Case report: A case of metastatic BRAFV600-mutated melanoma with heart failure treated with immune checkpoint inhibitors and BRAF/MEK inhibitors.

Background: Novel therapies, immune checkpoint inhibitors (ICIs), and BRAF/MEK inhibitors (BRAFi/MEKi) provide unprecedented survival benefits for patients with advanced melanoma. However, the management of drug-induced adverse events is problematic for both agents and, although rare, can cause serious cardiac dysfunction. Case report: A 42-year-old male patient with no significant medical history noticed a fading dark brown patch on his left anterior chest, which had been there for 20 years, after his second coronavirus disease 2019 (COVID-19) vaccination. The left axillary lymph node became swollen one week after a third booster vaccination. Thinking of it as an adverse reaction to the vaccine, but the swelling increased, so he visited a hospital. The patient presented with a brown macule with depigmentation on the left anterior chest and a 13 cm left axillary mass. A biopsy of the axillary mass showed a metastatic malignant melanoma. Positron emission tomography (PET) showed an accumulation only in the axillary lymph nodes. One month after the initial diagnosis, the axillary mass had further enlarged. In addition, pleural effusion, ascites, difficulty breathing, and systemic edema appeared, and he was diagnosed with heart failure (NYHA class III). Echocardiography showed an ejection fraction of 52% and electrocardiogram (ECG) showed no abnormal findings. Though it was (a life-threatening instead of the life-threatening) the life-threatening condition, we determined that the symptoms were associated with the current disease. Then nivolumab (nivo) plus ipilimumab (ipi) was initiated after explaining the risk of cardiac dysfunction associated with drug use to the patient. After initiation of ICIs, treatment was switched to BRAFi/MEKi (encorafenib/vinimetinib) after the patient tested positive for BRAF V600E. After one month of treatment, the tumor shrank significantly and achieved a complete remission after four months. Furthermore, as the tumor shrank, the patient's heart failure improved, and he was able to continue treatment without serious drug-induced cardiotoxicity. Conclusion: Both ICI and BRAFi/MEKi carry a risk of cardiac dysfunction. However, without any underlying cardiac disease or severe cardiac dysfunction, their administration should not necessarily be excluded if careful follow-up is provided.

Efficacy and safety of adapalene gel as a reactive treatment for cetuximab-induced skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck: A historical cohort comparison study.

INTRODUCTION: Despite the common occurrence of cetuximab (Cmab)-induced skin toxicity, management strategies are not well established. The traditional mainstay method consists of topical steroids, which, if used excessively, may give rise to other concerns. Alternatively, adapalene can activate epidermal growth factor receptor pathways to potentially alleviate these toxicities. METHODS: We prospectively studied 31 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) who were eligible to use adapalene gel as a reactive treatment for topical steroid-refractory skin toxicity. For comparison, we retrospectively reviewed 99 patients with R/M SCCHN (historical control cohort) whose skin toxicity was mainly treated with topical steroids. We compared the frequency and severity of Cmab-induced skin toxicity, Cmab therapy status (e.g., dose modification), side effects caused by topical steroids and adapalene gel itself, and other medical interventions. RESULTS: Adapalene gel was used by eight patients (25.8%) in the prospective cohort. Patients in the historical control cohort more frequently required escalation of topical steroid potency (34.3% vs. 12.9%, p = 0.022). Although there was no statistically significant difference in the frequency of grade ≥3 facial skin rash and paronychia between the two cohorts, the prospective cohort showed a significantly shorter time to complete recovery from grade 2/3 paronychia (16 vs. 47 days, p = 0.017). Further, while no skin infections were observed in the prospective cohort, 13 patients in the historical control cohort developed skin infections, especially periungual infection (0% vs. 13.1%, p = 0.024). In addition, no patients in the prospective cohort received a dose reduction of Cmab due to skin toxicities, compared to 20 patients in the historical control cohort (0% vs. 20.2%, p = 0.003). No apparent adapalene gel-related side effects were observed. CONCLUSIONS: Adapalene gel may be an effective management option for topical steroid-refractory Cmab-induced skin toxicities and could improve compliance with Cmab therapy.

Efficacy of aluminum chloride in severe regorafenib-associated hand-foot skin reactions: a single-arm trial.

BACKGROUND: Regorafenib, a multikinase inhibitor, causes a high frequency of hand-foot skin reactions (HFSRs). The present study evaluated the efficacy of topical aluminum chloride, a perspiration suppressant, in reducing the severity of hand-foot skin reactions (HFSRs) caused by regorafenib. METHODS: The present single-arm study included patients with metastatic colorectal cancer receiving regorafenib. Aluminum chloride ointment was applied topically one week prior to the start of regorafenib treatment, and the observation period was 12 weeks. The primary endpoint was the incidence of regorafenib-related grade 3 HFSR. Secondary endpoints were the incidence of all grades of HFSR, time to any grade of HFSR, time to improvement from grade 2 or higher to grade 1 or lower, treatment discontinuation rate, treatment interruption rate or dosage reduction due to HFSR, and incidence of adverse effects of aluminum chloride. RESULTS: In total 28 patients were enrolled, and 27 patients were analyzed. The incidence of grade 3 HFSR was 7.4%, meeting the primary endpoint. The incidence of all grades of HFSR was 66.7%, and the median time to the occurrence of any grade of HFSR was 15 days. No patients discontinued or reduced the regorafenib dosage because of HFSR. The most common reason for the interruption of regorafenib therapy was liver dysfunction in nine patients (33%) and HFSR in three patients (11%). No serious adverse events related to aluminum chloride were observed. CONCLUSIONS: Aluminum chloride ointment, a drug commonly used in routine practice to treat hyperhidrosis, is safe to use, has no serious side effects, and may be effective in reducing the occurrence of severe, regorafenib-related HFSR. TRAIL REGISTRATION: ClinicalTrials.gov. identifier: jRCTs031180096, Registered on 25/01/2019.

Myocarditis associated with immune-checkpoint inhibitors diagnosed by cardiac magnetic resonance imaging.

Myocarditis associated with immune-checkpoint inhibitors (ICIs) is a rare, but critical adverse event. Although endomyocardial biopsy (EMB) is the standard for diagnosis of myocarditis, there is a possibility of false negatives due to sampling errors and local nonavailability of EMB, which may hamper the appropriate diagnosis of myocarditis. Therefore, an alternative criterion based on cardiac magnetic resonance imaging (CMRI) combined with clinical presentation has been proposed, but not emphasized sufficiently. We report a case of myocarditis after ICIs administration, which was diagnosed using CMRI in a 48-year-old male with lung adenocarcinoma. CMRI provides an opportunity to diagnose myocarditis during cancer treatment.

Rab32/38-Dependent and -Independent Transport of Tyrosinase to Melanosomes in B16-F1 Melanoma Cells.

B16-F1 melanoma cells have often been used as a model to investigate melanogenesis, but the evidence that melanosome biogenesis and transport occur by the same mechanisms in normal melanocytes and B16-F1 cells is insufficient. In this study, we established knockout B16-F1 cells for each of several key factors in melanogenesis, i.e., tyrosinase (Tyr), Hps4, Rab27A, and Rab32·Rab38 (Rab32/38), and then compared their phenotypes with the phenotypes of corresponding mutant mouse melanocyte cell lines, i.e., melan-c, melan-le, melan-ash, and Rab32-deficient melan-cht cells, respectively. The results showed that Tyr and Rab27A are also indispensable for melanin synthesis and peripheral melanosome distribution, respectively, in B16-F1 cells, but that Hps4 or its downstream targets Rab32/38 are not essential for Tyr transport in B16-F1 cells, suggesting the existence of a Rab32/38-independent Tyr transport mechanism in B16-F1 cells. We then performed comprehensive knockdown screening of Rab small GTPases and identified Rab10 and Rab24, previously uncharacterized Rabs in melanocytes, as being involved in Tyr transport under Rab32/38-null conditions. Our findings indicate a difference between the Tyr transport mechanism in melanocytes and B16-F1 cells in terms of Rab32/38-dependency and a limitation in regard to using melanoma cells as a model for melanocytes, especially when investigating the mechanism of endosomal Tyr transport.

Case Report: A Case of Trimethoprim/Sulfamethoxazole-Triggered Hypotensive Shock: Cytokine Release Syndrome Related to Immune Checkpoint Inhibitors and Drug-Induced Hypersensitivity Syndrome.

Currently, only a few reports exist on the cytokine release syndrome (CRS) as one of the severe immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Notably, it is very rare that grade 4 CRS related to ICI therapy overlaps with the drug-induced hypersensitivity syndrome (DiHS). A 46-year old woman with metastatic kidney cancer had grade 3 interstitial pneumonitis induced by four cycles of combination therapy of anti-programmed death-1 and anti-cytotoxic T lymphocyte-4 antibodies after right cytoreductive nephrectomy. Prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) was started concomitantly with prednisolone therapy to treat the interstitial pneumonitis. She developed hypotensive shock when reducing the dosage of prednisolone, and required intubation and ventilation using vasopressors at the intensive care unit. She subsequently exhibited prominent leukocytosis and an increased level of C-reactive protein, suggesting markedly increased cytokine levels. Interestingly, facial edema and erythema increased in association with pyrexia, leukocytosis, liver dysfunction, and renal failure, suggesting that she developed DiHS. She received hemodialysis three times, a plasma exchange, and anti-interleukin-6 therapy to treat severe renal dysfunction, a thrombotic thrombocytopenic purpura-suspected condition, and possible grade 4 CRS, respectively. Although these therapies did not elicit sufficient effects, high-dose administration of intravenous immunoglobulin was successful. With steroid mini-pulse therapy and the subsequent administration of prednisolone, she recovered successfully. To the best of our knowledge, this is the first report that ICIs and TMP/SMX can induce hypotensive shock accompanied with CRS and DiHS during immunosuppressive therapy for an irAE. Importantly, the prophylactic administration of TMP/SMX should be performed cautiously to avoid severe drug reactions such as CRS or DiHS.

[Successful treatment with silver nitrate chemical cauterization for paronychia and granulation in a patient with chronic lymphocytic leukemia undergoing ibrutinib therapy].

A 72-year-old man with leukocytosis, anemia, and lymphadenopathy was diagnosed with chronic lymphocytic leukemia (CLL) in August 2017 and was carefully monitored in a "watch-and-wait" manner until it became an "active disease." Ibrutinib (IBR) was initiated orally in July 2018 at a dose of 420 mg/day after disease progression due to chromosome 17p deletion (del 17p). The patient showed partial response after transient lymphocytosis while on IBR treatment. IBR induces paronychia and skin disorder due to the disruption of disulfide bonds between cysteine and inhibition of epidermal growth factor receptor due to the off-target effect. This results in reduced quality of life. In February 2019, paronychia (grade 1) developed in the patient's right foot's first toe; hence, topical gentamicin and taping therapy were performed. However, the symptoms persisted without any improvements. In July 2019, paronychia/granulation (grade 2) was aggravated and successfully treated with silver nitrate chemical cauterization and taping therapy. The patient was continuously treated with 420 mg/day IBR without dose reduction or discontinuation, resulting in successful disease control of CLL with del 17p.

Analysis of sweating by optical coherence tomography in patients with palmoplantar hyperhidrosis.

Optical coherence tomography (OCT) is a high-resolution tomographic imaging technique that uses optical interference. OCT has enabled the non-invasive three-dimensional analysis of individual acrosyringia in the stratum corneum in human skin. However, no report on the measurement of sweating by OCT using clinical data from humans has been published to date. Twenty patients with hyperhidrosis and twenty healthy subjects were included in this study. Imaging of acrosyringia in the stratum corneum using OCT and measurement of the sweat rate using the ventilated capsule method were performed simultaneously. The hand grip exercise of the right hand was used as a load to induce sweating, and the left fingertip was measured before and after the exercise load. Five acrosyringia were extracted from each OCT image, and their volumes were calculated. The mean volume of each acrosyringium was divided by the thickness of the stratum corneum to calculate the mean cross-sectional area of the acrosyringium. Furthermore, the number of sweat droplets on the skin surface was measured. The mean cross-sectional area of acrosyringia after the load increased both in patients with hyperhidrosis and in healthy subjects (P < 0.001). The mean cross-sectional area of acrosyringia of patients with hyperhidrosis was larger than that of healthy subjects (P < 0.001). The mean cross-sectional area of acrosyringia and the sweat rate showed a positive correlation before and after the load (r = 0.88 to 0.91). The number of droplets also increased after the load (P < 0.001), and the number of droplets in patients with hyperhidrosis was higher than in healthy subjects (P < 0.001). Our study has shown that acrosyringia in the stratum corneum increase in proportion to the sweat rate. OCT is a rigorous and valuable method that can measure and quantify sweating in the body without being an invasive procedure.

Systemic steroid treatment can desensitize the skin reaction due to regorafenib in a recurrence colorectal cancer patient.

Oral intake of regorafenib has been shown to have survival benefits in patients with metastatic colorectal cancer progressing on standard therapies. However, because of adverse effects, the patients sometimes cannot continue treatment with regorafenib. Currently, there is no established supportive therapy that can be performed to aid in continuing regorafenib intake under these problematic conditions. We report the case of a 59-year-old Japanese woman diagnosed with recurrence after curative operation for sigmoid colon cancer (T3N2aM0, Stage IIIC). Despite undergoing multiple lines of standard chemotherapy, disease control could not be maintained. Consequently, regorafenib was started as a late-line treatment. However, after 2 weeks, the patient experienced regorafenib-induced serious erythema multiforme; thus, regorafenib was discontinued and oral prednisolone was started. Regorafenib administration was resumed when the adverse effects resolved and prednisolone was stopped, but skin rash rapidly reappeared. Prednisolone treatment was reintroduced, which cured the rash; thus, after the third attempt to administer regorafenib, prednisolone was continuously administered. There was no relapse of the rash under prednisolone administration, and the patient received a total of 13 courses of regorafenib. Moreover, the metastatic lesions that had started to regrow at the end of the regorafenib therapy showed good response to the rechallenge chemotherapy of folinic acid, fluorouracil, and irinotecan therapy with panitumumab. The sequence of therapies possibly had a positive impact on the patient's long survival of 30 months after the regorafenib treatment. Systemic administration of steroid is considered as a promising option as a supportive therapy for continuing regorafenib treatment in patients experiencing a severe skin rash.

Arabidopsis PARC6 Is Critical for Plastid Morphogenesis in Pavement, Trichome, and Guard Cells in Leaf Epidermis.

Recently, a recessive Arabidopsis thaliana mutant with abundant stromules in leaf epidermal pavement cells was visually screened and isolated. The gene responsible for this mutant phenotype was identified as PARC6, a chloroplast division site regulator gene. The mutant allele parc6-5 carried two point mutations (G62R and W700stop) at the N- and C-terminal ends of the coding sequence, respectively. Here, we further characterized parc6-5 and other parc6 mutant alleles, and showed that PARC6 plays a critical role in plastid morphogenesis in all cell types of the leaf epidermis: pavement cells, trichome cells, and guard cells. Transient expression of PARC6 transit peptide (TP) fused to the green fluorescent protein (GFP) in plant cells showed that the G62R mutation has no or little effect on the TP activity of the PARC6 N-terminal region. Then, plastid morphology was microscopically analyzed in the leaf epidermis of wild-type (WT) and parc6 mutants (parc6-1, parc6-3, parc6-4 and parc6-5) with the aid of stroma-targeted fluorescent proteins. In parc6 pavement cells, plastids often assumed aberrant grape-like morphology, similar to those in severe plastid division mutants, atminE1, and arc6. In parc6 trichome cells, plastids exhibited extreme grape-like aggregations, without the production of giant plastids (>6 µm diameter), as a general phenotype. In parc6 guard cells, plastids exhibited a variety of abnormal phenotypes, including reduced number, enlarged size, and activated stromules, similar to those in atminE1 and arc6 guard cells. Nevertheless, unlike atminE1 and arc6, parc6 exhibited a low number of mini-chloroplasts (< 2 µm diameter) and rarely produced chloroplast-deficient guard cells. Importantly, unlike parc6, the chloroplast division site mutant arc11 exhibited WT-like plastid phenotypes in trichome and guard cells. Finally, observation of parc6 complementation lines expressing a functional PARC6-GFP protein indicated that PARC6-GFP formed a ring-like structure in both constricting and non-constricting chloroplasts, and that PARC6 dynamically changes its configuration during the process of chloroplast division.

Predictive Value of Cetuximab-Induced Skin Toxicity in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and NECK.

Background: Skin toxicity is a common adverse event during cetuximab (Cmab) treatment. However, few reports have investigated the correlation between skin toxicity and the efficacy of Cmab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Methods: We retrospectively reviewed 112 R/M SCCHN patients who received palliative chemotherapy with Cmab. Main eligibility criteria included primary disease in the oral cavity, hypopharynx, nasopharynx, oropharynx, or larynx; no prior history of EGFR-directed therapy; receipt of Cmab plus chemotherapy as first-line therapy for recurrent or metastatic disease; and follow-up for more than 90 days. We analyzed the time to first occurrence and time of maximum grade skin toxicity, and its predictive value with regard to treatment efficacy. Results: After a median follow-up of 393 days (range 109-1501 days), 105 (94%) and 20 (18%) patients had skin toxicity of any grade and grade 3, respectively. Among them, 8 patients with grade 3 acneiform rash, skin rash, or paronychia within 90 days after treatment initiation ("early skin toxicity") had improved progression-free survival (PFS) (log-rank test, P = 0.045; 2-year PFS, 25.0 vs. 2.9%) and overall survival (OS) (log-rank test, P = 0.023, 2-year OS, 50.0 vs. 14.4%) compared with those with < grade 3 toxicity. A greater proportion of patients with early skin toxicity than patients without this toxicity could proceed with Cmab maintenance (88 vs. 44%, P = 0.021). Multivariate analysis identified early skin toxicity as an independent predictor of better PFS (hazard ratio [HR] = 0.363, 95% confidence interval [CI] 0.142-0.924, P = 0.034) and OS (HR = 0.187, 95% CI: 0.045-0.781, P = 0.022). Conclusion: Grade 3 Cmab-induced skin toxicity within 90 days was associated with better survival in R/M SCCHN. Effective rash management therefore seems necessary to realize the benefit of Cmab treatment.