Anti-PD1 checkpoint inhibitor therapy in acral melanoma: a multicenter study of 193 Japanese patients.

BACKGROUND: Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM. PATIENTS AND METHODS: We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies. RESULTS: In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03). CONCLUSIONS: Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

Fish collagen is an important panallergen in the Japanese population.

Collagen was identified as a fish allergen in early 2000s. Although its allergenic potential has been suggested to be low, risks associated with collagen as a fish allergen have not been evaluated to a greater extent. In this study, we aimed to clarify the importance of collagen as a fish allergen. Our results showed that 50% of Japanese patients with fish allergy had immunoglobulin E (IgE) against mackerel collagen, whereas 44% had IgE against mackerel parvalbumin. IgE inhibition assay revealed high cross-reactivity of mackerel collagen to 22 fish species (inhibition rates: 87-98%). Furthermore, a recently developed allergy test demonstrated that collagen triggered IgE cross-linking on mast cells. These data indicate that fish collagen is an important and very common panallergen in fish consumed in Japan. The high rate of individuals' collagen allergy may be attributable to the traditional Japanese custom of raw fish consumption.

Clinical course of drug-induced hypersensitivity syndrome treated without systemic corticosteroids.

BACKGROUND/AIM: Drug-induced hypersensitivity syndrome (DIHS) is a severe reaction to drugs which characteristically occurs after a long latency period. In addition, human herpes virus 6 (HHV-6) reactivation is a characteristic finding in DIHS, which has been known to be related to disease severity. Because DIHS has generally been treated by systemic corticosteroids, the natural clinical course is not clear. METHODS: Data for patients with both DIHS and HHV-6 reactivation were retrospectively collected from four hospitals. RESULTS: Data were collected on 12 patients ranging in age from 21 to 76 years (median, 65.5). All cases had been suspected of DIHS at their initial visit, and the elevation of serum anti-HHV-6 antibody had been confirmed (4-256 times: median; 32). The culprit drugs were carbamazepine (6), salazosulfapyridine (4), mexiletine (1) and zonisamide (1). The period of latency from the first administration of the drug ranged from 15 to 50 days (median, 30). All patients were treated conservatively for DIHS without systemic corticosteroids. The peaks of the patients' symptoms and laboratory findings were as follows (days from the onset of skin lesions): fever, 4-16 (median, 10.5); liver abnormality, 3-22 (median, 7.5); leukocytosis, 7-20 (median, 9). All patients recovered without pneumonia, myocarditis, nephritis or other systemic disease, from 7 to 37 days (median, 18) after withdrawal of the drug and from 11 to 44 days (median, 21) after the onset of skin lesions. CONCLUSION: It might be unnecessary to give systemic corticosteroids immediately to all patients suspected of having DIHS.

Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level.

BACKGROUND: The availability of molecular-targeted therapies for the treatment of melanoma has emphasised the need to identify mutations in target genes such as BRAF and KIT. Circulating tumour cells (CTC) are present in the peripheral blood of a significant proportion of cancer patients. METHODS: High molecular weight melanoma-associated antigen (HMW-MAA) was used to isolate melanoma cells from peripheral blood as it is selectively expressed at high levels on melanomas. The HMW-MAA-positive cells were isolated using immunomagnetic beads. After removing CD45(+) cells, CTC were identified by staining with MART-1- and gp100-specific antibodies (HMW-MAA(+), CD45(-), MART-1/gp100(+)). Single, isolated CTC were then subjected to BRAF and KIT mutational analysis. RESULTS: CTC (HMW-MAA(+), CD45(-), MART-1/gp100(+)) were isolated from the blood of 11 patients and BRAF and KIT were sequenced in nine and four patients, respectively. The BRAF sequences identified in the CTC were inconsistent with those identified in autologous melanoma tumours in three patients and the KIT sequences were inconsistent in three patients. In addition, polyclonal BRAF mutations were identified in one patient and concomitant mutations in BRAF and KIT were identified in another patient. CONCLUSION: Melanoma cells show clonal heterogeneity. Therefore, CTC genotyping may be crucial for successful molecular-targeted therapy.

Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan.

BACKGROUND: Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. METHODS: ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015. RESULTS: Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5-35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient. CONCLUSIONS: EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients.

Squamous cell carcinoma arising from lupus vulgaris with a >60-year history.

We report the case of a 71-year-old Japanese man with squamous cell carcinoma arising from lupus vulgaris on the face, >60 years after the appearance of the lupus vulgaris. The red plaque on the patient's face had been diagnosed as a hemangioma or rosacea at several hospitals, although he had had lung tuberculosis at the age of 4 and his father died from lung tuberculosis at 38 years of age. Although lupus vulgaris was the most frequent clinical form of true skin tuberculosis until the 1960s, it has become rare since then. Malignant tumors are known to occur in individuals with lupus vulgaris, with a reported rate of 0.5-10.5%. In light of Japan's "graying society," tuberculosis is still an important disorder, and clinicians must remain aware of cutaneous tuberculosis.

Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma.

PURPOSE: Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients. METHODS: Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity. RESULTS: All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities. CONCLUSIONS: IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212.

Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma.

PURPOSE: Ipilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma. METHODS: Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015). RESULTS: Data are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively. CONCLUSION: Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01990859.

Evaluation of 5-S-cysteinyldopa as a marker of melanoma progression: 10 years' experience.

5-S-Cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma progression. In this study, we measured serum levels of 5-S-CD in 2648 samples taken from 218 patients in order to evaluate the usefulness of this parameter in following melanoma progression and prognosis. 5-S-CD levels were significantly elevated above the upper limit of the normal range (10 nmol/l) in stage IV melanoma patients. The sensitivity of elevated serum 5-S-CD levels in detecting distant metastasis was 73%, while the specificity was 98% and the positive predictive value 94%. The sensitivity was improved to 77% when cases of amelanotic melanoma were excluded. Patients without metastases had elevated 5-S-CD values in 5% of the 1480 serum samples. Changes in serum 5-S-CD levels were followed during disease progression until the end stage in 49 patients. In 33% of the patients, elevation of serum 5-S-CD levels preceded clinical detection of visceral metastases, and in 37% elevation of 5-S-CD levels occurred at the same time as visceral metastasis. Patients with elevated 5-S-CD levels before or after surgical treatment had significantly shorter survival times than those with normal levels. These results show that the level of 5-S-CD in the serum is a sensitive and specific marker in predicting distant metastases. Elevated serum levels of 5-S-CD, before or after surgical treatment, is associated with a poor prognosis.

Detection of human papillomavirus DNA in laryngeal squamous cell carcinomas by polymerase chain reaction.

The presence of human papillomavirus genomes-16 and -6b in metastatic cervical lymph nodes was examined in 34 cases of laryngeal carcinomas by means of polymerase chain reaction, which had been fixed in formalin and embedded in paraffin. Human papillomavirus DNAs extracted from paraffin-embedded tumor tissues were used for polymerase chain reaction with amplification of the E6 region of human papillomavirus genome-16 and the E1 region of human papillomavirus genome-6b. Human papillomavirus genome-16 sequences were positively amplified in six (17.6%) metastatic tumors; -6b sequence was positively amplified in one (2.9%) metastatic tumor. Laryngeal carcinomas of glottic origin showed high human papillomavirus genome-16 DNA-positive rates (4 of 9 cases, 44.4%) compared to those of other sites. These results suggest that human papillomavirus genome-16 infection might be closely associated with the development of some laryngeal squamous cell carcinomas of glottic origin similar to uterine cervical carcino-genesis.

Detection of Epstein-Barr virus DNA in formalin-fixed paraffin-embedded tissue of nasopharyngeal carcinoma using polymerase chain reaction and in situ hybridization.

The polymerase chain reaction method for amplification of DNA in formalin-fixed, paraffin-embedded tissue sections was used to detect Epstein-Barr virus DNA in nasopharyngeal carcinomas from Japanese patients. Thirty-one cases of nasopharyngeal carcinoma and 8 cases of lymph node metastasis of nasopharyngeal carcinoma were studied. Detection rates of Epstein-Barr virus in various types of nasopharyngeal carcinoma according to the World Health Organization classification were as follows: 10 of 10 undifferentiated carcinomas, 8 of 13 nonkeratinizing carcinomas, and 5 of 7 keratinizing carcinomas. Eight lymph node metastases, for which the primary was positive for Epstein-Barr virus, also contained Epstein-Barr virus DNA. By in situ hybridization using a biotinylated Epstein-Barr virus probe, it was clearly demonstrated that Epstein-Barr virus DNA was localized in the nuclei of the neoplastic cells. The clinical features of nasopharyngeal carcinoma with or without Epstein-Barr virus were not different. These results demonstrate that nasopharyngeal carcinoma in Japanese patients is closely associated with Epstein-Barr virus infection, similar to nasopharyngeal carcinoma of other endemic and nonendemic areas.

Solid facial edema in a patient with rosacea.

We report a 53-year old man with symmetrical nonpitting edema, conjunctivitis, and acneiform eruptions on the face. Histopathological examination showed perifollicular lymphohistiocytic infiltration and telangiectasias in the upper dermis. Loosely aggregated non-caseating granulomas were scattered through the dermis; some of them were seen in the perifollicular regions. The patient was treated with fleroxacin (100 mg/day, orally) for two weeks with a marked reduction of both solid facial edema and periorbital edema.