Sensory perception testing by monofilaments in the digits of controls and workers with HAVS.

OBJECTIVE: To determine if heavy manual work affects sensory perception in the digits and whether Semmes-Weinstein monofilaments (SWM) can be used as a screening tool to detect sensory neuropathy in the digits of workers exposed to hand-transmitted vibration (HTV). METHODS: A cross-sectional study of office workers, heavy manual workers not exposed to HTV and workers with hand-arm vibration syndrome (HAVS). Sensory perception was measured in the digits by SWM using a forced-choice method to determine variability by sex, age, hand and digit. Frequency distributions were used to determine limit values and linear weighted kappa for intra-digit variability. Poisson regression was used to explore the relationship between sensory perception by SWM and abnormalities of thermal and vibration perception in the hands of workers with HAVS. RESULTS: The sensory perception threshold of office workers did not vary by hand or digit. It was significantly lower in women < 30 than women aged ≥ 30 years. The 95th percentile for heavy manual workers was 1.00 (95% CI 0.60-1.00) and significantly higher than for office workers at 0.16 (95% CI 0.16-0.16). Heavy manual workers > 50 years had the highest threshold at 1.40 (95% CI 1.00-2.00). Weighted kappa for reliability was 0.63 (95% CI 0.53-0.70). A mean SWM threshold of ≥ 1.0 gram-force had a 79% sensitivity and 64% specificity for detecting abnormalities of thermal and vibration perception in the ipsilateral index and little fingers of workers with HAVS. CONCLUSIONS: SWM are a useful screening tool for detecting sensory loss in the digits of workers exposed to HTV.

International consensus criteria for diagnosing and staging hand-arm vibration syndrome.

PURPOSE: In the 30 years since the Stockholm Workshop Scale (SWS) was published, the scientific literature on hand-arm vibration syndrome (HAVS) has grown and experience has been gained in its practical application. This research was undertaken to develop an up-to-date evidence-based classification for HAVS by seeking consensus between experts in the field. METHODS: Seven occupational physicians who are clinically active and have had work published on HAVS in the last 10 years were asked to independently take part in a three-round iterative Delphi process. Consensus was taken when 5/7 (72%) agreed with a particular statement. Experts were asked to provide evidence from the literature or data from their own research to support their views. RESULTS: Consensus was achieved for most of the questions that were used to develop an updated staging system for HAVS. The vascular and neurological components from the SWS are retained, but ambiguous descriptors and tests without adequately developed methodology such as tactile discrimination, or discriminating power such as grip strength, are not included in the new staging system. A blanching score taken from photographs of the hands during vasospastic episodes is recommended in place of self-recall and frequency of attacks to stage vascular HAVS. Methods with the best evidence base are described for assessing sensory perception and dexterity. CONCLUSIONS: A new classification has been developed with three stages for the clinical classification of vascular and neurological HAVS based on international consensus. We recommend it replaces the SWS for clinical and research purposes.

Systematic Review: Occupational illness in the waste and recycling sector.

BACKGROUND: The waste and recycling sector is a growing part of industry. Whether health surveillance is indicated and how it should be undertaken is unclear. AIMS: To undertake a review of the literature to identify hazards to health, biological effects and occupational illnesses for workers in the sector. METHODS: A systematic review of the published literature and two UK databases. RESULTS: Rates of fatal, non-fatal injuries and self-reported work-related illness were found to be higher in the waste and recycling sector than in UK industry as a whole. There was an increased prevalence of respiratory, gastro-intestinal and skin complaints in workers exposed to compost relative to controls. They may also be at increased risk of extrinsic allergic alveolitis, allergic bronchopulmonary aspergillosis, occupational asthma and abnormalities of lung function. Workers involved with the recycling of batteries and cables may be at risk of lead poisoning and exposure to other heavy metals. There were case reports of mercury poisoning from the recycling of fluorescent lights. Cases of occupational asthma have been reported in association with wood and paper recycling. The recycling of e-waste may cause exposure to heavy metals and organic pollutants, such as polybrominated diphenyl ethers, dioxins and polyaromatic hydrocarbons, which have been associated with damage to DNA and adverse neonatal outcomes. CONCLUSIONS: Ill-health and adverse biological effects have been described in waste and recycling workers, but their true prevalence has probably not been captured. Targeted health surveillance may be required to assess exposure and to identify occupational illness.

The relationship between clinical and standardized tests for hand-arm vibration syndrome.

BACKGROUND: Standardized laboratory tests are undertaken to assist the diagnosis and staging of hand-arm vibration syndrome (HAVS), but the strength of the relationship between the tests and clinical stages of HAVS is unknown. AIMS: To assess the relationship between the results of thermal aesthesiometry (TA), vibrotactile (VT) thresholds and cold provocation (CP) tests with the modified Stockholm scales for HAVS and to determine whether the relationship is affected by finger skin temperature. METHODS: Consecutive records of workers referred to a Tier 5 HAVS assessment centre from 2006 to 2015 were identified. The diagnosis and staging of cases was undertaken from the clinical information contained in the records. Cases with alternative or mixed diagnoses were excluded and staging performed according to the modified Stockholm scale without knowledge of the results of the standardized laboratory tests. RESULTS: A total of 279 cases of HAVS were analysed. Although there was a significant trend for sensorineural (SN) and vascular scores to increase with clinical stage (P < 0.01), there was no significant difference in scores between 2SN early and 2SN late or between 2SN late and 3SN. There was moderate correlation between the TA and VT scores and the clinical SN stages (r = 0.6). This correlation did not change when subjects were divided into those with a finger skin temperature <30 and >30°C. CP scores distributed bimodally and correlated poorly with clinical staging (r = 0.2). CONCLUSIONS: Standardized SN tests distinguish between the lower Stockholm stages, but not above 2SN early. This has implications for health surveillance and UK policy.

Vascular hand-arm vibration syndrome--magnetic resonance angiography.

The diagnosis of vascular hand-arm vibration syndrome (HAVS) requires consistent symptoms, photographic evidence of digital blanching and sufficient exposure to hand-transmitted vibration (HTV; A(8) > 2.5 m/s2). There is no reliable quantitative investigation for distinguishing HAVS from other causes of Raynaud's phenomenon and from normal individuals. Hypothenar and thenar hammer syndromes produce similar symptoms to HAVS but are difficult to diagnose clinically and may be confused with HAVS. Magnetic resonance angiography (MRA) is a safe and minimally invasive method of visualizing blood vessels. Three cases of vascular HAVS are described in which MRA revealed occlusions of the ulnar, radial and superficial palmar arteries. It is proposed that HTV was the cause of these occlusions, rather than blows to the hand unrelated to vibration, the assumed mechanism for the hammer syndromes. All three cases were advised not to expose their hands to HTV despite one of them being at Stockholm vascular stage 2 (early). MRA should be the investigation of choice for stage 2 vascular HAVS or vascular HAVS with unusual features or for a suspected hammer syndrome. The technique is however technically challenging and best done in specialist centres in collaboration with an occupational physician familiar with the examination of HAVS cases. Staging for HAVS should be developed to include anatomical arterial abnormalities as well as symptoms and signs of blanching. Workers with only one artery supplying a hand, or with only one palmar arch, may be at increased risk of progression and therefore should not be exposed to HTV irrespective of their Stockholm stage.

PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes.

BACKGROUND: Expression of programmed death ligand 1 (PD-L1) in solid tumours has been shown to predict whether patients are likely to respond to anti-PD-L1 therapies. To estimate the therapeutic potential of PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression in a large collection of breast tumours. PATIENTS AND METHODS: Correlations between CD274 (PD-L1) copy number, transcript and protein levels were evaluated in tumours from 418 patients recruited to the METABRIC genomic study. Immunohistochemistry was used to detect PD-L1 protein in breast tumours in tissue microarrays from 5763 patients recruited to the SEARCH population-based study (N = 4079) and the NEAT randomised, controlled trial (N = 1684). RESULTS: PD-L1 protein data was available for 3916 of the possible 5763 tumours from the SEARCH and NEAT studies. PD-L1 expression by immune cells was observed in 6% (235/3916) of tumours and expression by tumour cells was observed in just 1.7% (66/3916). PD-L1 was most frequently expressed in basal-like tumours. This was observed both where tumours were subtyped by combined copy number and expression profiling [39% (17/44) of IntClust 10 i.e. basal-like tumours were PD-L1 immune cell positive; P < 0.001] and where a surrogate IHC-based classifier was used [19% (56/302) of basal-like tumours were PD-L1 immune cell positive; P < 0.001]. Moreover, CD274 (PD-L1) amplification was observed in five tumours of which four were IntClust 10. Expression of PD-L1 by either tumour cells or infiltrating immune cells was positively correlated with infiltration by both cytotoxic and regulatory T cells (P < 0.001). There was a nominally significant association between PD-L1 and improved disease-specific survival (hazard ratio 0.53, 95% confidence interval 0.26-1.07; P = 0.08) in ER-negative disease. CONCLUSIONS: Expression of PD-L1 is rare in breast cancer, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. PD-L1 inhibition may benefit the 19% of patients with basal-like tumours in which the protein is expressed. NEAT CLINICALTRIALSGOV: NCT00003577.

Attribution of mental illness to work: a Delphi study.

BACKGROUND: Clinicians may be asked whether mental ill-health has been caused by work but there is no guidance on how this judgement should be made. AIMS: To seek a consensus on the factors that should be considered and how they should be sought when attributing mental ill-health to work. METHODS: A three-round Delphi study involving expert academics, occupational physicians, psychiatrists and psychologists. We deemed consensus had been reached when 66% or more of the experts were in agreement. RESULTS: Of 54 invited experts, 35 (65%) took part in the first round, 30 of these 35 (86%) in the second and 29 of these 30 (97%) in the final round. Consensus was reached for 11 workplace stressors: high job strain; effort-reward imbalance; major trauma; interpersonal conflict; inadequate support; role ambiguity; person-job mismatch; organizational injustice; organizational culture; work scheduling and threats to job security. Seven personal factors were identified as being important: previous mental illness; personality traits of neuroticism; adverse life events or social circumstances; resilience; a family history of mental illness and secondary gain. The worker, manager and co-workers were thought to be the most useful sources of workplace information. Consensus was reached for a definition of occupational mental illness but not for a threshold of work-relatedness. CONCLUSIONS: The attribution of mental ill-health to work is complex and involves the consideration of both workplace stressors and personal factors of vulnerability. Clinical consultation with an occupational physician who is familiar with the workplace is central to the process.

Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients.

BACKGROUND: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. PATIENTS AND METHODS: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. RESULTS: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1). CONCLUSIONS: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.

A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed, platinum-sensitive ovarian cancer.

BACKGROUND: Pertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer. PATIENTS AND METHODS: Patients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms. RESULTS: A total of 149 patients received either chemotherapy with pertuzumab (arm A, n=74) or chemotherapy alone (arm B, n=75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone. CONCLUSIONS: The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.

Allergic bronchopulmonary aspergillosis in garden waste (compost) collectors--occupational implications.

The separation of rotting garden material from general domestic waste and its collection for processing in industrial composting sites is a relatively new industry in the UK. Two cases of allergic bronchopulmonary aspergillosis and the results of health surveillance are described in a team of 28 garden waste (compost) collectors. A few cases of extrinsic allergic alveolitis due to Aspergillus fumigatus have previously been reported in compost workers. In the absence of any guidance from research and to prevent similar cases of a potentially serious illness, we advise that new starters to the job of collecting or processing compost are screened for asthma and aspergillus sensitivity, cystic fibrosis, bronchiectasis and immunodeficiency if their exposure to high levels of Aspergillus sp cannot be controlled. Annual health surveillance for these workers is also recommended.

Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. METHODS: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. RESULTS: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. CONCLUSION: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

Illness deception and work: incidence, manifestations and detection.

BACKGROUND: Illness deception (ID) may be difficult to detect. Objective techniques that improve a doctor's skills of detection will have benefits for the health economy. AIMS: To ascertain the incidence of ID in a general occupational medicine clinic, to give examples by way of case vignettes how it may manifest and to compare the variability of maximal grip strength measurements of patients with suspected simulated weakness of grip with controls. METHODS: Four hundred consecutive new patient referrals were examined by the author and those who met Diagnostic and Statistical Manual-IV criteria for factitious disorder (FD) or malingering identified. Those with suspected simulated weakness of grip were asked to perform three consecutive maximal grips with a Jamar hand dynamometer. One hundred normal subjects and 100 patients with rheumatoid arthritis (RA) of the hands were similarly tested. RESULTS: Thirty-two of 400 (8%) patients exhibited behaviour in keeping with ID (29 malingering and 3 FD). Cases included simulated hand-arm vibration syndrome, occupational asthma, deafness and weakness of a limb. The median and 90th percentile for coefficient of variation (CV) of three consecutive maximal grip strengths for normal subjects and patients with RA were 5.2, 10.5%; 5.4, 14.5% right and 4.5, 10.2%; 6.0, 14.4% left hand, respectively. The CV of the six patients who simulated weakness of grip was from 17.3 to 37.8%. CONCLUSIONS: ID is relatively common in occupational medical practice and multiform in its manifestations. Simulated weakness of grip should be suspected when consecutive declared maximal grip strengths are inexplicably submaximal for age and sex and highly variable in force.

tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation.

tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135 patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity was assessed during radiotherapy. No differences were detected in FEV(1) or FVC levels between treatment arms or time points. Diffusion capacity (TL(CO)) reduced during treatment (P<0.0001), with a significantly lower drop in EC-GT patients (P=0.02). Most of the reduction occurred during EC and recovered by 6-months post treatment. There was no difference in cardiac function between treatment arms. Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment, with only five having LVEF<50%. Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy (AST P=0.03, ALT P=0.003), although the majority was low grade. There was no correlation between transaminitis and other toxicities. Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels. Despite these being greater with EC-GT, both regimens appear well tolerated.

NEAT: National Epirubicin Adjuvant Trial--toxicity, delivered dose intensity and quality of life.

The NEAT trial reported considerable benefit for ECMF (epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil) of 28% for relapse-free survival (RFS) and 30% for overall survival (OS), when compared with classical CMF in early breast cancer. To assess tolerability, toxicity, dose intensity and quality of life (QoL) analyses were undertaken. All 2021 eligible patients had common toxicity criteria (CTC), delivered chemotherapy and supportive treatments details and long-term morbidities recorded. The QoL substudy used multiple validated measures. ECMF produced low CTC scores, although higher than CMF for nausea, vomiting, alopecia, constipation, stomatitis (P<0.001), infection (P=0.001) and fatigue (P=0.03). Supportive treatments required, however, were similar across randomised treatments. On-treatment deaths were more common with CMF (13) than ECMF(5). Optimal course-delivered dose intensity (CDDI > or =85%) was received more often by ECMF patients (83 vs 76%: P=0.0002), and was associated with better RFS (P=0.0006). QoL over 2 years was equivalent across treatments, despite minimally worse side effects for ECMF during treatment. ECMF benefit spanned all levels of toxicity, CDDI and QoL. There are no reported acute myeloid leukaemias or cardiac dysfunctions. ECMF is tolerable, deliverable, and significantly more effective than CMF, with no serious long-term toxicity or QoL detriment.

Cold haemagglutinin disease misdiagnosed as hand-arm vibration syndrome.

A patient with a diagnosis of hand-arm vibration syndrome was referred for a second opinion. He worked as a multi-skilled operative in the housing department of a local authority, a job not normally associated with high levels of exposure to hand-transmitted vibration ( > 2.5 m/s(2) A(8)). He described blanching of his fingers and a blue discolouration of his extremities in cold weather. On examination, his fingertips, toes and pinnae were acrocyanotic, the fingers were patchily pale and sensation was subjectively impaired in all of the digits. Investigations revealed a haemolytic anaemia and haemagglutination. He was diagnosed with idiopathic cold haemagglutinin disease. Exposure to vibration may confound with exposure to cold in which case the differential diagnoses of cold haemagglutinin disease or cryoglobulinaemia should be excluded before diagnosing hand-arm vibration syndrome.

A cluster of occupational mental illness in an NHS trust.

A cluster of clinical cases of occupational mental illness has not previously been reported. A prospective cross-sectional study of patients referred for examination and advice about rehabilitation was undertaken to ascertain a variety of employer's rates of occupational mental illness. A background rate of referral for occupational mental illness of 3.1/1,000 employees per year was found apart from in one NHS trust where the rate was 25.6/1,000. Most patients were nurses and diagnoses were anxiety and/or depression with a median length of time off work of four months. There was no evidence that patients from this employer were vulnerable to mental illness. The high rate of occupational mental illness was associated with organisational change and a hostile working climate. This study shows that NHS trusts may be associated with unhealthy working practices. A cluster of occupational mental illness should be statutorily reportable to the Health and Safety Executive for further investigation.

A randomised comparison of treosulfan and carboplatin in patients with ovarian cancer: a study by the Scottish Gynaecological Cancer Trials Group (SGCTG).

The management of older and unfit women with advanced ovarian cancer requires post-operative chemotherapy but many of these patients are not suitable for high-dose cisplatin-based regimes. Carboplatin has been an easier alternative and can be given in the ambulatory setting. Historical data suggests that oral alkylating agents to be just effective with similar efficacy. In this study we have compared platinum-based carboplatin to the alkylating agent treosulfan in a population unfit to receive high-dose cisplatin. The trial randomised patients to either intravenous carboplatin or treosulfan as single agent. The trial was stopped prematurely after the interim analysis showed improved survival and response rates in the carboplatin arm. We conclude that carboplatin is a safe and effective drug in a population that is unfit for high-dose cisplatin. Treosulfan showed limited activity but may be considered along with other oral drugs in limited circumstances. With the exception of myelosuppression, toxicity was mild in both arms. Carboplatin remains the gold standard in this older and less fit group of patients.