Necrotizing myopathy as a paraneoplastic syndrome associated with renal cell carcinoma

We report a 49-year-old patient with necrotizing myopathy and a right renal mass. After laparoscopic radical nephrectomy, a remission of myopathy was seen. Pathologic evaluation of the nephrectomy specimen revealed a clear cell renal cell carcinoma. Relapse of myopathy 6 months postoperatively coincided with the diagnosis of the appearance of liver metastatic disease. After initiation of treatment with an mTOR-inhibitor, myopathy became less active requiring smaller amounts of corticosteroids with a complete remission of myopathy after 3 months of systemic treatment for metastatic renal cell cancer

Neo-adjuvant treatment of adenocarcinoma and squamous cell carcinoma of the cervix results in significantly different pathological complete response rates

Abstract Background Previous studies on cervical cancer reported a worse outcome for adenocarcinoma (AC) compared with squamous cell carcinoma (SCC). Nevertheless, standard treatment remains identical. Insight in the impact of histological types on biological behavior and pathological complete response rates might result in a treatment paradigm shift. Methods Clinicopathological characteristics, survival rates and relapse patterns were compared between AC (n = 36) and SCC (n = 143) cervical cancer patients. Pathological response to treatment was evaluated in the patient subgroup treated with neo-adjuvant chemoradiation followed by surgery (NA-CRT group; n = 84). Results In the entire cohort, 5y Disease Specific Survival (DSS) was 97.1 and 84% for AC and SCC respectively (p = 0.150). In the NA-CRT group 5y DSS was 100 and 75.5% for AC and SCC respectively (p = 0.059). Relapse patterns did not differ significantly between AC and SCC in the entire cohort, or in the NA-CRT group. Adenocarcinoma patients treated with NA-CRT showed significantly less pathological complete response compared with SCC patients (AC = 7%, SCC = 43%, p = 0.027). Conclusions There were no statistically significant differences regarding relapse and DSS rates between SCC and AC in the entire cohort, or the NA-CRT group. However, a trend to better 5y DSS of AC in the NA-CRT group was observed. This analysis showed significant differences in treatment responses after NA-CRT: patients with AC responded remarkably less to chemoradiation, resulting in a significantly lower pathological complete response rate. These findings imply a need for a paradigm shift in the treatment of cervical AC patients

PRIMMO study protocol : a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer

Background: Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature.In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement.We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. Methods: PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma.Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6cycles. Radiation (3x8Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose.The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity.The primary objective is objective response rate at week 26 according to immune-related response criteria.Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life.Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. Discussion: In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. Trial registration: EU Clinical Trials Register: EudraCT 2016-001569-97, registered on 19-6-2017. Clinicaltrials.gov: NCT03192059, registered on 19-6-2017

EXclusion of non-Involved uterus from the Target Volume (EXIT-trial): An individualized treatment for locally advanced cervical cancer using modern radiotherapy and imaging techniques

Background: Definitive chemoradiotherapy is standard of care in locally advanced cervical cancer (LACC). Both toxicity and local relapse remain major concerns in this treatment. We hypothesize that a magnetic resonance imaging (MRI) based redefining of the radiotherapeutic target volume will lead to a reduction of acute and late toxicity. In our center, chemoradiotherapy followed by hysterectomy was implemented successfully in the past. This enables us to assess the safety of reducing the target volume but also to explore the biological effects of chemoradiation on the resected hysterectomy specimen. Methods: The EXIT-trial is a phase II, single arm study aimed at LACC patients. This study evaluates whether a MRI-based exclusion of the non-tumor-bearing parts of the uterus out of the target volume results in absence of tumor in the non-high doses irradiated part of the uterus in the hysterectomy specimen. Secondary endpoints include a dosimetric comparison of dose on normal tissue when comparing study treatment plans compared to treatment of the whole uterus at high doses; acute and chronic toxicity, overall survival, local relapse- and progression-free survival. In the translational part of the study, we will evaluate the hypothesis that the baseline apparent diffusion coefficient (ADC) values of diffusion weighted MRI and its evolution 2 weeks after start of CRT, for the whole tumor as well as for intra-tumoral regions, is prognostic for residual tumor on the hysterectomy specimen. Discussion: Although MRI is already used to guide target delineation in brachytherapy, the EXIT-trial is the first to use this information to guide target delineation in external beam radiotherapy. Early therapy resistance prediction using DW-MRI opens a window for early treatment adaptation or further dose-escalation on tumors/intratumoral regions at risk for treatment failure

CHEK2 mutations and papillary thyroid cancer : correlation or coincidence?

We report the case of a breast cancer survivor, diagnosed with an underlying CHEK2 c.1100delC heterozygosity, who developed a papillary thyroid cancer 5 years later. A CHEK2 c.1100delC (likely) pathogenic variant is associated with an increased risk of breast, prostate and colorectal cancer and therefore risk-specific screening will be offered. Current national and international screening guidelines do not recommend routine screening for thyroid cancer. Hence, we reviewed the literature to explore the possible association between a CHEK2 mutation and thyroid cancer. A weak association was found between the various CHEK2 mutations and papillary thyroid cancer. The evidence for an association with CHEK2 c.1100delC in particular is the least robust. In conclusion, there is insufficient evidence to warrant systematic thyroid screening in CHEK2 carriers

Een 75-jarige vrouw met inspanningsgebonden kortademigheid en desaturatie

A 75-year-old woman with a history of smoking was admitted to the hospital with dyspnea and desaturation on exertion. The clinical examination revealed bilateral crackles. The arterial blood gas revealed hypoxemia with an abnormally increased alveolar-arterial gradient. Pulmonary function testing demonstrated preserved lung volumes and a markedly decreased diffusing capacity. The high-resolution CT scan (HRCT) of the lung showed both emphysema and fibrosis. The emphysema occurred predominantly in both upper lobes, while fibrosis mostly occurs in both lower lobes. Pulmonary hypertension was disco­vered during the echocardiography. Based on these findings, the patient was diagnosed with combined pulmonary fibrosis and emphysema (CPFE). She was treated with moderate doses of oral steroids and long-term oxygen therapy. She died two months after admission due to respiratory insufficiency. CPFE is a rare cause of dyspnea. In 2005, it was described as a distinct clinical syndrome. It can occur isolated or in combination with a systemic disease. The condition is usually diagnosed with an HRCT with or without the addition of pathological findings on a lung biopsy. CPFE is often complicated by pulmonary hypertension, which is prognostically unfavorable. The pathogenesis is unknown but smoking remains the most important etiological factor. In addition to smoking cessation and supportive measures, the treatment possibilities are limited. It is important to include CPFE into the differential diagnosis of dyspnea on exertion because it is a syndrome with different therapeutic and prognostic implications when compared to fibrosis or chronic obstructive pulmonary disease (COPD)/emphysema alone

Risk of thrombo-embolic events in ovarian cancer : does bevacizumab tilt the scale? A systematic review and meta-analysis

Simple Summary Thromboembolic events (TEs) are the second cause of death in cancer patients. Two forms of thromboembolic events may arise: arterial, such as ischemic stroke or myocardial infarction; and venous, such as deep vein thrombosis or pulmonary embolism. Bevacizumab is a monoclonal antibody directed against vascular endothelial-derived growth factor, and is widely used in advanced ovarian cancer. However, whether bevacizumab increases the risk of thromboembolic events in ovarian cancer is matter of debate since studies have shown conflicting results. In our systematic review and meta-analysis, we included 14 trials with bevacizumab in ovarian cancer. We found that the risk of arterial thromboembolic events more than doubled with a risk ratio of 2.45. Also the risk of venous thromboembolism increased 30% with bevacizumab treatment. Bevacizumab, therefore, can be considered an additional risk factor for selecting patients for primary prophylaxis with anticoagulants. Thromboembolic events are the second cause of death in cancer patients. In ovarian cancer, 3-10% of patients present with venous thromboembolism (VTE), but the incidence may rise to 36% along the disease course. Bevacizumab is a monoclonal antibody directed against vascular endothelial-derived growth factor, and in in vitro studies it showed a predisposition to hemostasis perturbation, including thrombosis. However, in vivo and clinical studies have shown conflicting results for its use as a treatment for ovarian cancer, so we conducted a systematic review and meta-analysis on the risk of arterial thromboembolism (ATE) and VTE in ovarian cancer patients treated with bevacizumab. The review comprised 14 trials with 6221 patients: ATE incidence was reported in 5 (4811 patients) where the absolute risk was 2.4% with bevacizumab vs. 1.1% without (RR 2.45; 95% CI 1.27-4.27, p = 0.008). VTE incidence was reported in 9 trials (5121 patients) where the absolute risk was 5.4% with bevacizumab vs. 3.7% without (RR 1.32; 95% CI 1.02-1.79, p = 0.04). Our analysis showed that the risk of arterial and venous thromboembolism increased in patients treated with bevacizumab. Thrombolic events (TEs) are probably underreported, and studies should discriminate between ATE and VTE. Bevacizumab can be considered as an additional risk factor when selecting patients for primary prophylaxis with anticoagulants

A clearer view on ovarian clear cell carcinoma

Introduction: Ovarian clear cell carcinoma (OCCC) is a less common subtype accounting for approximately 5% of all epithelial ovarian cancers (EOCs). Clinical experience and research findings confirm the remarkable differences in clinical behavior, molecular alterations and pathogenesis of OCCC. The diagnosis of OCCC is typically set at a younger age, and earlier stage and in a background of endometriosis. Results: Molecularly, OCCCs rarely harbor BRCA1/BRCA2 mutations and have fewer copy number variants (CNVs). The most common molecular changes occur in the SWI/SNF chromatin remodeling complex genes, the PI3K/AKT signaling pathway and the receptor tyrosine kinase (RTK)/Ras signaling pathway. Five-year disease-specific survival of patients with OCCC is worse compared to high grade serous carcinomas (HGSOC). The current treatment options for OCCC are based on studies that included patients with predominantly HGSOC and only a minor proportion of cancers with clear cell histology. In order to improve outcomes for patients with OCCC, research should be specific for this subtype. Discussion: As the available information about the specific characteristics of OCCC is increasing, especially at a molecular level, it should be possible to continuously improve the specific diagnostics and treatment. Since OCCC is so rare, it is essential to collect new evidence at an international level. To avoid extrapolation from EOC trials with possible erroneous conclusions, patients should always be encouraged to participate in specific histological trials and basket trials, while paying extra attention to OCCC-like subtypes