Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease

The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg⁻¹) combined with nivolumab (3 mg kg⁻¹), pathological responses were observed in 77% of patients, while only 20% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far. Linked Comment:   Blankenstein and van Akkooi. Br J Dermatol 2020; 183 :421–422 .     

Microbial complexes detected in the second/third molar region in patients with asymptomatic third molars.

PURPOSE: Our goal was to report the detection and levels of pathogenic bacteria in subgingival plaque samples taken from the distal of all second molars in 295 patients with asymptomatic third molars. PATIENTS AND METHODS: Data assessing oral health were collected from each of these healthy patients (ASA Classes I and II). Probing depth (PD), at 6 sites per tooth, including third molars, was obtained to determine periodontal status. Subgingival plaque samples were taken from the distal of all second molars before periodontal probing. The presence and levels of 11 bacterial species were determined using whole chromosomal DNA probes and checkerboard DNA-DNA hybridization. Detected bacterial species were grouped into clusters of periodontal pathogens designated as "red" or "orange" complex microorganisms as described by Socransky et al (J Clin Periodontal 25:134, 1998) who found an association of these specific microorganisms with periodontitis. RESULTS: As a group these relatively young patients were periodontally healthy. "Orange and red" complex microorganisms were detected at levels equal to or greater than 10(5) more often if patients had a PD equal to or greater than 5 mm with periodontal attachment loss at the distal of second molars or around third molars at their entry examination. In patients with no PD equal to or greater than 5 mm in the third molar region, "orange and red" complex microorganisms were detected at levels equal to or greater than 10(5) more frequently than would be anticipated in patients with little clinical evidence of periodontal disease. CONCLUSIONS: The clinical findings of increased periodontal PDs and periodontal attachment loss coupled with colonization of periodontal pathogens support the concept that clinical and microbial changes associated with the initiation of periodontitis may present first in the third molar region in young adults.     

Chronic oral inflammation and the progression of periodontal pathology in the third molar region.

PURPOSE: To assess the association between risk markers of chronic oral inflammation and changes over time in periodontal probing depth (PD) in the third molar region, the distal of a second molar, or around a third molar. SUBJECTS AND METHODS: The data from these analyses are part of a study of subjects enrolled with 4 asymptomatic third molars with adjacent second molars in an institutional review board-approved longitudinal trial. Full-mouth periodontal probing was conducted at enrollment and follow-up. Enrollment levels of periodontal pathogens and gingival crevicular fluid inflammatory mediators were assayed as indicators of the degree of oral inflammation. Subjects were categorized as those who had at least a 2 mm change in periodontal PD between baseline and follow-up in the third molar region and those who did not. The relationship between aggregated subject baseline PD, levels of periodontal pathogens, and gingival crevicular fluid IL-1 beta, and the proportion of subjects with changes in PD >or=2 mm versus those with PD <2 mm were compared with Cochran-Mantel-Haenzsel statistics. Level of significance was set at 0.05. Risk assessment models for a change in PD >or=2 mm were developed using logistic regression analysis. RESULTS: Twenty-four percent of 254 subjects exhibited a change in PD from baseline to follow-up of >or=2 mm in the third molar region. Of these, 95% had a baseline PD of >or=4 mm. Both high (>or=10(5)) "orange" and "red" complex bacteria and PD of >or=4 mm detected at enrollment were significantly associated with a change in PD >or=2 mm. Odds of a change in PD >or=2 mm were increased if baseline pathogen levels were >or=10(5) or a PD of >or=4 mm was detected at enrollment. CONCLUSION: Our findings are consistent with chronic oral inflammation leading to a progression of periodontal disease in the third molar region.     

An epidemiologic survey of facial fractures and concomitant injuries

A 5-year review of facial fractures and concomitant injuries at a level 1 trauma center is presented. The anatomic location of the facial fractures, age and sex of the patients, cause of injury, and associated systems injuries are presented. The majority of facial fractures were found in males; the most prevalent age range was 16 to 30 years. Mandible fractures outranked zygomatic and maxillary fractures (6:2:1). Assaults and motor vehicle accidents were the most frequent causes of facial fractures, and lacerations followed by neurologic and orthopedic injury were the most frequently encountered concomitant injuries. Motor vehicle accidents were the most frequent cause of associated injury.     

Xeroradiography in the diagnosis of nonradiopaque sialoliths

Sialolithiasis may be the most common disease of the salivary glands in patients more than 20 years of age. Approximately 19% of sialoliths occur in the parotid gland. Of these, only up to 71% can be successfully diagnosed radiographically. The remaining 29% provide a diagnostic dilemma. Xeroradiography, because of its tissue-edge enhancement, can distinguish tissue margins of different density more dramatically than can conventional imaging and is an invaluable aid in the diagnosis of nonradiopaque sialoliths.     

Effects of environmental factors on maxillofacial elastomers: Part IV--Optical properties.

The optical properties of four currently used and two recently introduced maxillofacial prosthetic materials were evaluated after the materials were subjected to the following seven environmental variables: natural weathering; normal aging; two types of adhesives; two types of cleaning agents; and cosmetics. Optical density and color changes were evaluated. The currently used silicones Silastic 4-4210 and Silastic 4-4515, Medical Adhesive type A material, and polyurethane all showed more changes in color and optical density than the newly introduced silicone A-102 material.     

Primary hyperparathyroidism or hypercalcaemia of malignancy?

The introduction of two-site immunometric assays measuring intact parathyroid hormone (PTH) and radioimmunoassays measuring PTH-related peptide (PTH-RP) have simplified the evaluation of patients with hypercalcaemia. We present a 63-year-old man with recurrent hypercalcaemia after surgical treatment for primary hyperparathyroidism 3 years previously. PTH measured with a mid-region radioimmunoassay gave normal values, at the same level as during his primary hyperparathyroidism. Intact PTH was, however, clearly suppressed, and he had a highly elevated level of PTH-RP. This suggested that he had humoral hypercalcaemia of malignancy. The patient died after 2 months, and at autopsy an adenocarcinoma of the pancreas with no skeletal metastases was found.     

Mutant-enriched PCR and allele-specific hybridization reaction to detect K-ras mutations in stool DNA: high prevalence in a large sample of older adults

BACKGROUND: Testing for mutant K-ras in stool has been proposed for the detection of pancreatic and colorectal cancer (CRC). Different analytical techniques have been developed, but studies of this biomarker in the general population are lacking. We investigated the prevalence and potential determinants of mutant K-ras in stool in a large sample of unselected older adults and assessed the association with colonoscopic findings. METHODS: In stool samples from 875 older adults (age range 50-75 years) participating in a large-scale population-based cohort study, we used mutant-enriched PCR and allele-specific hybridization reaction to analyze mutations in codons 12 and 13 of the K-ras gene. We assessed the association between mutant K-ras in stool and risk factors for gastrointestinal cancer sites, exocrine pancreatic insufficiency determined by fecal pancreas elastase 1, and colonoscopic findings. RESULTS: The overall prevalence of mutant K-ras in stool was 8% (95% confidence interval 6%-10%). There was a tentative association between increased fecal pancreas elastase 1 and mutant K-ras in stool (P = 0.09). Patients with advanced colorectal neoplasia diagnosed within 2 years after stool collection (24 with advanced adenomas, 7 with CRC) all tested negative. CONCLUSION: The proposed assay identifies mutant K-ras in stool at a higher prevalence than has been reported for other analytical techniques. Our findings do not support the use of this assay for CRC screening, but its potential use for early detection of pancreatic cancer (in combination with other markers) requires further investigation.     

Press Review

Diversion of Initial Blood Flow to prevent Whole Blood Contamination by Skin-Surface Bacteria: An in vitro Model