Oxaliplatin-induced Acute Neurotoxicity Recovers Between Repeat Infusion Cycles: An Axonal Excitability Repeated Multiple Measurements Study.

Background/Aim: Oxaliplatin, a platinum-based chemotherapy used in the treatment of colorectal cancer, induces acute neurotoxicity following infusion. The aim of this study was to establish whether alterations in axonal excitability develop progressively with higher cumulative doses and whether there is a recovery in motor axons after each cycle of treatment. Patients and Methods: Twenty consecutive patients with a colorectal cancer diagnosis, referred from the Oncology Department of Aretaieion Hospital of Athens, were enrolled in this study between October 2018 and May 2019. None of the participants had diabetes, alcohol abuse, known neuropathy or were previously treated with another neo-adjuvant therapy. Threshold Tracking techniques and Qtrac software were used for assessing axonal excitability in motor axons. Excitability recordings were undertaken before and immediately after the end of oxaliplatin infusion. Results: Statistically significant changes were found (p<0.01) in axonal excitability (relative refractory period, refractoriness at 2 ms and 2.5 ms, sub-excitability and super-excitability) before and after oxaliplatin infusion. No statistically significant changes (p>0.05) were found in threshold electrotonus and strength-duration parameters before and after oxaliplatin infusion. We also did not find statistically significant differences (p>0.05) between means of excitability parameters before infusion at each cycle. Conclusion: Our study confirms oxaliplatin-induced acute neurotoxicity following infusion and suggests that motor axons recover between repeat infusion cycles.

Follicular (Infundibular-Tricholemmal) Squamous Cell Carcinoma: A New WHO Entity. Clinicopathological Features in 103 Cases, Including Follow-Up and Implications for Patient Management.

AIMS: Cutaneous follicular (infundibular-tricholemmal) squamous cell carcinoma (FSCC) is a new World Health Organization entity. We present the largest series of published cases, summarizing clinical data, diagnostic criteria, differential diagnosis, and implications for patient management. METHODS: Cases were identified from 2004 to 2011. Inclusion criteria included discrete attachment(s) of the tumor to the overlying epidermis via follicular infundibula, tricholemmal keratinization, and cellular pleomorphism. Keratoacanthoma and lesions with adjacent bowenoid epidermal dysplasia were excluded. RESULTS: One hundred three cases of FSCC identified. 48.5% demonstrated completely circumscript borders ( in situ for practical purposes), 12.6% uncertain for invasion (overwhelmingly pushing borders), and only 38.8% as clearly invasive. Follicular mucin in acantholytic spaces within tumor epithelium was a distinctive finding in 57.2% of cases. Clinical data indicated predominance in elderly (median 78.5 years) men (70.4%), with preferential head and neck location (81.6%). Many were clinically suspected as squamous cell carcinoma (48.5%). However, a significant minority were clinically diagnosed as basal cell carcinoma (40.8%). This may reflect that FSCC commonly presented as a papule or nodule (51.3%). By contrast, keratoacanthoma was less frequently suggested (17.2%) and still fewer lesions were suspected to be actinic keratosis/Bowen's disease (13.6%). Follow-up in 82 cases (median 26.5 months, range 3-144) identified 5 (6.1%) local recurrences. There was no instance of metastasis in the subgroup of lesions with completely circumscript borders. Three of 45 (6.7%) patients, with follow-up, considered to have tumors with invasive pushing, and/or infiltrative borders developed lymph node metastases. CONCLUSIONS: FSCC is identified as a common skin cancer, incorporating historical entities, such as infundibular carcinoma and tricholemmal carcinoma, with readily identifiable histologic features. Correct diagnosis has implications for patient management; a significant subgroup of lesions show completely circumscript borders that are considered in situ for practical purposes.

Mandibular angle fractures: a demographic review, with particular reference to post-operative complications.

BACKGROUND: Mandibular angle fractures (MAF) have a recognized complexity of treatment and an increased risk of incurring complications. METHODS: This retrospective study included 45 consecutive patients who were diagnosed with an isolated MAF and no other facial fractures. The average age was 27.3 (SD = 7.7). RESULTS: A comparatively low rate of complications (11.1%) and a low rate of reoperation (1.8%) are reported, along with a significant role of smoking in complications (p = 0.022). A non-significant association was noted between complications, male gender and assault as an aetiological factor. CONCLUSIONS: Review of the data from this study confirms that complication rates for patients attending the National Maxillofacial Unit are similar to or better than that of international studies. An overview of the aetiology of fracture complications is included.

Impact of dipeptidyl peptidase-4 inhibitors on glucose-dependent insulinotropic polypeptide in type 2 diabetes mellitus: a systematic review and meta-analysis.

Aims: Glucose-dependent insulinotropic polypeptide (GIP) confers a variety of metabolic benefits in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to investigate the impact of dipeptidyl peptidase 4 (DPP4) inhibitors on GIP levels in T2DM patients. Methods: Medline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) were searched and randomized controlled trials (RCTs) evaluating the impact of DPP4 inhibitors on fasting and postprandial GIP levels were obtained. For postprandial GIP, only studies with the data of GIP changes reported as the total area under the curve (AUCGIP) using a meal or oral glucose tolerance test were included. A random-effects model was used for data pooling after incorporating heterogeneity. Results: Overall, 14 RCTs with 541 T2DM patients were included. Compared to placebo/no treatment, the use of DPP4 inhibitors significantly increased the fasting GIP level (standard mean difference [SMD]: 0.77, 95% confidence interval [CI]: 0.48-1.05, P<0.001; I2 = 52%) and postprandial AUCGIP (SMD: 1.33, 95% CI: 1.02-1.64, P<0.001; I2 = 65%). Influence analysis by excluding one dataset at a time showed consistent results. Sensitivity analyses only including studies with radioimmunoassay showed also consistent results (fasting GIP: SMD: 0.75, 95% CI: 0.51-1.00, P<0.001; I2 = 0%; and postprandial AUCGIP: SMD: 1.48, 95% CI: 1.18-1.78, P<0.001; I2 = 54%). Further subgroup analyses demonstrated that the influence of DPP4 inhibitors on fasting and postprandial GIP levels in T2DM patients was not significantly changed by study characteristics such as study design, patient mean age, baseline glycated hemoglobin (HbA1c) concentration, body mass index (BMI), background treatment, treatment duration, or method for postprandial GIP measurement (all P for subgroup effects <0.05). Conclusion: The use of DPP4 inhibitors effectively increases the fasting and postprandial GIP concentrations in T2DM patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022356716.

Aberrant p16, p53 and Ki-67 immunohistochemistry staining patterns can distinguish solitary keratoacanthoma from cutaneous squamous cell carcinoma.

Keratoacanthoma (KA) is widely considered a benign, usually self-resolving, neoplasm distinct from cutaneous squamous cell carcinoma (cSCC), while some consider KA to be indistinguishable from cSCC. Published studies indicate utility for p16, p53, Ki-67 immunostaining and elastic van Gieson (EVG) in the assessment of KA and cSCC. We compared clinical features and staining patterns for p16, p53, Ki-67 and EVG in fully excised KA, cSCC with KA-like features (cSCC-KAL) and other cSCC (cSCC-OTHER). Significant differences between KA, cSCC-KAL and cSCC-OTHER were found for head and neck location (20%, 86%, 84%), and duration <5 months (95%, 63%, 36%). KA shows both a mosaic pattern for p16 (>25-90% of neoplasm area) and peripheral graded pattern for p53 (up to 50% moderate and strong nuclear staining) in 92% compared with 0% of cSCC-KAL and 0% of cSCC-OTHER. In contrast, a highly aberrant pattern (usually null) for one or both p16 and p53, was present in 0% of KA, 83.8% of cSCC-KAL and 90.9% of cSCC-OTHER. Abnormal distribution of Ki-67 beyond the peripheral 1-3 cells was uncommon in KA (4.2%) and common in cSCC-KAL (67.6%) and cSCC-OTHER (88.4%). Moderate to striking entrapment of elastic and collagen fibres was present in the majority of KA (84%), cSCC-KAL (81%) and cSCC-OTHER (65%). KA are clinically distinct neoplasms typically of short duration occurring preferentially outside the head and neck and generally lacking aberrations of p16, p53 and Ki-67, compared with cSCC that have high rates of aberrant or highly aberrant p16, p53 and Ki-67, but EVG lacked specificity.

Revision of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis Classification Schema for Melanocytic Lesions: A Consensus Statement.

Importance: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose. Objective: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG). Evidence Review: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0. Findings: The new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma. Conclusions and Relevance: The implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.

Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

BACKGROUND: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice. OBJECTIVE: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians. METHODS: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included. RESULTS: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images. CONCLUSIONS: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.

Superficial CD34-positive fibroblastic tumor and PRDM10-rearranged soft tissue tumor are overlapping entities: a comprehensive study of 20 cases.

AIMS: Superficial CD34-positive fibroblastic tumor (SCD34FT) and PRDM10-rearranged soft tissue tumor (PRDM10-STT) are rare mesenchymal tumors. These lesions have clinicopathological similarities, but their relationship remains controversial. This study aimed to characterise a series of cases of SCD34FT and PRDM10-STT. METHODS AND RESULTS: Ten lesions each of SCD34FT and PRDM10-STT were studied using immunohistochemistry, array-comparative genomic hybridisation (aCGH), RNA sequencing and exome sequencing. Tumors mainly occurred in young adults, were generally small (< 5 cm) and arose predominantly in the superficial soft tissues of the lower extremities. Follow-up data were available in 15 cases (SCD34FT, n = 7, median 16 months; PRDM10-STT, n = 8, median 14 months), local recurrences occurred in four cases (SCD34FT, two of 10; PRDM10-STT, two of 10), while no distant spread was documented. Morphologically, tumors were relatively well-circumscribed and composed of sheets and fascicles of spindle and pleomorphic cells showing low mitotic activity (< 1/mm²) without necrosis. Other findings included: granular cell change, lipoblast-like cells, ectatic blood vessels with fibrinous material, myxoid stromal changes, metaplastic bone and increased mitotic activity (> 1/mm²). All tumors diffusely expressed CD34, while pan-keratin and desmin were commonly seen focally. SynCAM3 was diffusely expressed in 12 cases (SCD34FT, n = 5; PRDM10-STT, n = 7), independently of fusion status. aCGH profiles were 'flat' (PRDM10-STT, n = 4; SCD34FT, n = 2) and exome sequencing showed no recurrent pathogenic mutations (PRDM10-STT, n = 2; SCD34FT, n = 4). Overall, the only morphological features seen exclusively in PRDM10-STT were myxoid stromal changes (three of 10) and metaplastic bone (two of 10). CONCLUSION: We expand the current knowledge on PRDM10-STT and SCD34FT and provide additional evidence for considering them as overlapping entities.

Cancer diagnostic rates during the 2020 'lockdown', due to COVID-19 pandemic, compared with the 2018-2019: an audit study from cellular pathology.

AIMS: We performed an audit to evaluate the impact of the COVID-19 pandemic-related delay in the diagnosis of major cancers at a Pathology Unit of a Secondary Care Hospital Network in Italy. METHODS: A comparison was made among the number of first cellular pathological diagnoses of malignancy made from the 11th to the 20th week of the years 2018-2020. RESULTS: Cancer diagnoses fell in 2020 by 39% compared with the average number recorded in 2018 and 2019. Prostate cancer (75%) bladder cancer (66%) and colorectal cancer (CRC; 62%) had the greatest decrease. CRC was identified as carrying a potentially important diagnostic delay. CONCLUSIONS: For CRC corrective procedures (continuing mass screening tests; patient triage by family physicians; diagnostic procedures alternative to colonoscopy; predictive evaluation on biopsy samples) were advised. Our simple audit model is widely applicable to avoid pandemic-related delay in clinical diagnosis of cancer.

Sympathetic efferent neurons are less sensitive than nociceptors to 4 Hz sinusoidal stimulation.

BACKGROUND: Sinusoidal current stimuli preferentially activate C-nociceptors. Sodium channel isoforms NaV1.7 and NaV1.8 have been implicated in this. Sympathetic efferent neurons lack NaV1.8 and were explored upon sinusoidal activation. METHODS: Quantitative Sudomotor Axon Reflex Test (QSART) was performed in hairy (n = 16) and glabrous (n = 12) skin. Responses of sympathetic efferents (n = 10) and nociceptive afferents (n = 21) to sinusoidal current stimulation (4 Hz, 0.05-0.15 mA) were recorded in humans by microneurography (n = 11). Activation of sympathetic units upon supra-threshold sinusoidal currents (>0.8 mA) was recorded in pigs (n = 8). RESULTS: Sinusoidal stimuli (4 Hz, 0.4 mA) evoked weak sweat output (30 ml/h/m2 ) in hairy skin compared to rectangular pulses (4 Hz, 5 mA, 53 ml/h/m2 , p < .00001, ANOVA). No change in sweat output was recorded from glabrous skin to sine wave stimuli. Sinusoidal current at intensities ranging from 0.05 to 0.15 mA activated almost all (85%) nociceptors but only 40% of sympathetic units in human. Stimuli lead to a significantly lower activation in sympathetic versus nociceptive fibres as measured by activity-dependent slowing (ADS) of conduction (sympathetic efferents average ADS 100 ± 0.2% vs. C-nociceptors average ADS 113 ± 4%, p < .003, ANOVA). CONCLUSIONS: Sympathetic efferent neurons are less apt to convert slow depolarizations into action potentials as compared to nociceptors. Distinctive sodium channel expression patterns between nociceptors and sympathetic efferent neurons may account for this difference. Sinusoidal stimulation therefore provokes weak sweat responses and provides no alternative for clinical assessment of autonomic function. SIGNIFICANCE: C-nociceptors in hairy skin are activated by 4 Hz sinusoidal current stimulation at lower intensities than myelinated fibres. Sympathetic efferent neurons-albeit also unmyelinated-are less responsive to sinusoidal activation than nociceptors within the same skin area. Cutaneous sympathetic efferent neurons apparently are less apt than nociceptors to convert slow depolarization into action potentials.

Poikilodermatous plaque-like hemangioma: Case series of a newly defined entity.

BACKGROUND: We present a distinctive type of acquired vascular proliferation, for which we propose the name of poikilodermatous plaque-like hemangioma. OBJECTIVE: The aim of this study was to summarize the clinical and histopathologic features in a case series of poikilodermatous plaque-like hemangioma. METHODS: Sixteen cases were identified from the routine clinical and referral practices of the authors. Clinical characteristics, including demographic details and clinical morphology, were collated. The salient histopathologic features, including immunohistochemical staining results, were summarized. RESULTS: The lesions were usually solitary erythematous-to-violaceous poikilodermatous plaques on the lower extremities and pelvic girdle, with an indolent clinical course. Mean age of affected patients was 72 (range 58-80) years, and there was a male predominance. Histology comprised a distinctive band-like proliferation of vascular channels suggestive of postcapillary venules within the superficial dermis with a background of fibrosis, edema, and loss of elastic fibers. Despite the clinical atrophic appearance, acanthosis was a frequent finding. LIMITATIONS: Retrospective study. CONCLUSION: Poikilodermatous plaque-like hemangioma is a distinctive and previously undescribed vascular proliferation defined by a constellation of consistent and reproducible clinical and histologic features.

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection-evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology.

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury.

Targeted Secure Messages to Facilitate Access to Tobacco Treatment Counseling for Veterans: Feasibility Study.

BACKGROUND: Studies show that combining nicotine replacement therapy (NRT) with tobacco treatment counseling is most effective for smoking cessation. However, tobacco treatment counseling has been underutilized across the nation. A secure email message sent to patients already taking NRT was hypothesized to increase the utilization of tobacco treatment counseling among Veterans in New Jersey. Secure messaging for communication between patients and providers was implemented through a web-based password-protected, secure messaging account, where veterans get notified through their personal email when they have a message awaiting them. OBJECTIVE: The main objective of this project was to determine if there was a significant increase in adoption of tobacco treatment counseling among Veterans who received a secure message describing the options for tobacco treatment counseling available to them. Secondary objectives were to demographically characterize Veterans who were and were not enrolled in secure messaging, as well as those who opened or did not open a message. Finally, because the language and content of the messages were changed across project phases, this project also sought to determine (by analysis of response rates) the type of language that was most effective at eliciting a response. METHODS: Over two phases, messages were sent to two samples of Veterans prescribed NRT within the prior 90 days of each phase. In phase 1, one message was sent in December 2015 (message 1). In phase 2, one message was sent in July 2016 (message 2) and the same message (message 3) was resent in August 2016 to persons who did not open message 2. Messages 2 and 3 were more directive than message 1. Response rates to message 1 versus message 2 were compared. A logistic regression analysis determined effect of age and gender on enrollment in secure messaging across both phases. The effectiveness of each phase at increasing tobacco treatment counseling was analyzed using a McNemar test. RESULTS: Message 2, sent to 423 Veterans, had a significantly higher response rate than message 1, sent to 348 Veterans (18%, 17/93 vs 8%, 6/78, P=.04). Phase 2 (ie, messages 2 and 3) significantly increased utilization of tobacco treatment counseling (net increase of six tobacco treatment counseling adopters, P=.04), whereas phase 1 (ie, message 1) did not (net increase of two tobacco treatment counseling adopters, P=.48). Women (odds ratio [OR] 1.6, 95% CI 1.1-2.3) and those aged 30 to 49 years (compared to other age groups) were more likely to be enrolled in secure messaging. Gender and age were not significant predictors of opening or replying to either message. CONCLUSIONS: Although the effect was small, secure messaging was a useful modality to increase tobacco treatment counseling. Directive content with a follow-up message appeared useful. Female Veterans and/or Veterans aged between 30 and 49 years are more likely to use secure messaging.