proband and medico-legal autopsy of the victim of the sudden death, including histopathological examinations, were performed. Genetic screening revealed an R541C mutation in the lamin A/C gene both in the proband and her daughter. None of the 16 first- or second-degree relatives, or 96 unrelated healthy subjects, carried the same mutation. In the proband, the size and the global function of the left ventricle (LV) were normal, but a local hypokinesia and thinning of inferoposterior area of the LV were seen in 2D echocardiography and magnetic resonance imaging. Coronary angiogram and the results of the electrophysiological study were normal. Autopsy of the victim of sudden death showed localized thinning and fibrosis in the inferoposterior area of the LV, with only minimal fibrosis in the right ventricle and no abnormalities in the interventricular septum.
Conclusion: These observations indicate that a fatal or near-fatal cardiac arrhythmia can be the first clinical manifestation of a "de novo" mutation R541C of the lamin A/C gene. Replacement of cardiac myocytes by fibrosis seems to be the predominant pathologic-anatomic finding.     

Late QRS Activity in Signal‐Averaged Magnetocardiography,Body Surface Potential Mapping,and Orthogonal ECG in Postinfarction Ventricular Tachycardia Patients

Background: Delayed electrical activity necessary for re‐entrant ventricular tachycardia (VT) is detectable noninvasively with high resolution techniques. We compared high resolution signalaveraged analysis of magnetocardiography (MCG), body surface potential mapping (BSPM), and orthogonal three‐lead ECG (SA‐ECG) in the identification of patients prone to VT after myocardial infarction (Ml). Methods: Patients with remote myocardial infarction and cardiac dysfunction were studied, 22 with (VT group) and 22 without VT (control group). MCG with seven channels and BSPM with 63 and SA‐ECG with three orthogonal leads were registered. After signal‐averaging and highpass filtering, three time domain analysis (TDA) parameters describing late electrical activity were computed: QRS duration (QRSd), root mean square amplitude (RMS) of the last 40 ms of QRS, and the duration of the low‐amplitude QRS end (LAS). Results: All parameters by each method were significantly different between the patients’groups. For example, LAS parameter in MCG was 59 (SD 22) ms in the VT group vs. 37 (SD 13) ms in controls (P < 0.001), 77 (SD 22) ms vs. 56 (SD 19) ms in BSPM (P = 0.002), and 60 (SD 24) ms vs. 39 (SD 22) ms in SA‐ECG (P = 0.005). The combination of LAS parameter in MCG and SA‐ECG resulted in improved performance in comparison to any single parameter with 95% sensitivity and 68% specificity. Conclusions: All three high resolution methods identified VT propensity among post‐Mi patients with cardiac dysfunction and between‐method differences were small. Information in MCG and SA‐ECG may be complementary and their combination could be of value in postinfarction arrhythmia risk assessment. A.N.E. 2002;7(4):389–398