Systematic review of the registered clinical trials for oncological hyperthermia treatment.

BACKGROUND: The use of heat to treat various diseases is called hyperthermia treatment (HT). Since the 1970s, the anti-cancer effects of HT have been investigated. Different HT techniques can be categorized as local, regional and whole-body hyperthermia treatment (WBHT). We aim to provide a summary of recent research done on HT to treat cancer. METHODS: In July 2020 ClinicalTrials.gov were systematically searched for all trials including hyperthermia and cancer registered between 2000 and 2020. Studies were excluded when they did not concern hyperthermal treatment, when they were not oncological studies, when they were observational or other non-interventional studies. RESULTS: Of 1654 identified trials, 235 were included. Of these 235 studies, 123 described the use of HIPEC (52.3%), 44 other types of regional HT (18.7%), 45 local HT (19.1%) and 15 WBHT (6.4%). A steady increase (720%) in research to hyperthermic intraperitoneal chemotherapy (HIPEC) can be observed in the last decade. Although HIPEC is the most researched HT modality, an evolution in other HT technologies could be observed during the past decade. CONCLUSIONS: Research to HT to treat cancer has expanded fast. Some techniques, for example HIPEC start to be used outside of research context, but overall, more research is needed to establish a clear effect of these HT techniques.

Tolerability of long-term temperature controlled whole-body thermal treatment in advanced cancer-bearing dogs.

Aim: In oncology, thermal therapy is the application of external heat to fight cancer cells. The goal of whole-body thermal treatment (WBTT) is to raise the patient's core temperature to 39-42 °C, and represents the only thermal treatment modality that can act on both the primary tumor and distant metastases. However, WBTT carries potential risks for toxicity when applied without accurate thermometry and monitoring.Methods: ElmediX has developed a medical device, HyperTherm, to deliver long-term controlled and accurate WBTT (41.5 °C, up to 8 h). The safety of the device and thermal treatment protocol was initially evaluated in minipigs, and we present the confirmation of tolerability of WBTT in dogs with advanced cancer, in combination with a reduced dose of radiotherapy or chemotherapy.Results: Thermometry in liver, rectum, and tumor confirmed a homogeneous heating of these body parts. Monitoring of clinical parameters showed acceptable and reversible changes in liver, cardiac, muscle and coagulation parameters, as was expected. Combination of WBTT with both radiotherapy and chemotherapy only caused some low-grade adverse events.Conclusion: We conclude that our findings support the safe use of HyperTherm-mediated WBTT for canine patients with advanced malignancies. They also tend to support a genuine therapeutic potential for long-term WBTT which needs to be confirmed on a larger dog patient population. Combined with previously reported safety results in minipigs, these contribute to support the ongoing clinical evaluation of WBTT in advanced human cancer patients.

[Clozapine treatment and COVID-19: continue despite leukocytopenia and increase of clozapine serum levels]. / Clozapinebehandeling en COVID-19: doorgaan ondanks leukocytopenie en spiegelstijging.

Clozapine is an antipsychotic with clozapine-induced agranulocytosis (CIA) as a rare, but potentially life-threatening side-effect, for which the white blood cell count and absolute neutrophil count are routinely monitored. Observed leukopenia may lead to more frequent monitoring, or even acute discontinuation of clozapine treatment. COVID-19 may cause deviating blood parameters such as leukopenia, and more exceptionally even granulocytopenia, just as clozapine does. In case of a SARS-CoV-2 infection and leukopenia, it is important to differentiate whether the reduced white blood cell count is caused by clozapine - in which case it needs to be stopped immediately - or as a consequence of infection with the coronavirus. In case of a mild leukopenia, based on a lymphopenia, clozapine can be safely continued with more frequent blood monitoring. Additionally, the dosage of clozapine should be reduced by half, due to the risk of a sudden increase of clozapine serum levels.

[COVID-19 and severe mental illness, especially in clozapine use]. / COVID-19 en ernstige psychiatrische aandoeningen, in het bijzonder bij clozapinegebruik.

BACKGROUND: The Clozapine Plus Working Group is frequently consulted for advice on measures in case of infection with SARSCoV-2 and on vaccination against COVID-19 in patients receiving clozapine.

AIM: Inform about risks of infection with SARS-CoV-2 in patients with severe mental illness (SMI), patients with schizophrenia spectrum disorders (SSD), and patients treated with clozapine. Advise on monitoring of clozapine plasma levels and white blood cell count and differential in COVID-19 and after vaccination, as well as measures to be taken.

METHOD: Literature research and case studies.

RESULTS: SMI patients and in particular SSD patients have an increased risk of infection with SARS-CoV-2 with more hospitalizations and higher mortality than non-psychiatric patients. Patients using clozapine may be at greater risk of infection. SARS-CoV-2 infection may cause a dangerous increase of clozapine plasma levels and generally mild and short-term granulocytopenia and lymphocytopenia, which are usually not a result of clozapine treatment.

CONCLUSION: In case of COVID-19 extra alertness is required in patients with SMI and especially SSD. In clozapine users, in case of COVID-19, reduction in dose by half to three quarters of the original dose is recommended. When patients develop granulocytopenia, SARS-CoV-2 should be considered as the cause and not immediately clozapine. SMI patients and clozapine users in particular belong to a high risk group with a medical indication for early vaccination.

[Referral of a stabilized patient with psychotic disorder to the general practitioner: a pilot study]. / Verwijzing van gestabiliseerde patiënt met psychotische stoornis naar huisarts: kan dat? Een vooronderzoek.

BACKGROUND: In various countries, general practitioners (GPs) play an important role after treatment for non-affective psychotic disorder (NAPD) in mental health care. It is unclear how these patients fare. AIM: To compare the clinical course of patients largely recovered from NAPD and referred to the GP with the course of patients who remain in treatment at mental healthcare. METHOD: In a retrospective cohort study, 20 patients referred to GPs by mental healthcare (GP cohort) were compared to 20 patients who remained in treatment at mental healthcare (MH cohort), matched by age and gender. The clinical course was evaluated with the GPs and the mental healthcare practitioner, respectively. In addition, medication adherence and reasons for referral to the GP and mental healthcare were registered. RESULTS: In the GP cohort more patients (70%) deteriorated than in the MH cohort (5%) (p <0.001). In the MH cohort more patients showed therapeutic compliance (90%) than in the GP cohort (67%) (p = 0.078). After about four years, 65% of the patients in the GP cohort were back in treatment at mental healthcare. Among the 13 patients who were referred to the GP while functioning stably, more patients (54%) deteriorated than their matched counterparts in the MH cohort (8%) (p = 0.034). CONCLUSION: The results confirm that caution is needed in referring patients recovered from non-affective psychotic disorder to the GP.

[Validation of the Dutch Glasgow Anti- psychotic Side-Effect Scale for Clozapine]. / Glasgow Antipsychotica Bijwerkingen Schaal voor Clozapine; validatie van de Nederlandstalige versie.

BACKGROUND: To monitor the unique side effect pattern of clozapine, the Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS-C) was developed in English and validated. This questionnaire was previously translated to Dutch, and revised, but not yet validated. AIM: The current study concerns the validation of the second revision of the GASS-C-NL-R2 for the Dutch language. METHOD: Two Spearman correlation tests were conducted to compare GASS-C-NL-R2 with the Dutch version of the Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) at two time p´oints. There was one week between these two time points. The test-retest reliability was determined using a Spearman correlation test and Cronbach's alpha on the GASS-C-NL-R2 between the two time points. In addition, a factor analysis was performed. RESULTS: Spearman's correlation coefficient between the GASS-C-NL-R2 and the LUNSERS was 0.830 (p < 0.001, n = 72) at the first time point and 0.684 (p < 0.001, n = 50) at the second time point. GASS-C-NL-R2 also had a strong test-retest reliability: Spearman's correlation coefficient was 0.680 (p < 0.001; n = 46), and Cronbach's alpha was 0.847, n = 78. Factor analysis showed that all questions were relevant. CONCLUSION: The current study shows that GASS-C-NL-R2 is a valid and reliable questionnaire to monitor side effects related to clozapine with a relatively high prevalence. Future studies should focus on the practical utility of GASS-C-NL-R2 with a larger sample size.

A national study to assess outcomes of definitive chemoradiation regimens in proximal esophageal cancer.

Background: Proximal esophageal cancer (EC) is commonly treated with definitive chemoradiation (CRT). The radiation dose and type of chemotherapy backbone are still under debate. The objective of this study was to compare the treatment outcomes of contemporary CRT regimens.Material and Methods: In this retrospective observational cohort study, we included patients with locally advanced squamous cell cancer of the proximal esophagus, from 11 centers in the Netherlands, treated with definitive CRT between 2004 and 2014. Each center had a preferential CRT regimen, based on cisplatin (Cis) or carboplatin-paclitaxel (CP) combined with low (≤50.4 Gy) or high (>50.4 Gy) dose radiotherapy (RT). Differences in overall survival (OS) between CRT regimens were assessed using a fully adjusted Cox proportional hazards and propensity score (PS) weighted model. Safety profiles were compared using a multilevel logistic regression model.Results: Two hundred patients were included. Fifty-four, 39, 95, and 12 patients were treated with Cis-low-dose RT, Cis-high-dose RT, CP-low-dose RT, and CP-high-dose RT, respectively. Median follow-up was 62.6 months (95% CI: 47.9-77.2 months). Median OS (21.9 months; 95% CI: 16.9-27.0 months) was comparable between treatment groups (logrank p = .88), confirmed in the fully adjusted and PS weighted model (p > .05). Grades 3-5 acute adverse events were less frequent in patients treated with CP-low-dose RT versus Cis-high-dose RT (OR 3.78; 95% CI: 1.31-10.87; p = .01). The occurrence of grades 3-5 late toxicities was not different between treatment groups.Conclusion: Our study was unable to demonstrate a difference in OS between the CRT regimens, probably related to the relatively small sample size. Based on the superior safety profile, carboplatin and paclitaxel-based CRT regimens are preferred in patients with locally advanced proximal EC.

Loop Electrosurgical Excision Procedure Treats Cervical Intraepithelial Neoplasia 2/3 Among HIV- and HIV+ Women in Kenya.

OBJECTIVE: The aim of the study was to compare loop electrosurgical excision procedure (LEEP) as treatment for cervical intraepithelial neoplasia (CIN) 2/3 in HIV- versus HIV+ women. MATERIALS AND METHODS: Seventy-five HIV- and 75 HIV+ women at 6 months or more after LEEP for CIN 2/3 were enrolled between September 2013 and November 2014 in this prospective cohort study at the cervical cancer screening clinic in Eldoret, Kenya. Visual inspection with acetic acid (VIA), followed by cervical cytology with conventional cytology, was performed on all women. Women with positive VIA or abnormal cervical cytology underwent colposcopy/biopsy. Lesion progression, persistence, and regression were assessed to quantify the efficacy of LEEP. RESULTS: Post-loop electrosurgical excision procedure screening test showed both a negative VIA and normal cervical cytology in 64 (85%) of HIV- and 57 (77%) HIV+ women (risk difference = 8.3%, CI = -4.2% to 21%, p = .20). Eleven (15%) HIV- and 17 (23%) HIV+ (p = .20) women had positive VIA, abnormal cervical cytology, or both and were referred for colposcopy/biopsy. Twenty-one (8 HIV-, 13 HIV+) women were biopsied. Of the 8 HIV- women, 4 (50%) had CIN lesions that regressed, 3 (38.0%) persisted, and 1 (12%) progressed to invasive cancer after LEEP. Of the 13 HIV+ women, 6 (46%) had CIN lesions that regressed, 7 (54%) had CIN lesions that persisted, and no HIV+ women had CIN lesions that progressed after LEEP. There was no difference in estimated efficacies of LEEP for HIV- and HIV+ women (92.7% versus 89.4%, risk difference = 3.3%, CI = -4.8% to 15.3%, p = .85). CONCLUSIONS: Loop electrosurgical excision procedure for CIN 2/3 is effective treatment for HIV- and HIV+ women in low-resource settings. Future efforts should improve follow-up after treatment.

Delegating Clozapine Monitoring to Advanced Nurse Practitioners: An Exploratory, Randomized Study to Assess the Effect on Prescription and Its Safety.

To test whether: (1) psychiatrists will prescribe clozapine more often if they can delegate the monitoring tasks to an advanced nurse practitioner (ANP), (2) clozapine monitoring by an ANP is at least as safe as monitoring by a psychiatrist. Patients from 23 Dutch outpatient teams were assessed for an indication for clozapine. ANPs affiliated to these teams were randomized to Condition A: clozapine monitoring by an ANP, or Condition B: monitoring by the psychiatrist. The safety of monitoring was evaluated by determining whether the weekly neutrophil measurements were performed. Staff and patients were blinded regarding the first hypothesis. Of the 173 patients with an indication for clozapine at baseline, only seven in Condition A and four in Condition B were prescribed clozapine (Odds Ratio = 2.24, 95% CI 0.61-8.21; p = 0.225). These low figures affected the power of this study. When we considered all patients who started with clozapine over the 15-month period (N = 49), the Odds Ratio was 1.90 (95% CI 0.93-3.87; p = 0.078). With regard to the safety of the monitoring of the latter group of patients, 71.2% of the required neutrophil measurements were performed in condition A and 67.3% in condition B (OR = 0.98; CI = 0.16-3.04; p = 0.98). Identifying patients with an indication for clozapine does not automatically lead to improved prescription rates, even when an ANP is available for the monitoring. Clozapine-monitoring performed by an ANP seemed as safe as that by a psychiatrist.

[Recognizing borderline intellectual functioning or mild intellectual disability in newly registered patients in a general psychiatric outpatient clinic]. / Onderkennen van zwakbegaafdheid of een lichte verstandelijke beperking bij aangemelde patiënten op een algemene psychiatrische polikliniek.

BACKGROUND: It is unclear whether borderline intellectual functioning (bif) and/or a mild intellectual disability (mid) in patients receiving treatment in mental health care are being recognized by care providers.
AIM: Exploratory study to register under-diagnosis of bif/mid in an outpatient clinic.
METHOD: The number of patients diagnosed with bif/mid according to the electronic patient file (epd) was determined. From 11 August to 11 December 2015, all newly registered patients for outpatient treatment with an mbo-2 or lower educational level were screened for the possible presence of bif/mid applying the screener for intelligence and mild intellectual disability (scil). For all patients, their mental health care practitioner was asked if they suspected bif/mid. These percentages were compared. The sensitivity and specificity and the positive and negative predictive value (ppv and npv) of the opinion of the mental health care practitioners were determined.
RESULTS: In the epd 2,8% of patients were diagnosed with bif, and 0,8% with mid. The percentage of suspected bif/mid of newly registered patients was 17,5%. The sensitivity of the assessors' opinion was 41%, the npv was 57%.
CONCLUSION: In newly registered patients at an outpatient clinic bif and mid are important but frequently missed co-morbidities.

Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population.

Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P=0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P=0.05). In patients developing neutropenia, ABCB1 3435TT and homozygosity for GSTT1null (glutathione-S-transferase; conjugates reactive clozapine metabolites into glutathione) were more frequent compared with control (34% versus 20%, P=0.05 and 31% versus 14%, P=0.03), whereas GSTM1null was less frequent in these patients (31% versus 52%, P=0.03). To investigate whether combinations of the identified genetic risk factors have a higher predictive value, should be confirmed in a larger case-control study.

Optimization of HPV DNA detection in urine by improving collection, storage, and extraction.

The benefits of using urine for the detection of human papillomavirus (HPV) DNA have been evaluated in disease surveillance, epidemiological studies, and screening for cervical cancers in specific subgroups. HPV DNA testing in urine is being considered for important purposes, notably the monitoring of HPV vaccination in adolescent girls and young women who do not wish to have a vaginal examination. The need to optimize and standardize sampling, storage, and processing has been reported.In this paper, we examined the impact of a DNA-conservation buffer, the extraction method, and urine sampling on the detection of HPV DNA and human DNA in urine provided by 44 women with a cytologically normal but HPV DNA-positive cervical sample. Ten women provided first-void and midstream urine samples. DNA analysis was performed using real-time PCR to allow quantification of HPV and human DNA.The results showed that an optimized method for HPV DNA detection in urine should (a) prevent DNA degradation during extraction and storage, (b) recover cell-free HPV DNA in addition to cell-associated DNA, (c) process a sufficient volume of urine, and (d) use a first-void sample.In addition, we found that detectable human DNA in urine may not be a good internal control for sample validity. HPV prevalence data that are based on urine samples collected, stored, and/or processed under suboptimal conditions may underestimate infection rates.

Real-world echocardiography in patients referred for mitral valve surgery: the gap between guidelines and clinical practice.

BACKGROUND AND AIM OF THE STUDY: Mitral regurgitation (MR) is a common disorder for which mitral valve surgery is an established therapy. Although surgical indications are clearly defined for the management of valvular heart disease, a gap exists between current guidelines and their effective application. The study aim was to provide an insight into the diagnostic information provided for cardiac surgeons before performing mitral valve surgery. METHODS: The source documents and echocardiographic studies of 100 patients, referred by nine hospitals, were screened for arguments for MR severity justifying referral for surgery. Details of the documented MR mechanism, mitral annulus (MA) size, tricuspid regurgitation (TR) severity and annulus size were also noted. RESULTS: According to the referring physician, MR was severe in 83% and moderate-to-severe in 17%. In the great majority of patients (98%) the MR mechanism was mentioned, although specific information on the prolapsing scallops was available in only 17% of cases. The recommended primary determinants of MR severity, vena contracta and proximal isovelocity surface area (PISA) were measured in only 22% and 31% of patients, respectively. In 94% of patients with available PISA information this was described only qualitatively. Correct image expansion using the zoom mode was performed in only 25% of these patients, and a correct adaptation of the Nyquist limit in only 6%. Tricuspid annulus measurements guiding the need for concomitant tricuspid valvuloplasty in patients with less than severe TR were reported in only 6% of patients. CONCLUSION: These data demonstrate a clear and important gap between current guidelines and real-world practice with regards to the echocardiographic diagnostic information provided to the surgeon before performing mitral valve surgery.

Clinical validation of a type-specific real-time quantitative human papillomavirus PCR against the performance of hybrid capture 2 for the purpose of cervical cancer screening.

To be acceptable for use in cervical cancer screening, a new assay that detects DNA of high-risk human papillomavirus (hrHPV) types must demonstrate high reproducibility and performance not inferior to that of a clinically validated HPV test. In the present study, a real-time quantitative PCR (qPCR) assay targeting the E6 and E7 genes of hrHPV was compared with Hybrid Capture 2 (hc2) in a Belgian cervical cancer screening setting. In women >30 years old, the sensitivity and specificity for intraepithelial neoplasias of grade 2 or worse (93 cases of cervical intraepithelial neoplasias of grade 2 or worse (CIN2+) and 1,207 cases of no CIN or CIN1) were 93.6% and 95.6%, respectively, and those of hc2 were 83.9% and 94.5%, respectively {relative sensitivity of qPCR/hc2 = 1.12 [95% confidence interval (CI), 1.01 to 1.23]; relative specificity = 1.01 [95% CI, 0.99 to 1.03]}. A score test showed that the sensitivity (P < 0.0001) and specificity (P < 0.0001) of the qPCR assay were not inferior to those of hc2 at the required thresholds of 90% and 98%, respectively. The overall agreement of hrHPV positivity between the two runs of the qPCR tests was 98.7% (95% CI, 97.5 to 99.4%), with a kappa value of 0.96 (95% CI, 0.83 to 1.00). The qPCR assay used in this study can be considered a reliable HPV assay that fulfills the clinical validation criteria defined for use in cervical cancer screening.

Detection of human papillomavirus DNA in urine. A review of the literature.

The detection of human papillomavirus (HPV) DNA in urine, a specimen easily obtained by a non-invasive self-sampling method, has been the subject of a considerable number of studies. This review provides an overview of 41 published studies; assesses how different methods and settings may contribute to the sometimes contradictory outcomes; and discusses the potential relevance of using urine samples in vaccine trials, disease surveillance, epidemiological studies, and specific settings of cervical cancer screening. Urine sampling, storage conditions, sample preparation, DNA extraction, and DNA amplification may all have an important impact on HPV DNA detection and the form of viral DNA that is detected. Possible trends in HPV DNA prevalence in urine could be inferred from the presence of risk factors or the diagnosis of cervical lesions. HPV DNA detection in urine is feasible and may become a useful tool but necessitates further improvement and standardization.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

Patterns of recurrence following definitive chemoradiation for patients with proximal esophageal cancer.

INTRODUCTION: The aim of this retrospective study was to determine the patterns of recurrence and overall survival (OS) in patients achieving clinical complete response after treatment with definitive chemoradiation (CRT) for proximal esophageal cancer. MATERIALS AND METHODS: Patients with proximal esophageal cancer treated with CRT between 2004 and 2014 in 11 centers in the Netherlands were included. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Cumulative incidence of first recurrence (locoregional or distant) and locoregional recurrence (LRR) were assessed using competing risk analyses. RESULTS: In 197 of the 200 identified patients, response was evaluated, 133 (68%) showed a complete response. In complete responders, median OS, three-year OS, and PFS were 45.0 months (95% CI 34.8-61.5 months), 58% (95% CI 48-66), and 49% (95% CI 40-57), respectively. Three- and five-year risk of recurrence were respectively 40% (95% CI 31-48), and 45% (95% CI 36-54). Three- and five-year risk of LRR were 26% (95% CI 19-33), and 30% (95% CI 22-38). Eight of 32 patients with an isolated LRR underwent salvage surgery, with a median OS of 32.0 months (95% CI 6.8-not reached). CONCLUSION: In patients with a complete response after definitive CRT for proximal esophageal cancer, most recurrences were locoregional and developed within the first three years after CRT. These findings suggest to shorten locoregional follow-up from five to three years.