Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study.

BACKGROUND: Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. PATIENTS AND METHODS: Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. RESULTS: Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. CONCLUSIONS: Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.

Bridging the communication gap between radiographers and patients to improve chest radiography image acquisition: A multilingual solution in the COVID-19 pandemic.

INTRODUCTION: A chest X-ray (CXR), taken in full inspiration, is important to ensure pathology in the lungs will not be missed. To achieve this, effective communication on breathing instructions for patients is crucial. During the COVID-19 pandemic, radiographers in Sengkang General Hospital (SKH) were challenged when performing CXR for the patients whose native language is not English. Most of these patients were foreign workers living in the same dormitory which had formed the largest COVID-19 cluster in Singapore. These dormitory residents found it difficult to understand and adhere to breathing instructions, resulting in a suboptimal degree of inspiration when the CXRs were taken. This may ultimately affect the diagnostic value of the radiographs. This paper aims to share and evaluate how radiographers tackled this issue and continued to acquire fully-inspired CXR for the dormitory residents despite the language barrier. METHODS: Using a combination of online survey and retrospective analysis of the rejection rates of CXR done over the period of early April to early June, a team of radiographers evaluated the effectiveness of using audio recordings in managing the issue of not achieving a fully inspired CXR for patients due to language barrier. RESULTS: The rejection rate for CXR due to suboptimal inspiration decreased from 26% to 9% upon implementation of the audio recordings. 92.3% of the CXRs taken within this period also fulfilled the criteria of a fully-inspired CXR, as evidenced by having at least 9 posterior ribs seen above the right hemi-diaphragm. Survey results found a fairly balanced number of radiographers who agreed and disagreed that a fully-inspired CXR was achieved for most of their patients after utilisation of translation manuals and audio recordings. CONCLUSION: After the implementation of audio recordings, the decrease in rejection rate of CXR and an audit which demonstrated that CXR quality was upheld had proven that the radiographers successfully achieved fully-inspired CXR for suspected COVID-19 patients. This confirmed that using pre-recorded audio instructions was an efficient intervention albeit being a one-way communication, leads to more accurate imaging results, aligning with existing literature on communication experiences between radiographers and patients. Moreover, the decreased rejection rate of CXRs had increased department efficiency consequently reducing departmental expenses in the long run. IMPLICATIONS OF PRACTICE: Given that we have an ageing population and the vast majority of the elderly converse in their various dialects, positive feedback from radiographers presented opportunities to expand the translation manual and audio recordings to include local dialects. These can be seamlessly integrated in CXR and other procedures in the hospital setting. To ensure that the translations are culturally sensitive, attention should be paid to the translation process of instructions into other languages and local dialects by enlisting the help of native speakers.

Comparison of published and unpublished phase I clinical cancer trials: an analysis of the CliniclTrials.gov database.

Introduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in 'go/no' decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017. Logistic regression was used to identify factors associated with unpublished trials. Linear regression was used to explore factors associated with time lag from study database lock to publication for published trials. Results The study cohort included 319 trials. 95 (30%) trials had no matching publication. Thirty (9%) trials were not published in abstract form as well. On multivariable analysis, the most significant factor associated with unpublished trials was industry funding (odds ratio 3.3, 95% confidence interval 1.7-6.6, p=0.019). For published trials, time lag between database lock and publication was longer by 10.9 months (standard error 3.6, p<0.001) for industry funded trials compared with medical center funded trials. Conclusions Timely publishing of early cancer clinical trials results remains unsatisfactory. Industry funded phase I cancer trials were more likely to remain unpublished, and were associated with a longer time lag from database lock to publication. Policies that promote transparency and data sharing in clinical trial research might improve accountability among industry and investigators and improve timely results publication.

Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications.

Background Data on completeness of reporting of phase I cancer clinical trials in publications are lacking. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching primary publications published prior to November 1, 2016. Reporting in primary publications was compared with the ClinicalTrials.gov database using a 28-point score (2=complete; 1=partial; 0=no reporting) for 14 items related to study design, outcome measures and safety profile. Inconsistencies between primary publications and ClinicalTrials.gov were recorded. Linear regression was used to identify factors associated with incomplete reporting. Results After a review of 583 trials in ClinicalTrials.gov , 163 matching primary publications were identified. Publications reported outcomes that did not appear in ClinicalTrials.gov in 25% of trials. Outcomes were upgraded, downgraded or omitted in publications in 47% of trials. The overall median reporting score was 23/28 (interquartile range 21-25). Incompletely reported items in >25% publications were: inclusion criteria (29%), primary outcome definition (26%), secondary outcome definitions (53%), adverse events (71%), serious adverse events (80%) and dates of study start and database lock (91%). Higher reporting scores were associated with phase I (vs phase I/II) trials (p<0.001), multicenter trials (p<0.001) and publication in journals with lower impact factor (p=0.004). Conclusions Reported results in primary publications for early phase cancer trials are frequently inconsistent or incomplete compared with ClinicalTrials.gov entries. ClinicalTrials.gov may provide more comprehensive data from new cancer drug trials.

Primary Sinonasal Clear Cell Carcinoma: Case Report.

UNLABELLED: Primary sinonasal clear cell carcinoma is a rare neoplasm classified under malignant epithelial tumours of salivary gland - type carcinomas under World Health Organization (WHO) classification. We report a case which occurred on a 69 year old gentleman presented with epistaxis and nasal endoscopy examination showed tumour arising from the right ethmoid cells. Endoscopic excision of the tumour was done and histopathological examination revealed clear cell carcinoma. In addition, other secondary or primary sites of the lesion were excluded by clinical, immunohistochemical and radiological examinations. 10 months into the postoperative period, patient remains well without recurrence of the tumour. IN CONCLUSION: We report a rare case of primary sinonasal clear cell carcinoma in addition to the limited literature available and emphasize the differentials with other probable tumour through meticulous microscopic examination and use of special immunostains.

A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck.

BACKGROUND: An open-label, multicenter, single-arm phase II trial was conducted to investigate the clinical activity of dacomitinib in recurrent/metastatic squamous-cell carcinoma of the head and neck (RM-SCCHN). PATIENTS AND METHODS: Eligible patients were administered dacomitinib at 45 mg orally daily, in 21-day cycles. Primary end point was objective response rate. RESULTS: Sixty-nine patients were enrolled with a median age of 62 years. Among response-evaluable patients, 8 [12.7%, 95% confidence interval (CI) 5.6% to 23.5%] achieved a partial response and 36 (57.1%) had stable disease, lasting ≥24 weeks in 9 patients (14.3%). The median progression-free survival (PFS) was 12.1 weeks and the median overall survival (OS) was 34.6 weeks. Most adverse events (AEs) were tolerable. The most common grade 3 or higher treatment-related AEs were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Treatment-related AEs led to at least one dose interruption in 28 (40.6%) patients and dose reductions in 26 (37.7%). Permanent treatment discontinuation occurred in 8 (11.6%) patients due to treatment-related AEs. CONCLUSIONS: Dacomitinib demonstrated clinical activity in RM-SCCHN, and the primary end point of this study was met. The toxicity profile of this agent was generally manageable with dose interruptions and adjustments.

Warfarin skin necrosis associated with protein S deficiency and a mutation in the methylenetetrahydrofolate reductase gene.

The use of warfarin is rarely complicated by skin necrosis. We describe a 50-year-old woman who presented with a left leg deep venous thrombosis and subsequent pulmonary embolism. She was initially anticoagulated with low-molecular weight heparin and subsequently warfarin. Within 4 days abdominal skin necrosis developed. Investigations revealed the presence of protein S deficiency and in addition, a mutation in the methylenetetrahydrofolate reductase gene (MTHFR). We present, to our best knowledge, the first case of warfarin skin necrosis associated with a methylenetetrahydrofolate reductase mutation.

Cockroaches from urban human dwellings: isolation of bacterial pathogens and control.

A study was carried out to determine the distribution of cockroaches in two different housing areas with central sewerage or individual septic tanks in an urban area in Kuala Lumpur, Malaysia. Six species of cockroaches were present and of these Periplaneta americana and Periplaneta brunnea were found in greater abundance. Seventeen species of bacteria were isolated and of these Escherichia coli and Klebsiella p. pneumoniae were isolated in greatest numbers. Control measures carried out using lambda cyhalothrin showed that there was no significant difference between treated and control sites.

Incidence of pain after biomechanical preparation: a review of 302 cases treated by dental students.

Records of 302 root-filled teeth treated by dental undergraduates were reviewed by four lecturers in the Department of Conservative Dentistry, University of Malaya. Preoperative and operative factors were evaluated for their association with postoperative pain experience of patients during the visit immediately after completion of biomechanical preparation. Eighty four percent of patients did not experience any pain after biomechanical preparation whilst the remaining 16 percent only complained of slight or moderate pain. The incidence of pain after biomechanical preparation is not high even when performed by inexperienced undergraduates. Teeth with a pre-existing painful condition had a higher chances of postoperative of pain. The incidence of postoperative pain was halved when teeth were associated with a sinus tract.

Mercury toxicity and its implications--a review of the literature.

With the current concern about mercury exposure to patients as well as dental personnel, it is important to re-evaluate the procedures to be taken in order to minimise the exposure. A review of the literature provides further insight into this important problem.

The gingival marginal discrepancies of posterior composite restorations.

The purpose of this study is to assess the gingival marginal discrepancies of various types of composite restoratives using contoured matrix bands. The result of this study demonstrated that despite the great care taken during insertion and adaptation of the various composite restoratives, and inspite of bevelling of all cavosurface enamel margins, gingival deficiencies and/or excesses do still occur.

Accuracy of tooth length measurements from periapical radiographs.

This study was undertaken to investigate and assess two radiographic techniques for measuring tooth length. The result of this study demonstrated the inadequacy of determining tooth lengths using radiographs alone without the introduction of instruments into the canal as close as possible to the root apex. Neither of the techniques proved ideal, however, the Paralleling Extension Tube Technique seemed relatively more accurate and reliable than the Bisecting-Angle Technique.

Clinical and laboratory evaluation of a commercial kit for measurement of serum free thyroxin ("Amerlex Free T4").

Different indexes of thyroid function were determined in conjunction with values obtained with a new commercial radioimmunoassay kit for serum free thyroxin, in 49 apparently healthy subjects, 87 pregnant women, and 142 outpatients attending the thyroid clinic. The results indicate a diagnostic success rate of 88% when free thyroxin was measured instead of estimating the so-called free thyroxin index. Furthermore, in three cases of papillary carcinoma the concentration of free thyroxin was increased, although all the other laboratory tests indicated a euthyroid state. Technically, the method is simple, rapid, and precise, and it would be of most value in the small hospital laboratory lacking the facilities of a comprehensive thyroid-function test service.