Efficacy of salvage therapies for advanced acral melanoma after anti-PD-1 monotherapy failure: a multicenter retrospective study of 108 Japanese patients.

Background: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF. Patients and methods: The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS (p = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups. Conclusion: Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma.

Efficacy comparison between anti-PD-1 antibody monotherapy and anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy for advanced acral melanoma: A retrospective, multicenter study of 254 Japanese patients.

BACKGROUND: Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM. METHODS: This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups. RESULTS: In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P < 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002). CONCLUSIONS: The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM.

A Case of Adult-Onset Eccrine Angiomatous Hamartoma-The Comparison with Epithelioid Hemangioma.

Eccrine angiomatous hamartoma (EAH) is a relatively rare benign skin disease characterized by the proliferation of eccrine sweat glands associated with capillary hemangioma and the proliferation of other skin elements such as adipose tissue, hair, and epidermis. The onset of the disease is usually at birth or in childhood and tends to occur in the extremities of females, but it occurred in an adult male in this case. The patient was a 72-year-old man with a 12 × 12 mm light brown, elastic, slightly firm skin nodule on the flexor aspect of his right forearm. A biopsy revealed enlargement of blood vessels, sweat glands, sweat ducts, and erector spongiosum with both lumen dilation and narrowing, leading to the diagnosis of EAH. The histopathological features of EAH include a marked proliferation of microvessels, epithelial-like changes in vascular endothelial cells (such as enlarged nuclei), and infiltration of inflammatory cells, mainly lymphocytes and plasma cells. In adult-onset cases, EAH can be clinically difficult to distinguish from epithelioid hemangioma (EH), which differs in the predominance of microvascular proliferation and the presence of eosinophils in the infiltrating inflammatory cells. It can also be distinguished from EAH by the negative results of S100 and anti-EMA in immunohistological staining. In the current cases, we were able to differentiate the two cases from characteristic findings on HE staining.

Progressive vitiligo induced by recurrent melanoma.

A woman had undergone excision for primary melanoma of the left heel and dissection of groin lymph nodes. The recurrent tumor on the lateral left lower leg developed six months ago and the depigmented plaques spread extensively on the left lower limb. The depigmented macules were localized to the left lower limb and were not seen in other areas. Although the left groin lymph node had been dissected, the local immune environment of anti-tumor immunity was preserved. The cause of melanoma-associated vitiligo is regarded to be anti-tumor autoimmune mediated, and this phenomenon is recently recognized during the therapy with immune checkpoint inhibitors in the treatment of stage III and IV melanoma.

Successful Treatment of Ulcerative-Type Pyoderma Gangrenosum with a Combination Therapy of Oral Prednisolone, Vacuum-Assisted Closure, and Skin Grafting.

Pyoderma gangrenosum (PG) is a relatively rare inflammatory skin disease that progressively causes necrotic ulceration mainly on the lower extremities and trunk. Systemic corticosteroid is considered a first-line treatment for PG as it facilitates wound healing; however, several cases where tumor necrosis factor-α inhibitors, adalimumab and infliximab, were administered showed good response. For intractable PG with a large ulcer or problematic epithelization, chemical or mechanical debridement of necrotic tissue in combination with skin grafting may be necessary to promote wound healing. Our report presents a case of intractable ulcerative PG requiring oral prednisolone and skin grafting. Although mechanical debridement was performed, granulation was poor; therefore, after the PG activity became quiescent, we utilized a vacuum-assisted closure (VAC) system to promote granulation and adaptation of the grafted skin. Although more cases are required for a definitive conclusion, the VAC system may be a choice for PG with large ulcers.

Six-dimensional dynamic tractography atlas of language connectivity in the developing brain.

During a verbal conversation, our brain moves through a series of complex linguistic processing stages: sound decoding, semantic comprehension, retrieval of semantically coherent words, and overt production of speech outputs. Each process is thought to be supported by a network consisting of local and long-range connections bridging between major cortical areas. Both temporal and extratemporal lobe regions have functional compartments responsible for distinct language domains, including the perception and production of phonological and semantic components. This study provides quantitative evidence of how directly connected inter-lobar neocortical networks support distinct stages of linguistic processing across brain development. Novel six-dimensional tractography was used to intuitively visualize the strength and temporal dynamics of direct inter-lobar effective connectivity between cortical areas activated during each linguistic processing stage. We analysed 3401 non-epileptic intracranial electrode sites from 37 children with focal epilepsy (aged 5-20 years) who underwent extra-operative electrocorticography recording. Principal component analysis of auditory naming-related high-gamma modulations determined the relative involvement of each cortical area during each linguistic processing stage. To quantify direct effective connectivity, we delivered single-pulse electrical stimulation to 488 temporal and 1581 extratemporal lobe sites and measured the early cortico-cortical spectral responses at distant electrodes. Mixed model analyses determined the effects of naming-related high-gamma co-augmentation between connecting regions, age, and cerebral hemisphere on the strength of effective connectivity independent of epilepsy-related factors. Direct effective connectivity was strongest between extratemporal and temporal lobe site pairs, which were simultaneously activated between sentence offset and verbal response onset (i.e. response preparation period); this connectivity was approximately twice more robust than that with temporal lobe sites activated during stimulus listening or overt response. Conversely, extratemporal lobe sites activated during overt response were equally connected with temporal lobe language sites. Older age was associated with increased strength of inter-lobar effective connectivity especially between those activated during response preparation. The arcuate fasciculus supported approximately two-thirds of the direct effective connectivity pathways from temporal to extratemporal auditory language-related areas but only up to half of those in the opposite direction. The uncinate fasciculus consisted of <2% of those in the temporal-to-extratemporal direction and up to 6% of those in the opposite direction. We, for the first time, provided an atlas which quantifies and animates the strength, dynamics, and direction specificity of inter-lobar neural communications between language areas via the white matter pathways. Language-related effective connectivity may be strengthened in an age-dependent manner even after the age of 5.

Reduction in Tumor Lesions and Exacerbation of Psoriatic Rash after Septic Shock in a Patient with Extramammary Paget's Disease.

We present a case of extramammary Paget's disease with bilateral inguinal lymph node metastasis treated by monthly docetaxel chemotherapy. He has also well-controlled psoriasis vulgaris for 20 years. One day after completing monthly chemotherapy, cellulitis by Group G Streptococcus occurred on both legs, resulting in septic shock and disseminated intravascular coagulation. During the infection, the tumor nodule volume and the exudate from the tumor decreased, and tumor markers carcinoembryonic antigen and cancer antigen 19-9 showed low values. Simultaneously, the psoriatic eruption reoccurred. We proposed that cytokine storm including tumor necrosis factor-alpha (TNF-α) during sepsis might have suppressed tumor lesions, and also TNF-α-dependent psoriatic rash appeared temporarily on his body.

Real-world efficacy of anti-PD-1 antibody or combined anti-PD-1 plus anti-CTLA-4 antibodies, with or without radiotherapy, in advanced mucosal melanoma patients: A retrospective, multicenter study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have a lower efficacy in mucosal melanoma (MUM) than in cutaneous melanoma. The use of combination treatments with radiotherapy (RT) to improve the efficacy in MUM, however, requires further investigation. METHODS: We retrospectively evaluated 225 advanced MUM patients treated with anti-PD-1 monotherapy (PD1; 115) or anti-PD-1 + anti-CTLA-4 combination therapy (PD1+CTLA4; 42) with or without RT (56 and 12, respectively). Treatment efficacy was estimated by determining the objective response rate (ORR) and survival rate with the Kaplan-Meier analysis. RESULTS: The baseline characteristics between the two groups in each ICI cohort were similar, except for Eastern Cooperative Oncology Group performance status in the PD1 cohort. No significant differences in ORR, progression-free survival (PFS), and overall survival (OS) were observed between the PD1 alone and PD1+RT groups in the PD1 cohort (ORR 26% versus 27%, P > 0.99; median PFS 6.2 versus 6.8 months, P = 0.63; median OS 19.2 versus 23.1 months, P = 0.70) or between the PD1+CTLA alone and PD1+CTLA4+RT groups in the PD1+CTLA4 cohort (ORR 28% vs 25%, P = 0.62; median PFS 5.8 versus 3.5 months, P = 0.21; median OS 31.7 versus 19.8 months, P = 0.79). Cox multivariate analysis indicated that RT in addition to PD1 or PD1+CTLA4 did not have a positive impact on the PFS or OS. CONCLUSIONS: A prolonged survival benefit with RT in combination with ICIs was not identified for advanced MUM patients, although RT may improve local control of the tumour and relieve local symptoms.

Whether to maintain or strengthen the treatment for pyoderma gangrenosum ulcerative type may depend on the response after two to four-week treatment intervention: The outcome of three cases with details clinical course.

Determining whether the treatment intensity needs to be increased or can be maintained at a constant level may be suggested after 2-4 weeks of treatment. The use of TNF-α inhibitor, removal of necrotic tissue, and skin grafting may promote epithelialization.

Outcome of combination therapy using BRAF and MEK inhibitors among Asian patients with advanced melanoma: An analysis of 112 cases.

BACKGROUND: As most clinical trials evaluating BRAF and MEK inhibitor combination therapy (B + Minh) have been conducted in Western countries, little is known about the effect of B + Minh among East Asian populations. MATERIAL AND METHODS: Data from patients with advanced melanoma treated using B + Minh (either dabrafenib + trametinib or encorafenib + binimetinib) were retrospectively collected from 16 institutes in Japan. Response rates, adverse events, patterns of failure and survival were analysed. RESULTS: We analysed 112 of 144 collected patient records and, of these, 14 had acral/mucosal melanoma. The response rate for the entire cohort was 75.0%. There were no statistical differences in response rates between acral/mucosal and cutaneous melanomas (64.3% versus 76.5%), whereas previous treatment using immune checkpoint inhibitors (ICIs) did not affect response (72.7% versus 73.9%) to B + Minh, response to ICI after B + Minh was only 20%. Patients who achieved complete response had the best overall survival rates at 24 months (94.7%). Elevated serum lactate dehydrogenase levels and 3 or more metastatic sites were independently associated with survival. The most common relapse site was the brain (17.9%). More than half of the patients (58.8%) experienced grade III/IV pyrexia. CONCLUSION: B + Minh was effective among Japanese patients with melanoma, including those with acral/mucosal melanoma. Factors associated with survival were similar to previous Western studies. B + Minh response was not affected by the previous use of ICI; however, vigilance against brain metastasis during B + Minh therapy is required as the brain was our most commonly encountered relapse site.

Regional abnormality of functional connectivity is associated with clinical manifestations in individuals with intractable focal epilepsy.

We explored regional functional connectivity alterations in intractable focal epilepsy brains using resting-state functional MRI. Distributions of the network parameters (corresponding to degree and eigenvector centrality) measured at each brain region for all 25 patients were significantly different from age- and sex-matched control data that were estimated by a healthy control dataset (n = 582, 18-84 years old). The number of abnormal regions whose parameters exceeded the mean + 2 SD of age- and sex-matched data for each patient were associated with various clinical parameters such as the duration of illness and seizure severity. Furthermore, abnormal regions for each patient tended to have functional connections with each other (mean ± SD = 58.6 ± 20.2%), the magnitude of which was negatively related to the quality of life. The abnormal regions distributed within the default mode network with significantly higher probability (p < 0.05) in 7 of 25 patients. We consider that the detection of abnormal regions by functional connectivity analysis using a large number of control datasets is useful for the numerical assessment of each patient's clinical conditions, although further study is necessary to elucidate etiology-specific abnormalities.

Results of the non-small cell lung cancer part of a phase III, open-label, randomized trial evaluating topical corticosteroid therapy for facial acneiform dermatitis induced by EGFR inhibitors: stepwise rank down from potent corticosteroid (FAEISS study, NCCH-1512).

PURPOSE: This FAEISS study was designed to confirm the superior efficacy of reactive topical corticosteroid strategies employing serially ranking-DOWN from very strong steroid levels for the treatment of facial acneiform rash induced by epidermal growth factor receptor (EGFR) inhibitors (EGFRIs), in comparison with strategies employing serially ranking-UP from weak steroid levels. This article reports the primary results of the non-small cell lung cancer (NSCLC) part of the trial. METHODS: Patients with EGFR-mutated advanced NSCLC treated with erlotinib or afatinib were enrolled in the first registration. All patients received preemptive therapy with oral minocycline and heparinoid moisturizer from the initiation of an EGFR inhibitor. Enrolled patients who developed facial acneiform rash within 2 weeks were randomized at second registration to either a ranking-UP (WEAK) group or a ranking-DOWN group. The primary endpoint was incidence of grade ≥ 2 facial acneiform rash over 8 weeks. RESULTS: Fifty-one patients were enrolled at the first registration and received EGFRIs (n = 30 for afatinib, n = 21 for erlotinib). However, 35 patients did not develop facial acneiform rash within 2 weeks; one patient discontinued preemptive treatment. Fifteen patients (29.4%) were enrolled in the second registration; nine were assigned to the WEAK group and six to the DOWN group. There was no significant difference in the incidence of grade ≥ 2 facial acneiform rash between the WEAK group (one patient, twice) and the DOWN group (one patient, twice; p = 0.8417). No patients developed severe facial acneiform rash within 10 weeks. CONCLUSION: In NSCLC patients who received EGFRIs, preemptive therapy of oral minocycline and heparinoid moisturizer reduced facial acneiform rash incidence. TRIAL REGISTRATION: UMIN000024113.

Voriconazole-Induced Squamous Cell Carcinoma after Hematopoietic Stem Cell Transplantation Showing Early-Stage Vascular Invasion.

Voriconazole is a triazole antifungal agent used for the prevention and treatment of fungal infections in immunocompromised patients. Prolonged voriconazole therapy may induce phototoxicity and lead to the development of malignant neoplasms of the epidermis, such as squamous cell carcinoma (SCC), especially in immunocompromised patients. We report a case of voriconazole-induced phototoxicity and SCC occurring after hematopoietic stem cell transplantation (HSCT) in a 56-year-old man with primary myelofibrosis. The patient developed chronic graft-versus-host disease (GVHD) post-transplantation and had been receiving long-term immunosuppressive treatment. A year after the initiation of voriconazole therapy for prophylaxis, he developed keratotic erythema, followed by SCC with vascular invasion after three years. A review of SCC in HSCT recipients suggests that the prolonged use of voriconazole is regarded as a risk for SCC after HSCT in patients with chronic GVHD on immunosuppressive therapy. Moreover, a histological examination of the completely resected tumor revealed vascular invasion in this case, although neither the clinical features nor the histological findings of the preoperative biopsy suggested invasive carcinoma. This case may partially explain why voriconazole-associated SCCs show a more aggressive clinical course than non-voriconazole SCCs do.

Neural dynamics during the vocalization of 'uh' or 'um'.

People occasionally use filler phrases or pauses, such as "uh", "um", or "y'know," that interrupt the flow of a sentence and fill silent moments between ordinary (non-filler) phrases. It remains unknown which brain networks are engaged during the utterance of fillers. We addressed this question by quantifying event-related cortical high gamma activity at 70-110 Hz. During extraoperative electrocorticography recordings performed as part of the presurgical evaluation, patients with drug-resistant focal epilepsy were instructed to overtly explain, in a sentence, 'what is in the image (subject)', 'doing what (verb)', 'where (location)', and 'when (time)'. Time-frequency analysis revealed that the utterance of fillers, compared to that of ordinary words, was associated with a greater magnitude of high gamma augmentation in association and visual cortex of either hemisphere. Our preliminary results raise the hypothesis that filler utterance would often occur when large-scale networks across the association and visual cortex are engaged in cognitive processing, including lexical retrieval as well as verbal working memory and visual scene scanning.

Non-invasive quantitative measures of qualitative grading effectiveness as the indices of acute radiation dermatitis in breast cancer patients.

BACKGROUND: Recent improvement of machinery evaluation for the skin changes in various therapies enabled us to evaluate fine changes quantitatively. In this study, we performed evaluation of the changes in radiation dermatitis (RD) using quantitative and qualitative methods, and verified the validity of the conventional qualitative assessment for clinical use. METHODS: Forty-three breast cancer patients received conventional fractionated radiotherapy to whole breast after breast-conserving surgery. Erythema, pigmentation and skin dryness were evaluated qualitatively, and biophysical parameters of RD were measured using a Multi-Display Device MDD4 with a Corneometer for capacitance, a Tewameter for transepidermal water loss (TEWL), a Mexameter for erythema index and melanin index. Measurements were performed periodically until 1 year. RESULTS: The quantitative manifestations developed serially from skin erythema followed by dryness and pigmentation. Quantitative measurements detected the effects of irradiation earlier than that of qualitative indices. However, the grades of the domains in RD by qualitative and quantitative assessment showed similar time courses and peak periods. However, no significant correlation was observed between the skin dryness grade and skin barrier function. In contrast to serial increase in pigmentation grades, melanin index showed initial decrease followed by marked increase with significant correlation with pigmentation grades. CONCLUSION: Subjectively and objectively measured results of RD were almost similar course and peak points through the study. Therefore, validity of the conventional qualitative scoring for RD is confirmed by the present quantitative assessments. Instrumental evaluations revealed the presence of modest inflammatory changes before radiotherapy and long-lasting skin dryness, suggesting indication of intervention for RD.

Aphasic status epilepticus of frontal origin treated by resective surgery.

Aphasic status epilepticus (SE) is a clinical entity of SE, but it has not been well recognized. We report a 43-year-old female with a chronic drug-resistant epilepsy with aphasic SE, treated by resective surgery. The patient showed long-lasting weekly episodes of hypokinesia, slow verbal response, and dysphasia, which were diagnosed as symptoms of aphasic SE. Magnetic resonance imaging showed encephalomalacia in the left frontal lobe with a hemosiderin rim. Intracranial electroencephalography revealed continuous spikes, predominantly on the left superior frontal gyrus with hemosiderin deposit. The aphasic symptoms were seen when ictal discharges gradually spread to the wide area of the left anterior frontal lobe, including the language area. The episodes of recurrent aphasic SE had disappeared by one year after the left anterior frontal resection. We should consider aphasic SE when language impairment is episodic, and consider surgical intervention in cases where it repeatedly occurs despite appropriate medical therapy.

Four-dimensional map of direct effective connectivity from posterior visual areas.

Lower- and higher-order visual cortices in the posterior brain, ranging from the medial- and lateral-occipital to fusiform regions, are suggested to support visual object recognition, whereas the frontal eye field (FEF) plays a role in saccadic eye movements which optimize visual processing. Previous studies using electrophysiology and functional MRI techniques have reported that tasks requiring visual object recognition elicited cortical activation sequentially in the aforementioned posterior visual regions and FEFs. The present study aims to provide unique evidence of direct effective connectivity outgoing from the posterior visual regions by measuring the early component (10-50 â€‹ms) of cortico-cortical spectral responses (CCSRs) elicited by weak single-pulse direct cortical electrical stimulation. We studied 22 patients who underwent extraoperative intracranial EEG recording for clinical localization of seizure foci and functionally-important brain regions. We used animations to visualize the spatiotemporal dynamics of gamma band CCSRs elicited by stimulation of three different posterior visual regions. We quantified the strength of CCSR-defined effective connectivity between the lower- and higher-order posterior visual regions as well as from the posterior visual regions to the FEFs. We found that effective connectivity within the posterior visual regions was larger in the feedforward (i.e., lower-to higher-order) direction compared to the opposite direction. Specifically, connectivity from the medial-occipital region was largest to the lateral-occipital region, whereas that from the lateral-occipital region was largest to the fusiform region. Among the posterior visual regions, connectivity to the FEF was largest from the lateral-occipital region and the mean peak latency of CCSR propagation from the lateral-occipital region to FEF was 26 â€‹ms. Our invasive study of the human brain using a stimulation-based intervention supports the model that the posterior visual regions have direct cortico-cortical connectivity pathways in which neural activity is transferred preferentially from the lower-to higher-order areas. The human brain has direct cortico-cortical connectivity allowing a rapid transfer of neural activity from the lateral-occipital region to the FEF.