Workers' views on involving significant others in occupational health care:a focus group study among workers with a chronic disease

Purpose: To explore workers’ views and considerations on involving their significant others (SOs) in occupational health care. Methods: Four focus group interviews in the Netherlands, with 21 workers who had visited an occupational health physician (OHP) due to work absence caused by a chronic disease. Data was analyzed using thematic analysis. Results: We distinguished four main themes: (i) attitudes towards involving SOs, (ii) preferences on how to involve SOs, (iii) benefits of involving SOs, and (iv) concerns with regard to involving SOs. Workers expressed both positive and critical opinions about involving SOs in occupational health care. Benefits mentioned included provision of emotional and informational support by SOs before, during, and after consultations. According to workers, support from SOs can be enhanced by informing SOs about re-integration plans and involving them in decision making. However, workers were concerned about overburdening SOs, and receiving unwanted support from them. Conclusions: According to interviewed workers, engagement of SOs in occupational health care can help workers with a chronic disease in their recovery and return to work. However, they felt it is important to take SO characteristics and the worker’s circumstances and preferences into account, and to balance the potential benefits and drawbacks of involving SOs.Implications for rehabilitation This study suggests that the worker’s re-integration process could benefit from informing significant others about the return to work plans, involving them in decision-making, and explicitly discussing how the significant other can support the worker. Occupational health physicians have an important role in informing workers about the possibility and potential benefits of involving their significant others in the re-integration process. The involvement of a significant other in the re-integration process needs to be tailored to the specific situation of the individual worker, taking into account the preferences of both the worker and significant other. Findings suggest that it is important that occupational health physicians, workers and significant others are not only aware of the possible benefits of significant other involvement, but also of potential drawbacks such as interference during consultations, overburdening significant others, and significant others providing unwanted support

Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in theJAK3gene

High-grade serous ovarian carcinoma (HGSOC) remains the deadliest form of epithelial ovarian cancer and despite major efforts little improvement in overall survival has been achieved. Identification of recurring "driver" genetic lesions has the potential to enable design of novel therapies for cancer. Here, we report on a study to find such new therapeutic targets for HGSOC using exome-capture sequencing approach targeting all kinase genes in 127 patient samples. Consistent with previous reports, the most frequently mutated gene wasTP53(97% mutation frequency) followed byBRCA1(10% mutation frequency). The average mutation frequency of the kinase genes mutated from our panel was 1.5%. Intriguingly, afterBRCA1,JAK3was the most frequently mutated gene (4% mutation frequency). We tested the transforming properties of JAK3 mutants using the Ba/F3 cell-basedin vitrofunctional assay and identified a novel gain-of-function mutation in the kinase domain ofJAK3(p.T1022I). Importantly, p.T1022IJAK3mutants displayed higher sensitivity to the JAK3-selective inhibitor Tofacitinib compared to controls. For independent validation, we re-sequenced the entireJAK3coding sequence using tagged amplicon sequencing (TAm-Seq) in 463 HGSOCs resulting in an overall somatic mutation frequency of 1%. TAm-Seq screening ofCDK12in the same population revealed a 7% mutation frequency. Our data confirms that the frequency of mutations in kinase genes in HGSOC is low and provides accurate estimates for the frequency ofJAK3andCDK12mutations in a large well characterized cohort. Although p.T1022IJAK3mutations are rare, our functional validation shows that if detected they should be considered as potentially actionable for therapy. The observation ofCDK12mutations in 7% of HGSOC cases provides a strong rationale for routine somatic testing, although more functional and clinical characterization is required to understand which nonsynonymous mutations alterations are associated with homologous recombination deficiency.ISSN:1932-620

Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in the JAK3 gene.

High-grade serous ovarian carcinoma (HGSOC) remains the deadliest form of epithelial ovarian cancer and despite major efforts little improvement in overall survival has been achieved. Identification of recurring "driver" genetic lesions has the potential to enable design of novel therapies for cancer. Here, we report on a study to find such new therapeutic targets for HGSOC using exome-capture sequencing approach targeting all kinase genes in 127 patient samples. Consistent with previous reports, the most frequently mutated gene was TP53 (97% mutation frequency) followed by BRCA1 (10% mutation frequency). The average mutation frequency of the kinase genes mutated from our panel was 1.5%. Intriguingly, after BRCA1, JAK3 was the most frequently mutated gene (4% mutation frequency). We tested the transforming properties of JAK3 mutants using the Ba/F3 cell-based in vitro functional assay and identified a novel gain-of-function mutation in the kinase domain of JAK3 (p.T1022I). Importantly, p.T1022I JAK3 mutants displayed higher sensitivity to the JAK3-selective inhibitor Tofacitinib compared to controls. For independent validation, we re-sequenced the entire JAK3 coding sequence using tagged amplicon sequencing (TAm-Seq) in 463 HGSOCs resulting in an overall somatic mutation frequency of 1%. TAm-Seq screening of CDK12 in the same population revealed a 7% mutation frequency. Our data confirms that the frequency of mutations in kinase genes in HGSOC is low and provides accurate estimates for the frequency of JAK3 and CDK12 mutations in a large well characterized cohort. Although p.T1022I JAK3 mutations are rare, our functional validation shows that if detected they should be considered as potentially actionable for therapy. The observation of CDK12 mutations in 7% of HGSOC cases provides a strong rationale for routine somatic testing, although more functional and clinical characterization is required to understand which nonsynonymous mutations alterations are associated with homologous recombination deficiency

Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer

Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC.This work was funded by the American Association for Cancer Research, Lustgarten Foundation, and Stand Up to Cancer as a Pancreatic Cancer Collective New Therapies Challenge grant (grant no. SU2C-AACR-PCC-01-18)

The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting.

BACKGROUND: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. METHODS: A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness signature was then tested in HER2-negative patients (n = 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1ness and pathologic complete response in the V-C and control arms alone using Fisher's exact test, and the relative performance between arms (biomarker × treatment interaction, likelihood ratio p < 0.05) using a logistic model and adjusting for hormone receptor status (HR). RESULTS: We developed a gene expression signature to identify BRCA1-like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated significantly with response to V-C (p = 0.03), but not in the control arm (p = 0.45). We identified a significant interaction between BRCA1ness and V-C (p = 0.023) after correcting for HR. CONCLUSIONS: A genomic-based BRCA1-like signature was successfully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone. TRIAL REGISTRATION: I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379

Workers’ views on involving significant others in occupational health care: a focus group study among workers with a chronic disease

Purpose: To explore workers’ views and considerations on involving their significant others (SOs) in occupational health care. Methods: Four focus group interviews in the Netherlands, with 21 workers who had visited an occupational health physician (OHP) due to work absence caused by a chronic disease. Data was analyzed using thematic analysis. Results: We distinguished four main themes: (i) attitudes towards involving SOs, (ii) preferences on how to involve SOs, (iii) benefits of involving SOs, and (iv) concerns with regard to involving SOs. Workers expressed both positive and critical opinions about involving SOs in occupational health care. Benefits mentioned included provision of emotional and informational support by SOs before, during, and after consultations. According to workers, support from SOs can be enhanced by informing SOs about re-integration plans and involving them in decision making. However, workers were concerned about overburdening SOs, and receiving unwanted support from them. Conclusions: According to interviewed workers, engagement of SOs in occupational health care can help workers with a chronic disease in their recovery and return to work. However, they felt it is important to take SO characteristics and the worker’s circumstances and preferences into account, and to balance the potential benefits and drawbacks of involving SOs.Implications for rehabilitation This study suggests that the worker’s re-integration process could benefit from informing significant others about the return to work plans, involving them in decision-making, and explicitly discussing how the significant other can support the worker. Occupational health physicians have an important role in informing workers about the possibility and potential benefits of involving their significant others in the re-integration process. The involvement of a significant other in the re-integration process needs to be tailored to the specific situation of the individual worker, taking into account the preferences of both the worker and significant other. Findings suggest that it is important that occupational health physicians, workers and significant others are not only aware of the possible benefits of significant other involvement, but also of potential drawbacks such as interference during consultations, overburdening significant others, and significant others providing unwanted support

Workers' views on involving significant others in occupational health care: a focus group study among workers with a chronic disease

PURPOSE: To explore workers' views and considerations on involving their significant others (SOs) in occupational health care. METHODS: Four focus group interviews in the Netherlands, with 21 workers who had visited an occupational health physician (OHP) due to work absence caused by a chronic disease. Data was analyzed using thematic analysis. RESULTS: We distinguished four main themes: (i) attitudes towards involving SOs, (ii) preferences on how to involve SOs, (iii) benefits of involving SOs, and (iv) concerns with regard to involving SOs. Workers expressed both positive and critical opinions about involving SOs in occupational health care. Benefits mentioned included provision of emotional and informational support by SOs before, during, and after consultations. According to workers, support from SOs can be enhanced by informing SOs about re-integration plans and involving them in decision making. However, workers were concerned about overburdening SOs, and receiving unwanted support from them. CONCLUSIONS: According to interviewed workers, engagement of SOs in occupational health care can help workers with a chronic disease in their recovery and return to work. However, they felt it is important to take SO characteristics and the worker's circumstances and preferences into account, and to balance the potential benefits and drawbacks of involving SOs.Implications for rehabilitationThis study suggests that the worker's re-integration process could benefit from informing significant others about the return to work plans, involving them in decision-making, and explicitly discussing how the significant other can support the worker.Occupational health physicians have an important role in informing workers about the possibility and potential benefits of involving their significant others in the re-integration process.The involvement of a significant other in the re-integration process needs to be tailored to the specific situation of the individual worker, taking into account the preferences of both the worker and significant other.Findings suggest that it is important that occupational health physicians, workers and significant others are not only aware of the possible benefits of significant other involvement, but also of potential drawbacks such as interference during consultations, overburdening significant others, and significant others providing unwanted support

The prognostic significance of tumor cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients

Abstract Introduction The detection of circulating tumour cells (CTCs) in the peripheral blood and disseminated tumour cells (DTCs) in the bone marrow are promising prognostic tools for risk stratification in early breast cancer. There is, however, a need for further validation of these techniques in larger patient cohorts with adequate follow-up periods. Methods We assayed CTCs and DTCs at primary surgery in 733 stage I or II breast cancer patients with a median follow-up time of 7.6 years. CTCs were detected in samples of peripheral blood mononuclear cells previously stored in liquid-nitrogen using a previously-developed multi-marker quantitative PCR (QPCR)-based assay. DTCs were detected in bone marrow samples by immunocytochemical analysis using anti-cytokeratin antibodies. Results CTCs were detected in 7.9% of patients, while DTCs were found in 11.7%. Both CTC and DTC positivity predicted poor metastasis-free survival (MFS) and breast cancer-specific survival (BCSS); MFS hazard ratio (HR) = 2.4 (P &lt; 0.001)/1.9 (P = 0.006), and BCSS HR = 2.5 (P &lt; 0.001)/2.3 (P = 0.01), for CTC/DTC status, respectively). Multivariate analyses demonstrated that CTC status was an independent prognostic variable for both MFS and BCSS. CTC status also identified a subset of patients with significantly poorer outcome among low-risk node negative patients that did not receive adjuvant systemic therapy (MFS HR 2.3 (P = 0.039), BCSS HR 2.9 (P = 0.017)). Using both tests provided increased prognostic information and indicated different relevance within biologically dissimilar breast cancer subtypes. Conclusions These results support the use of CTC analysis in early breast cancer to generate clinically useful prognostic information