Immune Response Dynamics and Biomarkers in COVID-19 Patients.

BACKGROUND: The immune response dynamics in COVID-19 patients remain a subject of intense investigation due to their implications for disease severity and treatment outcomes. We examined changes in leukocyte levels, eosinophil activity, and cytokine profiles in patients hospitalized with COVID-19. METHODS: Serum samples were collected within the first 10 days of hospitalization/confirmed infection and analyzed for eosinophil granule proteins (EGP) and cytokines. Information from medical records including comorbidities, clinical symptoms, medications, and complete blood counts were collected at the time of admission, during hospitalization and at follow up approximately 3 months later. RESULTS: Serum levels of eotaxin, type 1 and type 2 cytokines, and alarmin cytokines were elevated in COVID-19 patients, highlighting the heightened immune response (p < 0.05). However, COVID-19 patients exhibited lower levels of eosinophils and eosinophil degranulation products compared to hospitalized controls (p < 0.05). Leukocyte counts increased consistently from admission to follow-up, indicative of recovery. CONCLUSION: Attenuated eosinophil activity alongside elevated chemokine and cytokine levels during active infection, highlights the complex interplay of immune mediators in the pathogenesis COVID-19 and underscores the need for further investigation into immune biomarkers and treatment strategies.

The ulnar artery: A site suitable for arterial cannulation in pediatric patients.

BACKGROUND: Historically, the ulnar artery has rarely been considered for arterial cannulation as it is less easily palpated than the radial artery. With the current routine use of ultrasound in pediatric patients, the ulnar is as accessible as the radial and could be viewed as an equivalent site for cannulation. AIMS: The purpose of this study was to compare ulnar and radial artery suitability for arterial cannulation in pediatric patients using 2-dimensional ultrasound. METHODS: We examined the ulnar and radial arteries of pediatric patients aged birth to 6 years who were scheduled to undergo general anesthesia. Following anesthesia induction, the investigators positioned the patient's wrist to 30-45 degrees of extension and obtained images of the ulnar and radial arteries in the transverse and longitudinal planes. Assessments of the arteries' anterior-posterior diameter, cross-sectional area and depth were made by visual inspection at the time of image acquisition and by electronic caliper measurement of recorded images. RESULTS: In 108 patients, mean anterior-posterior diameter of the ulnar artery was larger than the radial artery in the transverse view, longitudinal view, and cross-sectional area in 63.6%, 59.4%, and 60.4% of patients (p = .002, .004, and .006, respectively). Mean ulnar artery size was, on average, larger than the radial artery by 7.7%, 8.1%, and 12.9% in the transverse AP diameter, longitudinal AP diameter, and cross-sectional area (95% CI 3.1-12.4%; 3.2-13.0%; 4.4-21.5%). The investigator's visual evaluation of vessel size at the bedside showed substantial agreement with the measured cross-sectional area (linear-weighted kappa of 0.73). In a subset of 13 patients age <24 months, the mean depth of the ulnar artery was 2.13 mm compared to 1.65 mm for the radial artery (difference -0.48 mm 95% CI 1.08-0.12). CONCLUSIONS: The ulnar artery was larger than the radial artery in 60% of pediatric patients thus may offer an arterial cannulation site advantage due to its larger size. The use of 2-dimensional ultrasound examination allows accurate assessment of upper extremity distal arteries in order to optimize site selection for arterial cannulation in pediatric patients.

Challenging cases in oncofertility: insights from a national specialized e-meeting for fertility preservation specialists.

PURPOSE: To determine the use of a new specialized E-Meeting for Complex Cases in Oncofertility by fertility preservation specialists (FPSs) MATERIAL AND METHODS: We present 3 years of activity of the E-Meeting for Complex Cases in Oncofertility, a new tool created in September 2016 which allows national oncofertility experts to share viewpoints about challenging cases for which they do not have experience or sufficient data in order to provide them an emergency advice within 48 h. Second, a survey was conducted to evaluate the use of this e-meeting for participating FPSs. RESULTS: One hundred and four experts have joined the e-meeting since its set-up, and 109 challenging cases have been submitted. The mean age of the patients was 22.4 ± 8.9 years, and 87.0% were female. Each submitted case received on average of 1.8 ± 1.1 different strategies for FP and the opinions of 7.1 ± 3.4 experts. Among the FPSs who submitted cases, seeking opinions from other FPSs allowed them to confirm their care plan (N = 49, 84.4%), to offer different options to their patients (N = 34, 58.6%), and to compare their practices with those of other specialists (N = 23, 39.6%). All respondents reported a self-perceived improvement in their practice of oncologic FP (n = 80, 100.0%). CONCLUSION: Specific attention should be paid to challenging cases for which the experiences of only a few individuals exist. Enhancing communication between FPSs through oncofertility networks, pooling experiences, and collecting the most complex cases is required to improve the management of these patients.

Sentinel Lymph Node Biopsy in Cutaneous Squamous Cell Carcinoma Series of 37 Cases and Systematic Review of the Literature.

Cutaneous squamous cell carcinoma (cSSC) is one of the most common skin cancers and can lead to patient death. Early detection of node metastasis is a major goal for dermatologists and oncologists. The procedure sentinel lymph node biopsy has been proposed to improve early detection of node metastasis. The aim of this study was to evaluate the efficacy and impact of this technique on the prognosis of cSSC. A total of 37 patients (Saint Louis Hospital, Paris, France) who had undergone sentinel lymph node biopsy and 290 cases from the literature were analysed. The mean rate of positive sentinel lymph node biopsy was 0.14 [95% CI 0.09-0.22]. However, relapse-free survival and overall survival were not affected by sentinel lymph node status (log-rank test; p = 0.08 and p = 0.31, respectively), suggesting that this procedure is not mandatory in the management of cSSC.

Machine learning enabled detection of COVID-19 pneumonia using exhaled breath analysis: a proof-of-concept study.

Detection of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) relies on real-time-reverse-transcriptase polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. The false-negative rate of RT-PCR can be high when viral burden and infection is localized distally in the lower airways and lung parenchyma. An alternate safe, simple and accessible method for sampling the lower airways is needed to aid in the early and rapid diagnosis of COVID-19 pneumonia. In a prospective unblinded observational study, patients admitted with a positive RT-PCR and symptoms of SARS-CoV-2 infection were enrolled from three hospitals in Ontario, Canada. Healthy individuals or hospitalized patients with negative RT-PCR and without respiratory symptoms were enrolled into the control group. Breath samples were collected and analyzed by laser absorption spectroscopy (LAS) for volatile organic compounds (VOCs) and classified by machine learning (ML) approaches to identify unique LAS-spectra patterns (breathprints) for SARS-CoV-2. Of the 135 patients enrolled, 115 patients provided analyzable breath samples. Using LAS-breathprints to train ML classifier models resulted in an accuracy of 72.2%-81.7% in differentiating between SARS-CoV2 positive and negative groups. The performance was consistent across subgroups of different age, sex, body mass index, SARS-CoV-2 variants, time of disease onset and oxygen requirement. The overall performance was higher than compared to VOC-trained classifier model, which had an accuracy of 63%-74.7%. This study demonstrates that a ML-based breathprint model using LAS analysis of exhaled breath may be a valuable non-invasive method for studying the lower airways and detecting SARS-CoV-2 and other respiratory pathogens. The technology and the ML approach can be easily deployed in any setting with minimal training. This will greatly improve access and scalability to meet surge capacity; allow early and rapid detection to inform therapy; and offers great versatility in developing new classifier models quickly for future outbreaks.

Long-term opioid therapy for chronic pain: optimizing management, minimizing risk.

Opioid analgesics are commonly used for the management of chronic noncancer pain. Although they can be beneficial for select patients, opioids are also at the heart of a nationwide epidemic of misuse and diversion.

Gene Polymorphisms of Epithelial Cell-Derived Alarmins and Their Effects on Protein Levels and Disease Severity in Patients with COVID-19.

BACKGROUND: The immune response in COVID-19 is characterized by the release of alarmin cytokines, which play crucial roles in immune activation and inflammation. The interplay between these cytokines and genetic variations may influence disease severity and outcomes, while sex differences might further contribute to variations in the immune response. METHODS: We measured the levels of alarmin cytokines in a cohort of COVID-19 and non-COVID-19 patients using a sensitive Meso Scale Discovery system. Additionally, we conducted an SNP analysis to identify genetic variations within the IL-33 and TSLP genes. The association between these genetic variations, cytokine production, and COVID-19 severity was examined. RESULTS: Our findings revealed elevated levels of IL-33 and IL-25 in COVID-19-positive patients compared to COVID-19-negative patients (p < 0.05), indicating their potential as therapeutic targets for disease modulation. Moreover, a minor allele within the IL-33 gene (rs3939286) was found to be associated with a protective effect against severe COVID-19 (p < 0.05), and minor alleles of the TSLP gene (rs2289276 and rs13806933) were found to significantly reduce TSLP protein levels in serum (p < 0.05). Sex-specific effects of TSLP and IL-33 SNPs were observed, suggesting a potential influence of sex hormones and genetic variations on the regulation of cytokine production. CONCLUSION: The present study highlights the importance of alarmin cytokines and genetic variations in COVID-19 severity, providing valuable insights into personalized treatment approaches. Our results suggest that targeting alarmin cytokines may offer potential therapeutic benefits in managing COVID-19. Furthermore, the sex-specific effects of genetic variations emphasize the need to consider individual genetic profiles and sex differences when designing targeted interventions.

Human Herpesvirus-6 cytopathic inclusions: an exceptional and recognizable finding on skin biopsy during HHV6 reactivation after autologous stem-cell transplantation.

Skin rash are common in immunocompromised patients, particularly after bone marrow transplantation. Human herpes virus 6 (HHV6) reactivation is often suspected, but its clinical presentation and the routine laboratory tests may be unspecific, thus leading to late diagnosis. In this case, we report specific intralymphocytic cytopathic inclusions on skin biopsy as a sign of systemic HHV6 reactivation. A 56-year-old patient presented progressive erythroderma and fever occurring after autologous hematopoietic stem-cell transplantation for mantle cell lymphoma. The skin biopsy showed a perivascular infiltrate of medium-to-large lymphocytes with irregular nuclei containing a large central basophilic inclusion surrounded by a clear halo. High levels of HHV-6 genomic in skin biopsy confirm HHV-6-induced cytopathic effect. The clinical course improved with intravenous foscavir. The specific histopathological findings encountered in this case are exceptional but recognizable, and along with HHV-6 DNA detection allow a prompt recognition of HHV6 skin rash.

Systemic Treatment Initiation in Classical and Endemic Kaposi's Sarcoma: Risk Factors and Global Multi-State Modelling in a Monocentric Cohort Study.

BACKGROUND: Although several studies described the clinical course of epidemic and post-transplant Kaposi's Sarcoma (KS), the lack of large cohorts of classic/endemic KS, precluded such characterization. METHODS: We used multi-state modelling in a retrospective monocentric study to evaluate global disease evolution and identify risk factors for systemic treatment (ST) initiation. 160 classic/endemic KS patients consecutively diagnosed between 1990 and 2013 were included. RESULTS: 41.2% of classic/endemic KS patients required ST. Cumulative incidence of ST after 2 years of follow-up was 28.4% [95% CI: 20.5; 35.5]. Multivariate analysis identified six risk factors for ST initiation: time between first symptoms and diagnosis ≥1 year, endemic KS, total number of lesions ≥10, visceral, head or neck localization and presence of edema. Type of ST, type of KS, age and time between diagnosis and ST were not associated with response. Mean treatment-free time during the first 5 years following ST was 44 months for interferon and 44.6 months for chemotherapy treated patients (Mean difference: -0.5 months [95% CI: -9.5; 4.9]). CONCLUSIONS: Our study reveals ST risk factors in classic/endemic KS and highlights the clinical aggressiveness of the endemic KS subtype. No efficacy difference was observed between standard of care treatments, enabling treatment choice based on patient's fitness.

Anti-programmed cell death protein 1 tolerance and efficacy after ipilimumab immunotherapy: observational study of 39 patients.

In patients with ipilimumab (IPI)-refractory melanoma, the anti-programmed cell death proteins 1 (PD1s) nivolumab (NIV) and pembrolizumab (PEM) are considered to be a new standard of treatment. Few data are available on anti-PD1 safety in patients who develop IPI-related severe adverse events (AEs) (grade≥3). The aim of this study was to compare the anti-PD1 safety and efficacy in patients with previous severe toxicity to IPI versus in those showing moderate and no previous IPI-related AEs. This single institution-based observational study included all patients treated with anti-PD1 (PEM or NIV) and previously treated with IPI for unresectable stage III or IV melanoma. The patients enrolled were classified according to the occurrence of IPI-related AEs: group A: no previous IPI-related AEs; group B: mild to moderate IPI-related AEs; and group C: severe to life-threatening IPI-related AEs. The main outcome measure was safety of the anti-PD1 among the three groups. The secondary endpoints included response parameters. Groups A, B, and C included, respectively, 16, 13, and 10 patients. The incidence of severe anti-PD1-related AEs (grades 3-4) was 12, 23, and 10% in groups A, B, and C, respectively. One-year estimates of survival were 52.2, 73.4, and 66.7% among the patients in groups A, B, and C, respectively. The number of patients was too small to enable a meaningful statistical comparison. We did not observe any difference in anti-PD1 toxicity onset incidence according to the occurrence of previous IPI AEs. These reassuring real-life data should be confirmed in a wider analysis.

Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma.

CONTEXT: Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known. OBJECTIVE: We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma. METHODS: We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients. RESULTS: 70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion. CONCLUSION: Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective.

Atypical severe immune-related adverse effects resulting from sequenced immunotherapy in melanoma.

We report unusual severe toxicity in three patients treated at our institution with sequenced immunotherapy for metastatic melanoma. These three patients illustrate the unusual potential toxicity of sequential administration of anti-programmed cell death 1 followed by ipilimumab, and the need for careful monitoring of these toxicities associated with sequential immunotherapies. Data from forthcoming trials and national databases such as MELBASE, recently implemented in France, will be helpful in providing further insights into the risks and benefits of sequential immunotherapy schedules.

BRAF inhibitor rechallenge in patients with advanced BRAF V600-mutant melanoma.

In around 50% of melanomas, the BRAF V600 mutation, resulting in an activation of the MAP kinase pathway, is detected. BRAF inhibitors have shown remarkable activity on the disease. However, efficacy is short-lived in most cases, with a median disease-free survival of 6 months. This short duration of response could be explained by the acquisition of resistance mechanisms. Some cancers show sensitivity to the reintroduction of previously active drugs after disease progression. We carried out a retrospective monocentric study on patients with BRAF V600-mutated melanoma who were rechallenged with BRAF inhibitors that were previously beneficial, but in whom the disease had progressed. Nine patients were included. Five patients showed a subsequent partial response, two showed a dissociated response leading to clinical improvement, and two showed no radiological nor clinical response. Eight patients who received rechallenge BRAF inhibitor had received an intercurrent treatment with ipilimumab. These cases suggest that intermittent treatment with BRAF inhibitors could provide clinical benefit and that sequential therapies should be further evaluated in clinical trials.

Single-center study under a French Temporary Authorization for Use (TAU) protocol for ipilimumab in metastatic melanoma: negative impact of baseline corticosteroids.

UNLABELLED: Ipilimumab is an anti-CTLA-4 antibody which has recently been approved in Europe as a monotherapy in the treatment of metastatic melanoma. We report a single-center study among patients treated within a Temporary Authorization for Use (TAU) protocol. We also performed a review of the literature involving expanded access program studies with a focus on factors associated with overall survival (OS). PATIENTS AND METHODS: This retrospective, observational study included patients between June 2010 and July 2011 with a diagnosis of non-resectable stage III or IV melanoma with at least one previous line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose of 3mg/kg every three weeks. RESULTS: 45 patients were included, among whom 23 (51%) had brain metastases. 33 (71%) of the patients completed the induction phase. The best overall response rate (BORR) was 13% and median overall survival (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with brain metastases at baseline and those without (p = 0.10), regardless of BRAF V600E status (p = 0.61). OS was poorer in patients who were being treated with corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008). CONCLUSION: A subset of patients most likely to benefit from ipilimumab should be defined. In our series we found a negative association of baseline corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain metastases should not be barriers to the initiation of treatment.

[Targeted molecular therapies (except immunotherapy)]. / Thérapies moléculaires ciblées (hors immunothérapie).

Metastatic melanoma has been a very poor prognostic cancer with a median of survival between six to eight months. A lot of new therapies have been discovered these last years. Two types of treatment have emerged: immunotherapy and targeted therapy. Targeted therapies have been developed because of the discovery of new oncogenic mutations with a big impact of melanoma development. The efficacy is great with a high overall response and a good tolerance. However, most of patients escape in few months of targeted therapy. The sequence of drug using and their combination are the question for the next years.

Vascular invasion and other invasive features in granular cell tumours of the skin: a multicentre study of 119 cases.

BACKGROUND: Incidental finding of vascular invasion has been described in some benign granular cell tumours. Malignancy in granular cell tumours is excessively rare and its assessment relies on necrosis and cytological criteria. AIMS: To assess histopathological invasive features, particularly vascular invasion, in a large series of granular cell tumours of the skin. METHODS: 119 granular cell tumours of the skin were collected in 114 patients between 2001 and 2011. Histopathological and epidemiological data were collected. Five step sections and one orcein staining were performed in all cases. RESULTS: Mean age of the patients was 43.7±18 years. Granular cell tumours were multiple in 7% of patients. They were classified as benign in 111 cases, and atypical in eight cases. No malignant granular cell tumour was present. Tumours had 1.48±1.3 cm mean diameter, showed peripheral invasive growth pattern in 71% of cases, had a mean depth of 8.8±4.7 mm, and reached the subcutis in 66% of cases. Infiltration of arrector pili muscle occurred in 23% (95% CI 16% to 32%), and perineural spread in 66% (95% CI 56% to 74%) of cases. Vascular invasion occurred in 23% (95% CI 16% to 32%) of cases, with subendothelial layers infiltration or vascular obliteration. No intraluminal embolus was found. No association was found between vascular invasion and clinical outcome. CONCLUSIONS: Histopathological features of local invasion are frequent in otherwise benign granular cell tumours. Vascular invasion consists of an infiltration of the subendothelial layers, without intraluminal cells, and may not be considered as a marker of adverse prognosis.