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.
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.
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).
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.
•Acral melanoma is a distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma.•We retrospectively examined advanced-stage acral melanoma patients treated with an anti-PD-1 antibody.•Anti-PD-1 antibodies have limited efficacy in Japanese acral melanoma patients.•Patients with nail apparatus melanoma had poorer response and survival than patients with palm and sole melanoma.
Many aquatic invertebrates adjust their behavior to the degree of predation risk, which can be inferred from various sensory cues. We assessed the ability of the hermit crab
Pagurus minutus
to ...process different types of cues during predator avoidance and to discriminate between predators and non-predators by measuring the length of time that the hermit crabs remained retracted within their shells (hiding time) after exposure to visual cues, chemical cues, or both. Video images were used as visual cues, and water from aquaria holding predators or non-predators were used as chemical cues. The predator species was the portunid crab
Charybdis japonica
, and the non-predator species was the hermit crab
Clibanarius infraspinatus.
Natural seawater and background video were used as controls. Test individuals were exposed to each cue for 100 s. Both visual and chemical predator cues significantly increased hiding time in comparison to the controls, whereas non-predator cues did not significantly affect hiding time, indicating that
P. minutus
can discriminate between predators and non-predators from both visual and chemical cues. However, exposure to visual and chemical cues simultaneously did not significantly lengthen hiding times in comparison to exposure to a single cue type, indicating that there is no dominance in risk hierarchy between visual and chemical cues, and that
P. minutus
integrates information from both types of cues as if they were a single cue. We discuss the differences in our results from those previously obtained with a similar experimental design for the hermit crab
P. granosimanus
.
Significance statement
Animals must identify the most informative cues and integrate information from multiple cues to make the appropriate decisions for predator avoidance. When exposed to two types of cues, prey animals may assess them as a sign of multiple nearby predators even if the cues come from a single predator, leading to stronger response to two simultaneous cues than to either cue in isolation. It is still possible that prey animals integrate information from multiple cues as originating from a single predator. However, most studies have not fully considered this possibility. Our study revealed that
P. minutus
were able to discriminate between predators and non-predators from visual and chemical cues in isolation, but did not respond stronger to the simultaneous cues than to either cue in isolation. Our results suggest an example of non-additive response to multiple cues due to information redundancy among cue types.
An accident occurred when an aircraft landed at Narita International Airport, Japan, on 20 June 2012. The aircraft encountered rapid changes of winds together with strong turbulence, although the ...weather was fair. In the present study, a two‐domain nested regional weather prediction models are used. The results in the outer domain show that southwesterly winds associated with a synoptic extratropical cyclone were locally accelerated to the southwest of the airport resulting in strong vertical shear. The simulation in the inner domain reproduces horizontal convective rolls, which are similar to those observed by a Doppler lidar at the airport. The wind velocity component parallel to the runway had a spatial variation of about 10 m s
−1. The present approach using a large eddy simulation is useful for clarifying environments and features of horizontal convective rolls and forecasting low‐level wind shear associated with them, which can be a significant risk for aircraft.
Plain Language Summary
Synoptic/mesoscale fronts and downbursts (strong downdrafts from a thunderstorm and diverging winds after they hit the ground) are known to be serious threats to airplanes during takeoff and landing. However, it is less known that there is another type of danger under fair weather conditions. An aircraft landing at Narita International Airport, Japan, in the afternoon of 20 June 2012 encountered rapid changes of wind and turbulence and made a hard landing, resulting in several injuries and damage to the fuselage. A Doppler lidar, a remote sensing device for monitoring low‐level winds at the airport observed alternating regions of strong and weak winds aligned southwest–northeast, perpendicular to the runway. In order to clarify the detailed structure and mechanism of these disturbances, numerical simulations using a fine‐resolution (horizontal resolution: 100 m) nested in a coarse resolution (horizontal resolution: 1 km) are made. The simulations show that horizontal convective rolls, which occur in convective boundary layers with strong vertical shear (vertical gradient of horizontal wind speed) were prevailing. These rolls are associated with the rapid changes in wind speed and turbulence similar to those observed by the Doppler lidar and flight recorder. The present study demonstrates that the large eddy simulation is useful for clarifying the structure and mechanisms of horizontal convective rolls, which caused the aircraft accident, and also for forecasting them.
Key Points
Horizontal convective rolls that caused an aircraft accident in a fair weather condition were successfully reproduced by a numerical model
Characteristics of the rolls and turbulence as observed by a Doppler lidar and flight recorder are clarified based on the model results
Capability of accessing and operationally predicting potentially hazardous rolls by use of a large eddy simulation is demonstrated
Summary
Background
The prognosis of cutaneous angiosarcoma (CAS), especially for patients with tumours > 5 cm has been reported to be dismal, even after conventional surgery and radiotherapy ...(S + RT).
Objectives
To demonstrate the efficacy of chemoradiotherapy with taxane (T + RT) and maintenance chemotherapy.
Methods
We retrospectively reviewed 16 patients with CAS treated with T + RT and 12 patients treated with S + RT. None had distant metastasis. Tumour sites included the scalp (n = 25) and limbs (n = 3). The chemotherapy regimens used in T + RT were monthly docetaxel (n = 10), biweekly docetaxel (n = 1), weekly docetaxel (n = 5) and weekly paclitaxel (n = 1). The median radiation dose was 70 Gy. Nine patients receiving T + RT continued chemotherapy as maintenance therapy (monthly docetaxel in nine patients and monthly paclitaxel in two patients) and four patients receiving S + RT received adjuvant chemotherapy (weekly docetaxel).
Results
The response ratio of T + RT was 94% (14 complete remission and one partial remission). The 5‐year overall survival (OS) rate of patients receiving T + RT was statistically higher than those receiving conventional S + RT (56% and 8%, respectively; P < 0·01). Moreover, patients who received T + RT with maintenance chemotherapy showed a significant improvement in OS than those receiving T + RT alone (P < 0·01). There was a strong trend for relapse‐free survival, but it was not significant (P = 0·07). These data indicate that maintenance chemotherapy is crucial for long‐term survival after T + RT.
Conclusions
From these results, we suggest that T + RT followed by maintenance chemotherapy is a plausible method for managing CAS, especially large tumours that are difficult to manage with S + RT alone.
What's already known about this topic?
The prognosis of cutaneous angiosarcoma (CAS), especially for patients with tumours > 5 cm, has been reported to be dismal, even after conventional surgery and radiotherapy.
What does this study add?
The treatment of CAS with chemoradiotherapy with taxane achieved a high response ratio (14 complete remissions and one partial remission), with significant improvement of overall survival compared with surgery and radiotherapy.
Continuation of chemotherapy after chemoradiotherapy offered significantly prolonged survival than chemoradiotherapy alone.
STUDY QUESTION
What percentage of cases with non-syndromic hypospadias can be ascribed to mutations in known causative/candidate/susceptibility genes or submicroscopic copy-number variations (CNVs) ...in the genome?
SUMMARY ANSWER
Monogenic and digenic mutations in known causative genes and cryptic CNVs account for >10% of cases with non-syndromic hypospadias. While known susceptibility polymorphisms appear to play a minor role in the development of this condition, further studies are required to validate this observation.
WHAT IS KNOWN ALREADY
Fifteen causative, three candidate, and 14 susceptible genes, and a few submicroscopic CNVs have been implicated in non-syndromic hypospadias.
STUDY DESIGN, SIZE, DURATION
Systematic mutation screening and genome-wide copy-number analysis of 62 patients.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The study group consisted of 57 Japanese and five Vietnamese patients with non-syndromic hypospadias. Systematic mutation screening was performed for 25 known causative/candidate/susceptibility genes using a next-generation sequencer. Functional consequences of nucleotide alterations were assessed by in silico assays. The frequencies of polymorphisms in the patient group were compared with those in the male general population. CNVs were analyzed by array-based comparative genomic hybridization and characterized by fluorescence in situ hybridization.
MAIN RESULTS AND THE ROLE OF CHANCE
Seven of 62 patients with anterior or posterior hypospadias carried putative pathogenic mutations, such as hemizygous mutations in AR, a heterozygous mutation in BNC2, and homozygous mutations in SRD5A2 and HSD3B2. Two of the seven patients had mutations in multiple genes. We did not find any rare polymorphisms that were abundant specifically in the patient group. One patient carried mosaic dicentric Y chromosome.
LIMITATIONS, REASONS FOR CAUTION
The patient group consisted solely of Japanese and Vietnamese individuals and clinical and hormonal information of the patients remained rather fragmentary. In addition, mutation analysis focused on protein-altering substitutions.
WIDER IMPLICATIONS OF THE FINDINGS
Our data provide evidence that pathogenic mutations can underlie both mild and severe hypospadias and that HSD3B2 mutations cause non-syndromic hypospadias as a sole clinical manifestation. Most importantly, this is the first report documenting possible oligogenicity of non-syndromic hypospadias.
STUDY FUNDING/COMPETING INTERESTS
This study was funded by the Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology; by the Grant-in-Aid from the Japan Society for the Promotion of Science; by the Grants from the Ministry of Health, Labour and Welfare, from the National Center for Child Health and Development and from the Takeda Foundation. The authors have no competing interests to disclose.
TRIAL REGISTRATION NUMBER
Not applicable.
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