Atrial fibrillation and QT prolongation after a single dose of hydroxychloroquine / Fibrilación auricular y prolongación del QT después de una dosis única de hidroxicloroquina

Non-antiarrhythmic drugs may induce QT-prolongation and increase the risk of arrhythmias. Recent studies have determined that there is a risk of atrial fibrillation (AF) due to QT prolongation. We report a case of FA associated to QT prolongation secondary to a single dose of hydroxychloroquine (HCQ) in an 83-years-old polymedicated patient admitted to our hospital due to SARS-CoV-2 infection. Quetiapine was prescribed as regular medicine after admission and a 5-days oral HCQ regimen was started for COVID-19. Thirty minutes after HCQ loading dose, FA was reported on electrocardiogram (EKG). COVID-19 treatment is leading to use off-label drugs that may generate adverse effects. It should be considered that drugs that induce QT prolongation may be triggers for atrial arrhythmias. There is not any report of sudden onset of increased QT interval with associated arrythmia after a single dose of HCQ, even in a short course treatment. (AU)

Los fármacos no antiarrítmicos pueden inducir la prolongación del intervalo QT y aumentar el riesgo de arritmias. Estudios recientes han determinado que existe riesgo de desarrollar fibrilación auricular (FA) asociada a la prolongación del intervalo QT. Presentamos un caso de FA asociado a prolongación del QT secundario a una dosis única de hidroxicloroquina (HCQ) en una paciente polimedicada de 83 años ingresada en nuestro hospital por infección por SARS-CoV-2. A la paciente se le prescribió quetiapina como parte de su medicamento habitual al ingreso y se inició tratamiento frente a COVID-19 basado en HCQ oral. Treinta minutos tras la dosis de carga de HCQ, se informó FA en el electrocardiograma (ECG). El tratamiento de COVID-19 está llevando al uso de medicamentos no aprobados que pueden generar efectos adversos. Además, debe considerarse que los fármacos que inducen la prolongación del QT pueden desencadenar arritmias auriculares. No se han reportado casos de aparición repentina de aumento del intervalo QT con arritmia asociada después de una dosis única de HCQ. (AU)

Acute seizure crisis after an unexpected sudden hypomagnesemia / Crisis convulsiva aguda después de una hipomagnesemia repentina inesperada

Hypomagnesemia, one of the most common underdiagnosed metabolic disorders in patients admitted to Postoperative Intensive Care. It is associated with presence of hypocalcemia, hypokalemia, and alkalosis. Severe magnesium deficiency can trigger life-threatening cardiac and neurological disorders however those clinical effects have not been reported immediately after surgery or magnesium infusion cessation. We present a case of women who had several switch-off episodes and generalized sudden seizures secondary to hypomagnesemia without any metabolic disturbances, even after replenishing magnesium levels. It underlines the importance, of continuous patient´s motorization who undergoes intestinal elective surgery and gene screening. Although this side effect has been reported, evidence not showed the immediacy of our case and different course than expected due to concomitant electrolytes disturbances were not found. Magnesium deficiency should be taken in patients undergoing elective bowel surgery with greater resection than 50 centimeters. This deficiency may occur as single electrolyte disturbance with sudden onset. (AU)

La hipomagnesemia es uno de los trastornos metabólicos infradiagnosticados más frecuentemente en pacientes ingresados en cuidados intensivos postoperatorios. Se asocia con la presencia de hipocalcemia, hipopotasemia y alcalosis. La deficiencia severa de magnesio puede desencadenar trastornos cardíacos y neurológicos potencialmente mortales, sin embargo, esos efectos clínicos no han sido identificados de una manera inmediata tras la cirugía o el cese de la infusión de magnesio. Presentamos el caso de una mujer que tuvo varios episodios de desconexión y crisis comiciales repentinas generalizadas secundarias a hipomagnesemia, sin alteraciones metabólicas, incluso después de reponer los niveles de magnesio. Casos como el que presentamos, destaca la importancia de la motorización continua del paciente sometido a cirugía intestinal electiva y un cribado genético. Aunque este efecto secundario ha sido reportado, la evidencia no mostró la inmediatez de nuestro caso y no se encontró un curso diferente al esperado debido a alteraciones electrolíticas concomitantes. La deficiencia de magnesio debe tomarse en serio en pacientes sometidos a cirugía intestinal electiva con resección mayor de 50 centímetros. Esta deficiencia puede ocurrir como una alteración electrolítica única con inicio repentino. (AU)

Solución de St Marks como alternativa al manejo de la hiponatremia en la fístula ileal / St Marks solution as an alternative to the management of hyponatremia in ileal fistula

Las fístulas, especialmente las de alto débito, frecuentemente precisan hidratación y reposición electrolítica agresiva, destacando las pérdidas de sodio como principal complicación hidroelectrolítica.Varón de 53 años intervenido en julio de 2017 y que en noviembre 2018 ingresó para reconstrucción del tránsito intestinal. Tras varias intervenciones quirúrgicas apareció una fístula pioestercoracea de alto débito a nivel de íleo. El manejo de la fístula fue conservador con nutrición parenteral total individualizada lográndose balance hidroelectrolítico óptimo. Posteriormente el paciente perdió tanto el acceso venoso central como los periféricos, siendo imposible la canalización de una vía periférica en varios días. Durante este periodo el paciente desarrolló una hiponatremia severa que desde el servicio de Farmacia fue abordada por la vía oral con una solución de hidratación específica, como la solución de St Marks, que se caracteriza por su alto contenido en sodio y bajo en potasio para evitar hiperpotasemias que pueden dar lugar en estos pacientes. Con el tratamiento instaurado se logró recuperar las cifras de natremia evitando complicaciones neurológicas hasta que finalmente se canalizó una vía periférica. En nuestro paciente esta solución resultó ser efectiva logrando remontar drásticamente las cifras de natremia cercana a valores normales. Así pues, la solución de St Marks puede ser una alternativa a la vía intravenosa cuando no esté disponible o ser incluso complementaria a ésta. (AU)

Fistulas, especially those with high output, frequently require hydration and aggressive electrolyte replacement, highlighting sodium losses as the main hydroelectrolytic complication.53-year-old man who underwent surgery in July 2017 and who was admitted in November 2018 for intestinal transit reconstruction. After several surgical interventions, a high-output piostercoraceous fistula appeared at the ileus level. Management of the fistula was conservative with individualized total parenteral nutrition, achieving optimal fluid and electrolyte balance. Subsequently, the patient lost both the central and peripheral venous access, being several days without vascular access. During this period, the patient developed severe hyponatremia that the Pharmacy service treated orally with a specific hydration solution, St Marks’s solution, which is characterized by its high sodium and low potassium content to avoid hyperkalemias that can give rise in these patients. With the established treatment, it was possible to recover the levels of natraemia avoiding neurological complications until finally peripheral venous catheterization was placed. In our patient, this solution turned out to be effective, managing to drastically raise the levels of natraemia close to normal values. Thus, the St Marks solution can be an alternative to the intravenous access when it is not available or even be complementary to it. (AU)

Cutaneous SCC with orbital invasion: case series.

Cutaneous squamous cell carcinoma (cSCC) is the most common tumour entity that grows secondarily into the orbital area, while basal cell carcinoma (BCC) is the most common periocular and eyelid tumour. Diagnostic delays are common and may increase post-treatment complications. The therapy is challenging and must be discussed at an interdisciplinary tumour board. We discuss four cases of cSCC with orbital invasion treated with immune-checkpoint inhibitors with variable responses.

Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

A multicentre study of naevus-associated melanoma vs. de novo melanoma, tumour thickness and body site differences.

BACKGROUND: Whether melanoma in histological contiguity with a naevus [naevus-associated melanoma (NAM)] is distinctly different from melanoma arising de novo remains unclear. OBJECTIVES: To determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours. METHODS: We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015. RESULTS: In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n = 5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70 years) when located on the head/neck [odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55-8·46], the trunk (OR 1·82, 95% CI 1·40-2·36) or the upper extremity (OR 1·69, 95% CI 1·14-2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03-1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14-4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM. CONCLUSIONS: Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B-rapidly accelerated fibrosarcoma-mutated advanced melanoma.

BACKGROUND: B-rapidly accelerated fibrosarcoma (BRAF) inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF-mutated melanoma patients. So far, the range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib). OBJECTIVE: The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib. METHODS: Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature. RESULTS: The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n = 24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug-induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n = 25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n = 49) were palmoplantar hyperkeratosis (10%). CONCLUSION: Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination of encorafenib and binimetinib is well tolerated and induces few cutaneous adverse events.

Successful retreatment with combined BRAF/MEK inhibition in metastatic BRAFV600-mutated melanoma.

BACKGROUND: The combination treatment with BRAF and MEK inhibitors is amongst the current standard of care for stage IIIC/IV BRAF-mutated melanoma. However, therapeutic options are limited once patients have progressed upon both targeted and immunotherapy. OBJECTIVE: To investigate whether retreatment with BRAF and MEK inhibitor combination is an option for patients with metastatic BRAF-mutated melanoma upon previous progression on kinase inhibitors. METHODS: Two patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF and MEK inhibitor combination after progression on targeted therapy and subsequent immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies. RESULTS: Both patients responded to retreatment. Responses were limited to a few months and associated with a considerable increase in quality of life. CONCLUSION: Retreatment with BRAF and MEK inhibitors may present a feasible treatment option upon progression on both kinase inhibitors and immunotherapy, and should be considered when all other treatment options have been exhausted.

Developments in targeted therapy in melanoma.

Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF- and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.

A prospective clinical trial to assess lapatinib effects on cutaneous squamous cell carcinoma and actinic keratosis.

BACKGROUND: Antiepidermal growth factor receptor (EGFR)-targeted therapy is widely used in many epithelial cancer types. We investigated lapatinib effects on cutaneous squamous cell carcinoma (cSCC) scheduled for resection and in coexisting precursor lesions (actinic keratosis (AK) and Bowen's disease (BD)) in a phase 2 mode of action clinical trial including a histological workup of the cSCC. PATIENTS AND METHODS: We initiated a prospective single-centre, open-label, non-controlled clinical study with translational intentions to investigate changes in size and histopathological features in cSCC after a 14-day period of neoadjuvant lapatinib therapy at a dose of 1500 mg/day prior to surgery, to quantify the impact on AK and BD in the same patient after 56 days and to evaluate the tolerability in patients with cSCC and precursor lesions. RESULTS: 10 immunocompetent male patients were included with a mean age of 73 years (range 59-87). 8 patients were treated with the study medication lapatinib 1500 mg/day for a total duration of 56 days according to the protocol and were available for full analysis, whereas 2 patients had to discontinue treatment during the first 2 weeks because of adverse events (diarrhoea, pancreatitis). Tolerability was acceptable with only 1 related grade III adverse event. A reduction in tumour size of cSCC was documented in 2 of 8 evaluable patients after 14 days of treatment. The mean regression of captured precursor lesions was 30% after 56 days of treatment and 36% 28 days after therapy cessation. CONCLUSIONS: Short-term lapatinib resulted in a cSCC tumour reduction in 2 of 8 patients. In addition, there was a clinically documented reduction of AK in 7 of 8 patients encouraging larger clinical trials, especially in high-risk patients with cSCC such as organ transplant recipients. TRIAL REGISTRATION NUMBER: NCT0166431.

An exploratory study investigating the metabolic activity and local cytokine profile in patients with melanoma treated with pazopanib and paclitaxel.

BACKGROUND: There is a medical need for new drugs in patients with BRAF wild-type metastatic melanoma. Pazopanib is a multitarget tyrosine kinase inhibitor with antitumour and antiangiogenic activity. OBJECTIVES: The primary aim was to investigate the metabolic response to pazopanib monotherapy and pazopanib plus paclitaxel in patients with BRAF wild-type melanoma. Secondary end points were the early cytokine and chemokine profiles and histological findings. METHODS: Pazopanib (400 mg twice daily) was administered orally from days 1 to 10 and from days 14 to 70. An intravenous infusion with paclitaxel (150 mg m-2 body surface) was administered on days 14, 35 and 56. Metabolic response evaluation was performed before treatment, after treatment with pazopanib (day 10) and after treatment with pazopanib and paclitaxel (day 70). Skin biopsy of metastatic tissue for chemokine and cytokine expression analysis and histology and immunohistochemistry (CD68, CD163) evaluation, and blood samples were taken at the same time points. RESULTS: Two patients failed screening and 17 were dosed. Of 67 adverse events, nine (13%) were grade 3 or 4. Five of 14 evaluable patients had a partial metabolic response at day 10 under pazopanib monotherapy. The response rate at day 70 under combined pazopanib-paclitaxel treatment was 0%. Immunohistochemistry revealed an increase of M2-like macrophages in nonresponders compared with responders. We observed a significant upregulation of five cytokines (CXCL1, CXCL2, CXCL13, CCL22 and SPP1) in responding vs. nonresponding lesions. Overall, the median progression-free survival was 70 days (range 5-331), which did not differ significantly between responders (148 days) and nonresponders (70 days, P = 0·17). CONCLUSIONS: In this patient population pazopanib efficacy was limited. Response is associated with low M2-like macrophage density and increased expression of several chemokines.

Efficacy and safety of oral alitretinoin in severe oral lichen planus--results of a prospective pilot study.

BACKGROUND: Patients with severe oral lichen planus refractory to standard topical treatment currently have limited options of therapy suitable for long-term use. Oral alitretinoin (9-cis retinoic acid) was never systematically investigated in clinical trials, although case reports suggest its possible efficacy. OBJECTIVES: To assess the efficacy and safety of oral alitretinoin taken at 30 mg once daily for up to 24 weeks in the treatment of severe oral lichen planus refractory to standard topical therapy. METHODS: We conducted a prospective open-label single arm pilot study to test the efficacy and safety of 30 mg oral alitretinoin once daily for up to 24 weeks in severe oral lichen planus. Ten patients were included in the study. Primary end point was reduction in signs and symptoms measured by the Escudier severity score. Secondary parameters included pain and quality of life scores. Safety parameters were assessed during a follow-up period of 5 weeks. RESULTS: A substantial response at the end of treatment, i.e. >50% reduction in disease severity measured by the Escudier severity score, was apparent in 40% of patients. Therapy was well tolerated. Adverse events were mild and included headache, mucocutaneous dryness, musculoskeletal pain, increased thyroid-stimulating hormone and dyslipidaemia. CONCLUSIONS: Alitretinoin given at 30 mg daily reduced disease severity of severe oral lichen planus in a substantial proportion of patients refractory to standard treatment, was well tolerated and may thus represent one therapeutic option for this special group of patients.

Prognostic relevance of lactate dehydrogenase and serum S100 levels in stage IV melanoma with known BRAF mutation status.

BACKGROUND: Activating mutations of BRAF provide an important treatment target in patients with melanoma. The prognostic role of several biochemical markers in relation to mutation status is not clear. OBJECTIVES: To analyse the prognostic significance of BRAF mutation in patients with melanoma and correlate it to different markers. METHODS: In total, 162 patients with stage IV melanoma and known BRAF mutation status were included. Clinical, histopathological and laboratory information was collected and compared between patients with BRAF mutant (BRAFm) and wild-type (BRAFwt) melanoma at the time of first distant metastasis. RESULTS: In total, 88 patients (54%) had BRAFm melanoma (V600E/V600K). At the first distant metastasis, S100B levels in BRAFm patients were more frequently elevated (P = 0·01) and significantly higher (P = 0·02). Median overall survival (mOS) was significantly longer in BRAFwt patients with normal compared with patients with elevated S100B levels (P < 0·01). In BRAFm melanoma, elevated S100B levels showed no prognostic influence (P = 0·18). Elevated lactate dehydrogenase (LDH) levels had a significantly negative impact on mOS in both groups. mOS was increased for BRAFm patients treated with a BRAF inhibitor (BRAFi) compared with BRAFm patients not receiving BRAFi (P = 0·01). No difference in mOS between BRAFm patients who did not receive BRAFi treatment and BRAFwt patients was observed. CONCLUSIONS: Better mOS was observed in BRAFm patients treated with BRAFi. BRAFm patients not treated with BRAFi show similar survival curves to BRAFwt patients. Elevated LDH is a BRAF-independent prognostic parameter; S100B has prognostic significance in BRAFwt melanoma only.