Oromandibular dystonia: a serious side effect of capecitabine

textabstractBackground: Capecitabine has activity against several types of cancer. In 10-15% of patients treated with capecitabine, treatment is discontinued because of serious adverse reactions, mostly within the first weeks of treatment. Case presentation: A 56 year-old female patient presented at the emergency department after ten days of chemotherapy with progressive airway obstruction and complaints of numbness of the tongue. She also had difficulty swallowing and was unable to speak. Laboratory findings were completely normal and no co-medication was used, in particular no dopamine antagonists. A diagnosis of oromandibular dystonia due to capecitabine use was made. After the anticholinergic drug biperiden (Akineton) was given intravenously, complaints disappeared within twenty minutes. Due to an early discontinuation of biperiden, however, the symptoms of oromandibular dystonia recurred. Again, she was successfully treated with an anticholinergic drug. Capecitabine was permanently discontinued. Three days after the initial presentation the anticholinergic drug was stopped after which symptoms did not reappear. Conclusion: The case highlights the need for awareness that capecitabine may potentially lead to severe life-threatening complaints of oromandibular dystonia. We hypothesize that capecitabine passed the blood brain barrier which led to a disruption within the basal ganglia in this case. Prompt treatment with an anticholinergic drug and cessation of capecitabine in the patient case led to disappearance of complaints

Ten-year experience of a national multidisciplinary tumour board for cancer and pregnancy in the Netherlands

Background: Most physicians encounter pregnant women with cancer incidentally, leading to a lack of expertise or confidence to inform and treat these patients based on the most recent guidelines and expert opinions. In the Netherlands, a national multidisciplinary tumour board for cancer, infertility and pregnancy (CIP-MDT) was founded in December 2012, including 35 specialists from a variety of disciplines. This study evaluates the frequency of consultation of the CIP-MDT, the types of questions asked and the satisfaction of consulting physicians with its existence. Methodology: Of all requests to the CIP-MDT between December 2012 and June 2021, tumour type, stage, gestational age at diagnosis and recommendations were collected and analysed. For evaluating the methods of the CIP-MDT, a survey with questions regarding experiences with the CIP-MDT and its impact on treatment decisions was sent out to physicians that consulted the CIP-MDT. Results: Recommendations (n = 213) concerned preferred and safest options for imaging, treatment options during pregnancy, possible effects on the child and fertility preserving options. Most frequently discussed malignancies were breast cancer (n = 66), cervical cancer (n = 34), haematological malignancies (n = 32) and melanoma (n = 21). The questionnaire was completed by 54% of the physicians (n = 50). Satisfaction with the recommendations of the CIP-MDT was high, and 94% of the physicians informed their patients about consulting the CIP-MDT and felt supported by the received recommendations. Discussion: The national Dutch CIP-MDT contributes to a high level of satisfaction among physicians requesting advice. Further research should be executed to confirm that a CIP-MDT improves the outcomes for pregnant women and their children

Survival of Women with Advanced Stage Cervical Cancer:Neo-Adjuvant Chemotherapy Followed by Radiotherapy and Hyperthermia versus Chemoradiotherapy

Aim: To investigate and compare overall survival (OS), disease-free survival (DFS) and toxicity of women who underwent either chemoradiotherapy with or without prior lymph node debulking or upfront chemotherapy followed by radiotherapy and hyperthermia (triple therapy) for locally advanced cervical cancer (LACC) to identify a potential role for triple therapy. Methods: Women with histologically proven LACC and with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 and IIA2 to IVA were included. Cox regression analyses were used for calculating hazard ratios and to adjust for confounding variables. A multivariable logistic regression analysis was used to examine the influence of covariates on toxicity. Results: A total of 370 patients were included of whom 58% (n = 213) received chemoradiotherapy (CRT), 18% (n = 66) received node-debulking followed by chemoradiotherapy (LND-CRT) and 25% (n = 91) received triple therapy (TT). Five-year OS was comparable between the three treatment groups, with 53% (95% confidence interval 46–59%) in the CRT group, 45% (33–56%) in the LND-CRT group and 53% (40–64%) in the TT group (p = 0.472). In the adjusted analysis, 5-year OS and DFS were comparable between the three treatment groups. No chemotherapy-related differences in toxicity were observed. Conclusion: This study suggests that the toxicity and survival of TT is similar to CRT or LND-CRT.</p

Survival of Women with Advanced Stage Cervical Cancer:Neo-Adjuvant Chemotherapy Followed by Radiotherapy and Hyperthermia versus Chemoradiotherapy

Aim: To investigate and compare overall survival (OS), disease-free survival (DFS) and toxicity of women who underwent either chemoradiotherapy with or without prior lymph node debulking or upfront chemotherapy followed by radiotherapy and hyperthermia (triple therapy) for locally advanced cervical cancer (LACC) to identify a potential role for triple therapy. Methods: Women with histologically proven LACC and with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 and IIA2 to IVA were included. Cox regression analyses were used for calculating hazard ratios and to adjust for confounding variables. A multivariable logistic regression analysis was used to examine the influence of covariates on toxicity. Results: A total of 370 patients were included of whom 58% (n = 213) received chemoradiotherapy (CRT), 18% (n = 66) received node-debulking followed by chemoradiotherapy (LND-CRT) and 25% (n = 91) received triple therapy (TT). Five-year OS was comparable between the three treatment groups, with 53% (95% confidence interval 46–59%) in the CRT group, 45% (33–56%) in the LND-CRT group and 53% (40–64%) in the TT group (p = 0.472). In the adjusted analysis, 5-year OS and DFS were comparable between the three treatment groups. No chemotherapy-related differences in toxicity were observed. Conclusion: This study suggests that the toxicity and survival of TT is similar to CRT or LND-CRT.</p

The added value of H-2 antagonists in premedication regimens during paclitaxel treatment

BACKGROUND: Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine. METHODS: This prospective, pre-post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade >= 3. Non-inferiority was determined by checking whether the upper bound of the twosided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin. RESULTS: In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade >= 3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference -2.7% (90% CI: -6.2 to 0.1). CONCLUSIONS: As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine

Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer:A matched cohort study

INTRODUCTION: Germline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are lacking. METHODS: We matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage ( = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2) and their matched sporadic controls. RESULTS: The median follow-up was 4.4 years (range 0.1-30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74-1.04) and BRCA2 (HR 0.58, 95% CI 0.41-0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58-0.84) and BRCA2 (HR 0.41, 95% CI 0.29-0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients. CONCLUSION: For epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis

Distinct Genomic Profiles Are Associated with Treatment Response and Survival in Ovarian Cancer

SIMPLE SUMMARY: In most patients with ovarian cancer, their disease eventually becomes resistant to chemotherapy. The timing and type of treatment given are therefore highly important. Currently, treatment choice is mainly based on the subtype of cancer (from a histological point of view), prior response to chemotherapy, and the time it takes for the disease to recur. In this study, we combined complete genome data of the tumor with clinical data to better understand treatment responses. In total, 132 tumor samples were included, all from patients with disease that had spread beyond the primary location. By clustering the samples based on genetic characteristics, we have identified subgroups with distinct response rates and survival outcomes. We suggest that in the future, this data can be used to make more informed treatment choices for individuals with ovarian cancer. ABSTRACT: The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency, and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability, and duplications. The clusters exhibited distinct response rates and survival probabilities which could thus potentially be used for genome-informed therapy stratification for more personalized ovarian cancer treatment

Pharmacokinetic boosting of olaparib:A randomised, cross-over study (PROACTIVE-study)

Background: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. Methods: This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0–12 h) within no-effect boundaries. These boundaries were set at 0.57–1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. Results: Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0–12 h was 1.45 (90% CI 1.27–1.65). No grade ≥3 adverse events were reported during the study. Conclusions: Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.</p

Phenotype-guided targeted therapy based on functional signal transduction pathway activity in recurrent ovarian cancer patients:The STAPOVER study protocol

Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for alternative diagnostics that better predict targeted therapy, as current diagnostics are generally inaccurate predictors. Quantitative assessment of functional signal transduction pathway (STP) activity from mRNA measurements of target genes is an alternative approach. Therefore, we aim to identify aberrantly activated STPs in tumour tissue of patients with recurrent ovarian cancer and start phenotype-guided targeted therapy to improve survival without compromising quality of life. Study design: Patients with recurrent ovarian cancer and either 1) have platinum-resistant disease, 2) refrain from standard therapy or 3) are asymptomatic and not yet eligible for standard therapy will be included in this multi-centre prospective cohort study with multiple stepwise executed treatment arms. Targeted therapy will be available for patients with aberrantly high functional activity of the oestrogen receptor, androgen receptor, phosphoinositide 3-kinase or Hedgehog STP. The primary endpoint of this study is the progression-free survival (PFS) ratio (PFS2/PFS1 ratio) according to RECIST 1.1 determined by the PFS on matched targeted therapy (PFS2) compared to PFS on prior therapy (PFS1). Secondary endpoints include among others best overall response, overall survival, side effects, health-related quality of life and cost-effectiveness. Conclusion: The results of this study will show the clinical applicability of STP activity in selecting recurrent ovarian cancer patients for effective therapies.</p

Symptomatic asymmetry in the first six months of life: differential diagnosis

Asymmetry in infancy is a clinical condition with a wide variation in appearances (shape, posture, and movement), etiology, localization, and severity. The prevalence of an asymmetric positional preference is 12% of all newborns during the first six months of life. The asymmetry is either idiopathic or symptomatic. Pediatricians and physiotherapists have to distinguish symptomatic asymmetry (SA) from idiopathic asymmetry (IA) when examining young infants with a positional preference to determine the prognosis and the intervention strategy. The majority of cases will be idiopathic, but the initial presentation of a positional preference might be a symptom of a more serious underlying disorder. The purpose of this review is to synthesize the current information on the incidence of SA, as well as the possible causes and the accompanying signs that differentiate SA from IA. This review presents an overview of the nine most prevalent disorders in infants in their first six months of life leading to SA. We have discovered that the literature does not provide a comprehensive analysis of the incidence, characteristics, signs, and symptoms of SA. Knowledge of the presented clues is important in the clinical decision making with regard to young infants with asymmetry. We recommend to design a valid and useful screening instrument