How Many Times Can One Go Back to the Drawing Board before the Accurate Diagnosis and Surgical Treatment of Glucagonoma?

Glucagonomas are neuroendocrine tumors (NETs) that arise from the alpha cells of the pancreatic islets. They are typically slow-growing tumors associated with abnormal glucagon secretion, resulting in one or more non-specific clinical features, such as necrolytic migratory erythema (NME), diabetes, diarrhea, deep vein thrombosis, weight loss, and depression. Here, we report the case of a 44-year-old male with a history of diabetes mellitus, presenting with a pruritic and painful disseminated cutaneous eruption of erythematous plaques, with scales and peripheral pustules, misdiagnosed as disseminated pustular psoriasis and treated for 2 years with oral retinoid and glucocorticoids. During this period, the patient complained of weight loss of 32 kg and diarrhea and developed deep vein thrombosis. These symptoms, together with an inadequate response to therapy of the skin lesions, led to the reassessment of the initial diagnosis. Laboratory tests confirmed elevated plasma glucagon levels (>1000 pg/mL) and computed tomography (CT) scans revealed a 35/44 mm tumor in the pancreatic tail. Due to considerable disease complications and the COVID-19 pandemic, the surgical removal of the tumor was delayed for nearly 2 years. During this time, somatostatin analogue therapy efficiently controlled the glucagonoma syndrome and likely prevented tumor progression. As in other functional pancreatic NETs, the early clinical recognition of hormonal hypersecretion syndrome and the multidisciplinary approach are the keys for best patient management.

Canadian Adalimumab Post-Marketing Observational Epidemiological Study Effectiveness in Psoriatic Arthritis (COMPLETE-PsA): 12-Month Results of Comparative Effectiveness of Adalimumab and nbDMARDs

Objective COMPLETE-PsA was an observational study of biologic-naïve Canadian adults with active psoriatic arthritis (PsA) treated with adalimumab or a non-biologic disease-modifying antirheumatic drug (nbDMARDs) regimen, after inadequate response/intolerance to a current nbDMARD treatment regimen. The aim of this analysis was to assess 12-month effectiveness of adalimumab versus nbDMARDs. Methods Patients enrolled between March 2012 and November 2017 were included. The following clinical parameters and patient-reported outcomes were collected/calculated per routine care: DAPSA28, DAS28, ESR, CRP, MDGA, PtGA, pain, HAQ-DI, SF-12, enthesitis, dactylitis, BSA, and time to achieving ACR50, ACR70 and modified MDA (mMDA). Results Two hundred seventy-seven adalimumab-treated and 148 nbDMARD-treated patients were included. At baseline, adalimumab-treated patients were less likely to be employed; had longer morning stiffness; higher DAPSA28, DAS28, MDGA, PtGA, pain, and HAQ-DI; and lower prevalence of dactylitis (all p<0.05). Adalimumab-treated patients showed lower baseline-adjusted DAPSA28 (16.5 vs. 26.6), DAS28 (2.8 vs. 3.9), MDGA (25.3 vs. 37.1), and ESR (10.2 vs. 15.4 mm/hr) after 3 months compared to nbDMARD-treated patients, with observed improvements maintained to month 12. Time to achievement of ACR50, ACR70, and mMDA was significantly (p<0.01) shorter among adalimumab-treated patients, with the likelihood of having dactylitis [OR: 0.4 (0.2–0.6)] and BSA<3% [2.7 (1.5–5.0)] significantly lower and higher, respectively. Switching to another biologic was less likely in adalimumab-treated vs. nbDMARD -treated patients (HR [95% CI]: 0.3 [0.2-0.5]). Conclusion In a real-world Canadian PsA population, adalimumab was more effective than nbDMARDs at reducing disease activity and the severity of skin involvement and demonstrated higher retention.

Physiological Response to Short-Term Heat Stress in the Leaves of Traditional and Modern Plum (Prunus domestica L.) Cultivars

The aim of this study was to evaluate physiological responses to short-term heat stress in the leaves of traditional (Bistrica) and modern (Toptaste) plum cultivars. In this study, detached plum leaves were incubated at 25 °C (control) and 40 °C (stress). After 1 h of exposure to heat (40 °C), chlorophyll a fluorescence transients were measured, and several biochemical parameters were analyzed. Elevated temperature caused heat stress in both plum cultivars, seen as a decrease in water content (WT), but in the leaves of the cultivar Bistrica, an accumulation of proline and phenols, as well as an accumulation of photosynthetic pigments, suggest the activation of a significant response to unfavorable conditions. Conversely, in the leaves of Toptaste, a significant accumulation of malondialdehyde (MDA) and an activation of guaiacol peroxidase (GPOD), all together with a decreased soluble proteins content, indicate an inadequate response to maintaining homeostasis in the leaf metabolism. The impact of an elevated temperature on photosynthesis was significant in both plum cultivars as reflected in the decrease in performance indexes (PIABS and PItotal) and the maximum quantum yield of PSII (Fv/Fm), with significantly pronounced changes found in Toptaste. Unlike the traditional plum cultivar, Bistrica, in the modern cultivar, Toptaste, short-term heat stress increased the minimal fluorescence (F0) and absorption (ABS/RC), as well as Chl b in total chlorophylls. Additionally, the inactivation of RCs (RC/ABS) suggests that excitation energy was not trapped efficiently in the electron chain transport, which resulted in stronger dissipation (DI0/RC) and the formation of ROSs. Considering all presented results, it can be presumed that the traditional cultivar Bistrica has better tolerance to heat stress than the modern cultivar Toptaste. The cultivar, Bistrica, can be used as a basis in further plum breeding programs, as a source of tolerance for high temperature stress.

Humoral and T-cell immune response after three doses of mRNA SARS-CoV-2 vaccines in fragile patients: the Italian VAX4FRAIL study

Background: Patients with solid or hematological tumors, neurological and immune-inflammatory disorders represent potentially fragile subjects with increased risk to experience severe COVID-19 and inadequate response to SARS-CoV2 vaccination. Methods: We designed a prospective Italian multicentric study to assess humoral and T-cell response to SARS-CoV2 vaccination in patients (n=378) with solid tumors (ST), hematological malignancies (HM), neurological (ND) and immuno-rheumatological diseases (ID). The immunogenicity of primary vaccination schedule and of the booster dose were analyzed. Results: Overall, patient seroconversion rate after two doses was 62.1%. A significant lower rate was observed in HM (52.4%) and ID (51.9%) patients compared to ST (95.6%) and ND (70.7%); a lower median level of antibodies was detected in HM and ID versus the others (p<0.0001). A similar rate of patients with a positive SARS-CoV2 T-cell response was observed in all disease groups, with a higher level observed in the ND group. The booster dose improved humoral responses in all disease groups, although with a lower response in HM patients, while the T-cell response increased similarly in all groups. In the multivariable logistic model, the independent predictors for seroconversion were disease subgroups, type of therapies and age. Notably, the ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (p<0.0001), but had no effects on the T-cell responses. Conclusions: Immunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination. The booster dose can improve both humoral and T-cell response.

The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort’s experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.

The impact of filgotinib on patient-reported outcomes and health-related quality of life for patients with active rheumatoid arthritis: a post hoc analysis of Phase 3 studies

Background The effects of filgotinib on patient-reported outcomes (PROs) from 3 trials in patients with active rheumatoid arthritis were investigated. Methods Methotrexate (MTX)-naïve patients received filgotinib 200 or 100 mg plus MTX (FIL200+MTX, FIL100+MTX), filgotinib 200 mg monotherapy (FIL200), or MTX monotherapy through 52 weeks (NCT02886728). Patients with inadequate response (IR) to MTX (MTX-IR) received FIL200+MTX, FIL100+MTX, adalimumab 40 mg +MTX (ADA+MTX), or placebo (PBO)+MTX (rerandomized to FIL200+MTX or FIL100+MTX at week 24) through 52 weeks (NCT02889796). Patients with IR to biologic disease-modifying antirheumatic drugs (bDMARD-IR) received FIL200 or FIL100 or PBO with background stable conventional synthetic (cs) DMARDs for up to 24 weeks (NCT02873936). PROs included Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) physical/mental component summary (PCS/MCS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and Patient Global Assessment of Disease Activity (PtGA). Data are reported as least-squares mean changes from baseline with standard error to the timepoint representing each study’s primary endpoint. All statistical comparisons are of filgotinib groups vs their respective control groups. Results At week 24, among MTX-naïve patients, change from baseline (standard deviation) in HAQ-DI was − 1.00 (0.03; P < 0.001) with FIL200+MTX, − 0.94 (0.04; P < 0.01) with FIL100+MTX, and − 0.91 (0.04; P < 0.05) with FIL200 alone compared with − 0.81 (0.03) with MTX alone. At week 12, among MTX-IR patients, change from baseline in HAQ-DI was − 0.69 (0.04; P < 0.001 vs PBO+MTX, P < 0.05 vs ADA) with FIL200+MTX, − 0.57 (0.04; P < 0.001 vs placebo) with FIL100+MTX, and − 0.60 (0.04) with ADA vs − 0.40 (0.04) with PBO+MTX. At week 12, among bDMARD-IR patients, change from baseline in HAQ-DI was − 0.50 (0.06; P < 0.001) with FIL200+csDMARD and − 0.46 (0.05; P < 0.001) with FIL100+csDMARD vs − 0.19 (0.06) with placebo+csDMARD. Changes in SF-36 PCS and MCS, FACIT-Fatigue, WPAI, and PtGA tended to favor filgotinib over PBO, MTX, and ADA. Greater proportions of patients experienced clinically meaningful differences with either dosage of FIL in combination with csDMARDs (including MTX) and with FIL200 monotherapy vs comparators. Conclusions Filgotinib provided improvements in PROs across patient populations. These findings suggest filgotinib can be an effective treatment option for patients with insufficient response to MTX or bDMARDs and patients who are MTX-naïve. Trial registration ClinicalTrials.gov, FINCH 1, NCT02889796, first posted September 7, 2016; FINCH 2, NCT02873936, first posted August 22, 2016, retrospectively registered; FINCH 3, NCT02886728, first posted September 1, 2016, retrospectively registered.

Medical Burnout

The WHO defines burnout as an inadequate response to chronic workplace stress, with emotional exhaustion, depersonalization, and reduced professional efficacy. Its growing incidence among physicians may adversely affect their personal and professional lives. Mindfulness aims to reach a state of consciousness in which one's attention is purposefully focused on the present. This chapter uses a narrative review of articles published between 2015 and 2019, with the MeSH terms “Burnout,” “Professional,” “Mindfulness,” and “Health Personnel.” Sixty-six articles were obtained, of which one meta-analysis, two systematic reviews, and two randomized clinical trials (RCT) met the inclusion criteria. All studies showed some degree of burnout improvement, more statistically significant as regards emotional exhaustion. One RCT also showed a reduction in heart rate. Available evidence suggests that mindfulness may improve physicians' well-being, mental health, and resilience, asserting itself as a possible coping strategy for burnout, namely regarding emotional exhaustion.

Systemic lupus erythematosus: challenges of early detection

The article presents a clinical case of such difficult for detection disease assystemic lupus erythematosus (SLE), which is characterized by atypical debut options, rapid development of complications, inadequate response to therapy. It is emphasized that the first clinical manifestations of the disease are the most important for its timely diagnosis, beginning of treatment and prevention of complications. The study concludes that mistakes in the diagnosis, late beginning of treatment may be related to the absence of SLE awareness among physicians.

Non-Simultaneous Bilateral Ischemic Optic Neuropathy Related to High Altitude and Airplane Flight in a Patient with Cerebral Small Vessel Disease

Non-arteritic anterior ischemic optic neuropathy (NA-AION) is considered the most frequent type of acute optic neuropathy. A 61-year-old woman presented with a NA-AION in her right eye within 24 h following an airplane flight. One year later, after driving for 10 days with a daily accumulated altitude of 1500 m, she developed a NA-AION in her left eye. Systemic disorders were investigated, and cerebral small vessel disease was observed via cranial computed tomography. An inadequate response to hypoxia, in a patient with individual susceptibility, could lead to reduced blood supply to the optic nerve head, which could represent an underlying cause of NA-AION.