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IntroductionAdolescents and young adults with an uncertain or poor cancer prognosis (UPCP) are confronted with ongoing and unique age-specific challenges, which forms an enormous burden. To date, little is known about the way AYAs living with a UPCP cope with their situation. Therefore, this study explores how AYAs with a UPCP cope with the daily challenges of their disease.MethodWe conducted semi-structured in-depth interviews among AYAs with a UPCP. Patients of the three AYA subgroups were interviewed (traditional survivors, new survivors, low-grade glioma survivors), since we expected different coping strategies among these subgroups. Interviews were analyzed using elements of the Grounded Theory by Corbin and Strauss. AYA patients were actively involved as research partners.ResultsIn total 46 AYAs with UPCP participated, they were on average 33.4 years old (age range 23–44) and most of them were woman (63%). Most common tumor types were low-grade gliomas (16), sarcomas (7), breast cancers (6) and lung cancers (6). We identified seven coping strategies in order to reduce the suffering from the experienced challenges: (1) minimizing impact of cancer, (2) taking and seeking control, (3) coming to terms, (4) being positive, (5) seeking and receiving support, (6) carpe diem and (7) being consciously alive.ConclusionThis study found seven coping strategies around the concept of ‘double awareness’ and showcases that AYAs are able to actively cope with their disease but prefer to actively choose life over illness. The findings call for CALM therapy and informal AYA support meetings to support this group to cope well with their disease.

Additional file 3. Quotes from interviews.

Additional file 2. COREQ checklist.

Additional file 1. Interview guides.

IntroductionAngiosarcoma is a rare and aggressive malignancy with a high metastatic potential and recurrence rate. Despite optimal treatment with surgery, with or without radiation, the prognosis remains poor and, therefore, new treatment strategies are warranted. Recently, propranolol has effectively been repurposed for the treatment of infantile haemangioma. Propranolol is a β3-sparing antagonist of the β-adrenergic receptor. In infantile haemangioma, the β1, β2 and β3 receptors are highly expressed. Angiosarcoma has several similarities with haemangioma, including its high β-adrenergic receptor expression and the supposedly important role of vascular endothelial growth factor in malignant growth. As a result, propranolol has been administered small scale in individual angiosarcoma cases with promising results. The precise effect of propranolol, however, is not yet established.Methods and analysisThe goal of this neoadjuvant window of opportunity study is to prospectively evaluate the activity of propranolol monotherapy in patients with cutaneous angiosarcoma. The neoadjuvant setting provides a good opportunity to rapidly evaluate both the clinical response and histological response, without a significant delay in standard anticancer treatment. Fourteen patients with primary, recurrent or metastatic cutaneous angiosarcoma will be included. Propranolol will be administered orally in an escalating dose during 3–6 weeks, before the initiation of standard treatment. The primary endpoint is clinical response according to Response Evaluation Criteria in Solid Tumours, as measured on consecutive coloured photographs or CT/MRI. The histological response will be determined as secondary endpoint, comparing the difference in proliferation index before and after propranolol by measuring the change in immunohistochemistry staining of Ki-67. The study will be considered positive when at least three patients have a response to propranolol.Ethics and disseminationEthical approval was obtained from the Medical Ethical Committee of the Netherlands Cancer Institute. Independent of the outcome, results of this study will be shared and submitted for publication in an international peer-reviewed journal.Trial registration numberNL8118; registry through the Netherlands Trial Register.

Contains fulltext : 200423.pdf (Publisher’s version ) (Closed access) BACKGROUND/AIM: Synovial sarcoma is a soft tissue sarcoma that tends to affect young adults. There are few reports on primary synovial sarcoma of the thyroid and the aim of this study was to document the clinical and pathological features of synovial sarcoma occurring at this site. CASE PRESENTATION: A retrospective review of a prospectively maintained database was performed to identify patients with synovial sarcoma of the thyroid treated at the Royal Marsden Hospital between 2000 and 2017. Five patients were identified that underwent initial surgical management of localized disease. The mean age at presentation was 38 years, and male to female ratio was 4:1. In 3 out of 5 cases, the diagnosis of synovial sarcoma was made on the post-operative excision specimen. Two of these patients were treated at our institution on the development of metastatic disease. We conducted a literature review and identified 12 previously reported cases of synovial sarcoma of the thyroid. CONCLUSION: Synovial sarcoma of the thyroid is rare and can be challenging to diagnose. The clinical presentation is typically indistinguishable from that of thyroid cancer and most cases are diagnosed post-operatively on an excision specimen. The clinical and pathological features are similar to synovial sarcoma arising at other sites. In our experience, the rarity of the diagnosis can lead to difficulty in establishing the correct diagnosis and determining the appropriate treatment pathway. It is important that physicians are aware of this diagnosis to facilitate prompt referral to a specialist centre, for specialist follow-up and treatment which is different to the thyroid cancer pathway.

Contains fulltext : 203015.pdf (Publisher’s version ) (Open Access) BACKGROUND/AIM: Treatment options for patients with metastatic soft tissue sarcomas are limited. Re-challenge with a previously successful gemcitabine-based regimen is common. There are no published data to support this practice. PATIENTS AND METHODS: We conducted a retrospective search to identify patients re-challenged with gemcitabine-based chemotherapy (GBC) from 2003 to 2015. RESULTS: Twenty-nine patients re-challenged with gemcitabine were identified. The response rate for initial GBC was 55% (n=15) and for re-challenge GBC 26% (n=6). The median progression-free survival was 11.1 months (95%CI=7.2-11.9) for initial GBC and 5.3 months (95%CI=2.0-7.5) for re-challenge GBC. Overall survival following gemcitabine re-challenge was 12.2 months (95%CI=7.0-18.2). Twelve out of 26 evaluable patients (46%) treated with re-challenge GBC experienced grade 3-4 adverse events (CTCAE 4.03) with 31% (n=8) of patients requiring dose reduction. CONCLUSION: In selected patients, gemcitabine re-challenge can be considered in advanced sarcomas, however, this approach is associated with toxicity.

Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo‐ and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease‐free survival (DFS), distant metastasis‐free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in‐situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and—to a lesser extent—HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting., What's new? Salivary duct carcinoma (SDC) is a rare and often fatal malignancy. Little is known about associations between its pathological features and clinical outcome. In this study, clinicopathological factors were analyzed for 177 patients diagnosed with SDC in The Netherlands between 1990 and 2014. The data show that median overall survival (OS) and distant metastasis‐free survival (DMFS) were 51 and 26 months, respectively. At diagnosis, 68% of patients presented with lymph node metastases. Lymph node positivity was associated with poor OS and poor DMFS. The absolute number of metastatic lymph nodes was the only significant prognostic factor for survival in a multivariate analysis. Androgen receptor and human epidermal growth factor 2 (HER2) were positive in 96% and 29%, respectively and were not a prognostic factor.

Adolescents and young adults (AYAs) diagnosed with cancer between ages 15-39 years may harbour germline variants associated with cancer predisposition. Such variants represent putative therapeutic targets, as may somatic variants in the tumour. Germline and tumour molecular profiling is increasingly utilised to facilitate personalisation of cancer treatment in such individuals.Considering AYAs with advanced solid tumours managed in a specialist drug development unit (DDU), the aims of this study were to investigate the use and impact of: 1. Germline genetic assessment. 2. Tumour molecular profiling.AYAs treated in the DDU at the Royal Marsden Hospital between 2002 and 2016 were identified from departmental databases. Data regarding clinicopathological features, clinical assessments and germline and tumour genetic testing were retrieved by chart review.The study cohort included 219 AYAs. Common cancer types included sarcoma (41, 19%); cervical (27, 12%); breast (25, 11%); ovarian (23, 11%) and colorectal (21, 10%) cancers. Germline testing was undertaken in 34 (16%) patients, 22 of whom carried a pathogenic variant. Using current testing criteria, an additional 32 (15%) would be eligible for germline testing based on their personal history of cancer alone. Tumour testing was undertaken in 46 (21%) individuals. Somatic mutations were commonly identified in TP53 13 (28%); PIK3CA (8, 18%); KRAS (4, 9%) and MET 5 (11%).A significant proportion of AYAs with advanced cancer have targetable somatic or germline mutations. Consideration of familial risk factors and inclusion of germline testing wherever appropriate can complement tumour testing to optimise patient management and inform management of at-risk relatives.

In patients with diabetes treated with sunitinib symptomatic hypoglycaemia has been reported. To explore the mechanism of this adverse effect we performed a prospective study to investigate the effect of sunitinib on insulin concentration, insulin clearance and insulin sensitivity.We studied the early effects of sunitinib on insulin sensitivity and insulin clearance with a hyperinsulinaemic euglycaemic clamp (insulin infusion rate 60 mU m−2 min−1; steady-state 90–120 min) in patients with renal cell carcinoma before and 1 week after the start of sunitinib 50 mg day−1. Insulin sensitivity index (SI) was defined as steady-state glucose disposal divided by the steady-state plasma insulin.Ten patients (one with diabetes, treated with metformin) were included in the study protocol. Steady-state insulin concentrations during the clamp increased after 1 week of sunitinib (from 128.9 ± 9.0 mU l−1 to 170.8 ± 12.8 mU l−1, P0.05; 95% CI on difference − 64.3, −19.6). The calculated insulin sensitivity index decreased from 0.22 ± 0.04 before to 0.18 ± 0.02 μmol kg−1 min−1 per mU l−1 insulin (P0.05; 95% CI on difference 0.07, 0.08). As the insulin infusion rate was similar for both clamps, the increased steady-state insulin concentration indicates reduced insulin clearance.Sunitinib affects insulin clearance which could possibly lead to overexposure to insulin in patients using insulin or insulin-secretion stimulating agents.

Objective: Fatigue is the most frequently occurring and distressing symptom in patients with advanced cancer, caused by multiple factors. Neither a specific histological diagnosis of malignancy nor the type of anticancer treatment seem to be strongly related to fatigue, which support the idea that other factors may play a role. This study investigated to what extent the model of fatigue-perpetuating factors that is known for cancer survivors was applicable for patients with advanced cancer. Methods: Patients on active treatment for various incurable cancers were asked to complete the Checklist Individual Strength, subscale fatigue severity and physical activity, the Acceptance scale of the Illness Cognition Questionnaire, the Hospital Anxiety and Depression Scale, the Fatigue Catastrophizing Scale, the Symptom Checklist subscale sleep, and the van Sonderen Social Support List-Discrepancies. Results: The questionnaires were filled in by 137 patients. Inappropriate coping, fear of progression, fatigue catastrophizing, discrepancies in social support, depressive mood, self reported physical activity, and sleeping problems were all related to fatigue severity in univariate analyses, of which the latter two were significant in a multivariate linear regression analysis. Conclusion: This study tested fatigue-perpetuating factors known to be of relevance in cancer survivors, for their relation with fatigue severity in palliative patients. We demonstrated that these factors were also relevant for patients on palliative treatment. On the basis of our results, we suggest clinicians confronted with palliative patients with serious fatigue to address sleeping problems and promote physical activity. In case of persistent fatigue, personalized cognitive behavioral therapy can be considered. Copyright (C) 2014 John Wiley & Sons, Ltd.

Bevacizumab (antivascular endothelial growth factor [anti-VEGF]) and cetuximab (antiepidermal growth factor receptor [anti-EGFR]) are approved antibodies for treatment of cancer. However, in advanced colorectal cancer, the combination fails to improve survival. As the reason for the lack of activity is unknown, our study aims to determine the effect of bevacizumab on targeting of anti-EGFR and insulin-like growth factor 1 receptor (IGF-1R) antibodies in tumors with single-photon emission computed tomography (SPECT)/CT imaging. Mice with subcutaneous EGFR and IGF-1R-expressing SUM149 xenografts received a single dose of bevacizumab (10 mg/kg) or saline. After 4 days, mice were injected with radiolabeled cetuximab or R1507, an anti-IGF-1R antibody. A control group received a radiolabeled irrelevant IgG (hLL2). Three days later, SPECT/CT images were acquired and mice were dissected to determine the concentration of antibodies in the tissues. Tumors were analyzed immunohistochemically to determine vascular density (CD34), VEGF, EGFR and IGF-1R expression. SPECT/CT imaging revealed that bevacizumab treatment significantly reduced tumor targeting of radiolabeled cetuximab by 40% from 33.1 +/- 1.1 %ID/g to 19.8 +/- 5.7 %ID/g (p=0.009) for untreated and bevacizumab-treated tumors, respectively. A similar effect was found for 111In-R1507: tumor targeting of R1507 decreased by 35%. No significant differences in tumor uptake were observed in mice that received an irrelevant IgG. Uptake in normal organs was not altered by bevacizumab. Immunohistochemical analysis showed that vascular density decreased with 43%, whereas EGFR and IGF-1R expression was unaltered. In conclusion, bevacizumab treatment significantly reduces tumor targeting of anti-EGFR and anti-IGF-1R antibodies. This emphasizes the importance of timing and sequencing of bevacizumab in combination with other antibodies

Background: The prognosis of rhabdomyosarcoma (RMS) in children and adolescents has improved since the introduction of multi-agent chemotherapy. However, outcome data of adults with RMS are scarce. This multicenter retrospective study investigated the effect of age on outcome of RMS. Patients and Methods: Data were collected from three Dutch University Medical Centers between 1977-2009. The effect of age and clinical prognostic factors on relapse-free and disease-specific survival (DSS) were analyzed. Results: Age as a continuous variable predicted poor survival in multivariate analysis. Five-year DSS was highest for non-metastatic embryonal RMS, followed by non-metastatic alveolar RMS and was poor in metastatic disease. Higher age correlated with unfavorable histological subtype (alveolar RMS) and with metastatic disease at presentation in embryonal RMS. In non-metastatic embryonal RMS and in all alveolar RMS, higher age was an adverse prognostic factor of outcome. Conclusion: This study indicates that age is a negative predictor of survival in patients with embryonal and alveolar RMS.

The insulin-like growth factor 1 receptor (IGF-1R) is a potential new target for the treatment of breast cancer. Patients with breast cancer lesions that express IGF-1R may benefit from treatment with anti-IGF-IR antibodies. IGF-1R expression can be visualized using radiolabeled R1507, a monoclonal antibody directed against IGF-1R. However, antibodies clear slowly from the circulation, resulting in low tumor-to-background ratios early after injection. Therefore, we aimed to accelerate targeting of IGF-1R using radiolabeled R1507 F(ab')(2) and Fab fragments. In vitro, immunoreactivity, binding affinity and internalization of R1507 IgG, F(ab')(2) and Fab were determined using the triple negative IGF-1R-expressing breast cancer cell line SUM149. In vivo, pharmacokinetics of In-111-labeled R1507 IgG, F(ab')(2) and Fab were studied in mice bearing subcutaneous SUM149 xenografts. SPECT/CT images were acquired and the biodistribution was measured ex vivo. The in vitro binding characteristics of radiolabeled R1507 IgG and F(ab')(2) were comparable, whereas the affinity of Fab fragments was significantly lower (K-d: 0.6 nM, 0.7 nM and 3.0 nM for R1507 IgG, F(ab')(2) and Fab, respectively). Biodistribution studies showed that the maximum tumor uptake of In-111-R1507 IgG, F(ab')(2) and Fab was 31.8% ID/g (72 h p.i.), 10.0% ID/g (6 h p.i.), and 1.8% ID/g (1 h p.i.), respectively. However, maximal tumor-to-blood ratios for F(ab')(2) (24 h p.i.: 7.5) were more than twice as high as those obtained with R1507 (72 h p.i.: 2.8) and Fab (6 h p.i.: 2.8). Injection of an excess of unlabeled R1507 significantly reduced tumor uptake, suggesting that the uptake of R1507 IgG and F(ab')(2) was specific for IGF-1R, while the major fraction of the tumor uptake of Fab was nonspecific. IGF-1R-expressing xenografts were visualized with In-111-F(ab')(2) SPECT/CT as early as 6 h p.i., while with R1507 IgG, the tumor could be visualized after 24 h. No specific targeting was observed with In-111-Fab. In-111-F(ab')(2) fragments showed improved targeting of IGF-1R expressing tumors. Tumor-to-blood ratios were twice as high as those obtained with In-111-R1507, and adequate tumor targeting on SPECT/CT images was observed as early as 6 h p.i. For individualization and optimization of IGF-1R targeted therapy, In-111-F(ab')(2) may be the tracer of choice

We present two patients with colorectal carcinoma who were admitted with fever and diarrhoea during treatment with chemotherapy. Blood cultures taken from both patients revealed an infection with Listeria monocytogenes. A contaminated ice cream was probably the source of infection in one patient. The other patient died of the listeriosis. Patients with diminished cellular immunity are at risk of invasive listeriosis. Listeriosis has a high mortality rate in this group of patients. Intravenous penicillin or ampicillin for 4 to 6 weeks is the first choice of antibiotic treatment. These antibiotics can be combined with an aminoglycoside or trimethoprim-sulfamethoxazole for a synergistic effect. To prevent invasive listeriosis we recommend strict dietary advice to all patients with diminished cellular immunity

It is uncommon for patients to present with bone metastases while the primary tumor is still unknown. The case of a patient with bone metastases as primary presentation of leiomyosarcoma, who was diagnosed after a 18F-FDG PET-CT and a CT-guided biopsy of the adrenal gland is described. If after routine physical, laboratory and radiological investigations no diagnosis can be made, 18F-FDG PET should be added to the conventional work-up of patients with unknown primary cancer. In this way, unnecessary and enduring suffering of symptomatic patients may be prevented

Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase receptor mediating cell growth and survival. IGF-1R signaling has been implicated in malignant behavior of tumors and drugs targeting the IGF-1R as anticancer treatment have been developed. We aimed to determine clinical indicators of IGF-1 dependency and responsiveness to IGF-1R targeted therapy in breast cancer in two large cohorts of breast cancer patients and in breast cancer cell lines. We found that IGF-1R was frequently expressed in hormone receptor positive tumors and in those tumors related to a favorable prognosis, while IGF-1R expression was associated with a shorter disease-free survival in triple negative tumors. Overall, IGF-1 plasma levels in breast cancer patients did not show a strong relation to prognosis, however, in the subgroup of patients treated with endocrine therapy high IGF-1 levels were related to worse overall survival. We tested sensitivity of breast cancer cell lines to IGF-1R tyrosine kinase inhibition (TKI). IGF-1R TKI resulted in reduced proliferation in all cell lines but the extent of the effect was not directly related to IGF-1R expression. Both synergistic and contrary effects were seen when IGF-1R TKI was combined with several conventional systemic anti-(breast)cancer drugs. In conclusion, our study may support approaches of combining IGF-1R-directed antibodies with endocrine therapy in breast cancer and the use of IGF-1R targeted therapy in triple negative breast tumors. However, selection of patients who could benefit from IGF-1R-targeted therapy is likely hampered by the complex interrelationships of the IGF-1R system and lack of biomarkers to predict response.