Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT).

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. DISCUSSION: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. PROTOCOL VERSION: Version 3 dd 11-4-2022.

The relative effectiveness of eribulin for advanced breast cancer treatment: a study of the southeast Netherlands advanced breast cancer registry.

Background: Eribulin provided significant overall survival (OS) benefit in heavily pretreated advanced breast cancer patients in the EMBRACE trial. We investigated the use of eribulin in daily clinical practice, the relative effectiveness of eribulin versus non-eribulin chemotherapy, and the safety of eribulin in real-world patients included in the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry.Material and methods: Patients treated with eribulin and eligible patients for eribulin who received a different chemotherapy (i.e., non-eribulin group) in ten hospitals in 2013-2017 were included. A multivariate matching algorithm was applied to correct for differences in baseline characteristics between the groups, including the number of previous treatment lines. Progression-free survival (PFS) and OS of eribulin were compared with the matched non-eribulin group through Kaplan-Meier curves and multivariate Cox proportional hazard models. The occurrence of dose delay and reduction was described.Results: Forty-five patients received eribulin according to its registration criteria and 74 patients were eligible for eribulin but received non-eribulin chemotherapy. Matching increased the similarity in baseline characteristics between the eribulin and non-eribulin groups. Median PFS was 3.5 months (95% confidence interval (CI): 2.7-5.5) in the eribulin group and 3.2 months (95% CI: 2.0-4.8) in the matched non-eribulin group (adjusted hazard ratio (HR): 0.83, 95% CI: 0.49-1.38). Median OS was 5.9 months (95% CI: 4.6-11.0) and 5.2 months (95% CI: 4.6-9.5) in the eribulin and non-eribulin groups, respectively (adjusted HR: 0.66, 95% CI: 0.38-1.13). Dose delay or reduction occurred in 14 patients (31%) receiving eribulin.Conclusions: No difference in PFS and OS was observed between eribulin and non-eribulin treated patients. Eribulin had a manageable toxicity profile.

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival, but recurrence rates are high. The aim of this study was to create a preclinical platform for the development of more effective intraperitoneal chemotherapy strategies. METHODS: Using organoid technology, five tumour cultures were generated from malignant ascites and resected peritoneal metastases. These were used in an in vitro HIPEC model to assess sensitivity to mitomycin C (MMC) and oxaliplatin, the drugs used most commonly in HIPEC. The model was also used to test a rational combination treatment involving MMC and inhibitors of the checkpoint kinase ATR. RESULTS: MMC was more effective in eliminating peritoneal metastasis-derived organoids than oxaliplatin at clinically relevant concentrations. However, the drug concentrations required to eliminate 50 per cent of the tumour cells (IC50) were higher than the median clinical dose in two of five organoid lines for MMC, and all five lines for oxaliplatin, indicating a general resistance to monotherapy. ATR inhibition increased the sensitivity of all peritoneal metastasis-derived organoids to MMC, as the IC50 decreased 2·6-12·4-fold to well below concentrations commonly attained in clinical practice. Live-cell imaging and flow cytometric analysis showed that ATR inhibition did not release cells from MMC-induced cell cycle arrest, but caused increased replication stress and accelerated cell death. CONCLUSION: Peritoneal metastasis-derived organoids can be used to evaluate existing HIPEC regimens on an individual-patient level and for development of more effective treatment strategies. Surgical relevance Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has improved prognosis of patients with peritoneal metastases from colorectal cancer, but disease recurrence is common. More effective and personalized HIPEC is urgently needed. Organoid technology is frequently used for drug screens, as patient-derived organoids can accurately predict clinical therapeutic response in vitro. A panel of organoids was established from peritoneal metastases from colorectal cancer and used to develop a model for testing HIPEC regimens in vitro. Patient-derived organoids differed in sensitivity to commonly used chemotherapeutics, in line with variable clinical outcomes following cytoreductive surgery-HIPEC. Combining MMC with an ATR inhibitor improved the efficacy of MMC. Peritoneal metastasis-derived organoids can be used as a platform to test novel (combination) strategies that increase HIPEC efficacy. In the future, organoids could be used to select patent-tailored HIPEC regimens.

ANTECEDENTES: Los pacientes con metástasis peritoneales (peritoneal metastasis, PM) de cáncer colorrectal tienen un mal pronóstico. Si la carga tumoral intraperitoneal es reducida, los pacientes pueden ser candidatos a cirugía citorreductora seguida de quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC). Este tratamiento ha mejorado la supervivencia global, pero las tasas de recidiva son altas. El objetivo de este estudio fue crear una plataforma preclínica para el desarrollo de las estrategias de quimioterapia intraperitoneal más efectivas. MÉTODOS: Mediante la utilización de la tecnología de organoides, se generaron cinco cultivos tumorales a partir de ascitis maligna y PM resecadas. Se utilizó un modelo de HIPEC in vitro para evaluar la sensibilidad a la mitomicina C (mitomycin C, MMC) y al oxaliplatino, los fármacos más utilizados en la HIPEC. El modelo también se usó para probar un tratamiento combinado de MMC e inhibidores de control inmunitario de la quinasa ATR. RESULTADOS: A concentraciones clínicamente relevantes, la MMC fue más efectiva que el oxaliplatino para eliminar los organoides derivados de PM. Sin embargo, las concentraciones de fármaco necesarias para eliminar el 50% de las células tumorales (IC50) fueron más elevadas que la mediana de la dosis clínica en 2/5 (MMC) o 5/5 (oxaliplatino) de las líneas de organoides, lo que indica una resistencia general a la monoterapia. La inhibición de ATR aumentó la sensibilidad a MMC de todos los organoides derivados de PM, ya que la IC50 disminuyó (2,6-12,4 veces) a concentraciones muy por debajo de las que se alcanzan comúnmente en la práctica clínica. Los análisis de viabilidad celular y de citometría de flujo (FACS) mostraron que la inhibición de ATR no liberaba células tras la detención del ciclo celular inducida por la MMC, sino que causaba un aumento en el estrés replicativo y muerte celular acelerada. CONCLUSIÓN: Se pueden usar los organoides derivados de PM para evaluar los regímenes HIPEC existentes a nivel del paciente individual y para desarrollar estrategias terapéuticas más efectivas.

In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.

BACKGROUND: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. PATIENTS AND METHODS: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. RESULTS: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. CONCLUSIONS: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.

Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer?

BACKGROUND: We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients. METHODS: Consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy. RESULTS: Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49-2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy. CONCLUSION: Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.

Continuously active interferometer stabilization and control for time-bin entanglement distribution.

We describe a new method enabling continuous stabilization and fine-level phase control of time-bin entanglement interferometers. Using this technique we demonstrate entangled photon transmission through 50 km of standard single-mode fiber. This technique reuses the entangled-pair generation pump which is co-propagated with the transmitted entangled photons. The co-propagating pump adds minimal noise to the entangled photons which are characterized by measuring a two-photon interference fringe.

Hydronephrosis in Acute Uncomplicated Appendicitis.

BACKGROUND: Right-sided hydronephrosis as a sign of appendicitis occurs rarely in the literature. To our knowledge, this is the first published account of the occurrence of right-sided hydronephrosis as a result of uncomplicated appendicitis. CASE DESCRIPTION: We describe a 15 year old patient referred to the emergency department with suspected appendicitis. Additional ultrasound examination showed a right-sided hydronephrosis. This finding was discussed with the urologist who noted the hydronephrosis as a chance finding. Because of persistent clinical suspicion of appendicitis, a diagnostic laparoscopy was performed. A retrocaecal appendicitis with secondary hydronephrosis was found. CONCLUSION: Right-sided hydronephrosis may be a sign of acute uncomplicated (retrocaecal) appendicitis. It is important to keep sight of these findings, especially in view of the emphasis on imaging techniques in the current Dutch guideline on appendicitis.

Hydronephrosis in acute uncomplicated appendicitis.

BACKGROUND: Right-sided hydronephrosis as a sign of appendicitis occurs rarely in the literature. To our knowledge, this is the first published account of the occurrence of right-sided hydronephrosis as a result of uncomplicated appendicitis. CASE DESCRIPTION: We describe a 15 year old patient referred to the emergency department with suspected appendicitis. Additional ultrasound examination showed a right-sided hydronephrosis. This finding was discussed with the urologist who noted the hydronephrosis as a chance finding. Because of persistent clinical suspicion of appendicitis, a diagnostic laparoscopy was performed. A retrocaecal appendicitis with secondary hydronephrosis was found. CONCLUSIONS: Right-sided hydronephrosis may be a sign of acute uncomplicated (retrocaecal) appendicitis. It is important to keep sight of these findings, especially in view of the emphasis on imaging techniques in the current Dutch guideline on appendicitis.

Perspectives on the preventability of emergency department visits by older patients.

BACKGROUND: Older people increasingly demand emergency department (ED) care. ED visits have a profound impact on older patients, including high risk of adverse outcomes and loss of independency. In this study, we evaluated the opinions of patients, caregivers, general practitioners, and ED physicians on the preventability of ED visits. METHODS: Prospective, mixed-method observational and qualitative study of 200 patients aged ≥ 70 years visiting a teaching hospital ED in the Netherlands. Semi-structured interviews were performed with patients, caregivers, and general practitioners. ED physicians were provided with written surveys. Patient data were extracted to determine vulnerability. RESULTS: The mean age of the patients was 79.6 years; 49.5% were male. Ninety-five percent lived independently before the ED visit. Most patients reported domiciliary care (23%), a caregiver (21.5%), or both (29.5%). Patients considered 12.2% of visits potentially preventable, caregivers 9%, general practitioners 20.7%, and ED physicians 31.2%. Consensus on preventability was poor, especially among patients and professionals. While patients most frequently blamed themselves, healthcare providers predominantly mentioned lack of communication and organisational issues as contributing factors. CONCLUSION: Patients and caregivers consider an ED visit preventable less frequently than professionals do. Little consensus was found among patients and healthcare providers, and the perspectives on contributing factors to a preventable visit differ between groups. To help improve geriatric emergency care, future studies should focus on why these perspectives are so different and aim to align them.

Real-world and trial-based cost-effectiveness analysis of bevacizumab in HER2-negative metastatic breast cancer patients: a study of the Southeast Netherlands Breast Cancer Consortium.

INTRODUCTION: The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial. METHODS: A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted. RESULTS: In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of €56,213 and €52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of €155,261 per QALY gained. In the trial scenario, the ICER amounted to €278,711 per QALY gained. CONCLUSION: According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario.

[Postmenopausal hormone replacement therapy and cancer of the female genitalia and breast]. / Postmenopauzale hormonale suppletietherapie en kanker van de vrouwelijke geslachtsorganen en de mamma.

Oestrogen replacement therapy (ORT) significantly increases the relative risk (RR) of endometrial cancer, especially long-term oestrogen use (RR: 9.5; 95% confidence interval (CI): 7.4-12.3). Addition of a progestin to ORT reduces this increased risk completely or largely. The risk of breast cancer is increased after ORT of 5 years or longer (RR: 1.23; 95% CI: 1.08-1.40). Addition of a progestin does not reduce this increased risk. The possibility cannot be excluded that long-term ORT increases the risk of epithelial ovarian cancer. No significant association between ORT and cervical cancer has been demonstrated. It is safe to prescribe ORT for a period shorter than 5 years for women with menopausal symptoms. Addition of a progestin is indicated when the uterus is in situ. Hormonal supplementation therapy is to be discouraged in women treated for breast cancer, may be considered in young women previously treated for endometrial or ovarian cancer with a good prognosis and severe menopausal symptoms and is justified in women previously treated for cervical cancer.