Low estimated glomerular filtration rate is an independent risk factor for higher hydroxychloroquine concentration.

BACKGROUND: The aim of this study was to analyze the relationship of the estimated glomerular filtration rate (eGFR) to hydroxychloroquine (HCQ) blood concentrations in systemic lupus erythematosus (SLE) patients. METHOD: Patients with SLE who had been taking HCQ for more than 12 months were recruited. All subjects gave written informed consent. Various clinical characteristics and laboratory values were examined. The blood concentration of HCQ was measured by high-performance liquid chromatography, and the relationship of eGFR to HCQ blood concentration was mainly investigated. RESULT: In total, 115 patients with SLE receiving long-term HCQ therapy were included in the study. The median concentration of HCQ was 1096 ng/ml (range 116-8240 ng/ml). The eGFR was strongly associated with blood concentration of HCQ (P = 0.011, P < 0.05), when adjusted for age, sex, body mass index (BMI), weight-adjusted dose, prednisone use and immunosuppressive drug use. No statistically significant association were found between age, duration, BMI, weight-adjusted HCQ dose, corticosteroid use, immunosuppressant use and blood concentrations of HCQ. CONCLUSION: We provided novel evidence that impaired renal function influenced the blood concentration of HCQ. Patients with low eGFR need to adjust the HCQ dosage according to the monitoring results of HCQ blood concentrations.

Apatinib combined with camrelizumab in advanced acral melanoma patients: An open-label, single-arm phase 2 trial.

BACKGROUND: At present, immune monotherapy and combination therapy has not shown satisfactory effects on acral melanoma, and still no standard treatment is available for advanced acral melanoma. Here, a phase II trial was performed to explore the safety and efficacy of apatinib combined with camrelizumab in advanced acral melanoma patients as first-line therapy (NCT03955354). METHODS: Patients with pathologically confirmed, locally unresectable or metastatic treatment native acral melanoma received 250 mg apatinib once daily and camrelizumab 200 mg once every two weeks intravenously every 28-day cycle. The primary end-point was objective response rate and the secondary end-points were disease control rate, overall survival, progression-free survival and safety. RESULTS: Thirty patients were recruited between January 2015 and January 2022. Among them, 21 (70.0%) had stage IV, and a median tumour burden was 50 mm (range: 11-187). Objective response rate was 24.1%, and 7 of 29 patients had an anti-tumour response, including partial response (n = 5) and complete response (n = 2). Disease control rate was 82.8%, median progression-free survival was 7.39 months (confidence interval: 3.65-9.92), and median overall survival was 13.4 months (confidence interval: 1.9-25.0). Grade 3-4 treatment-related toxicity (grade 3 50.5%; grade 4 3.3%) included transaminase elevations, proteinuria, leukocytopenia, vomiting, diarrhea and drug-induced liver injury. No treatment-related mortality occurred. The mutations of TTN, MUC16, VPS13D, ALPK2 and SCUBE1 showed significant alterations with survival outcome. CONCLUSIONS: Apatinib combined with camrelizumab showed manageable safety profile and reasonable anti-tumour activity in advanced acral melanoma patients as first-line therapy.

Safety and efficacy of Pucotenlimab (HX008) - a humanized immunoglobulin G4 monoclonal antibody in patients with locally advanced or metastatic melanoma: a single-arm, multicenter, phase II study.

BACKGROUND: Pucotenlimab is a novel recombinant humanized anti-PD-1 (Programmed death-1) monoclonal antibody, which belongs to the human IgG4/kappa subtype, and can selectively block the binding of PD-1 with its ligands PD-L1 and PD-L2. METHODS: In this phase 2 trial, patients with locally advanced or metastatic melanoma who had failed conventional treatment (chemotherapy, targeted therapy, interferon, IL-2, et al.) were recruited. The patients were administrated with Pucotenlimab of 3 mg/kg every 3 weeks until disease progression, intolerable toxicity, or treatment discontinuation for any other reasons. The primary endpoint was the overall response rate (ORR). The secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: One-hundred and nineteen patients were enrolled and followed up for 19.32 (ranging from 15.901 to 24.608) months by the cutoff date of July 30th, 2021. The ORR was 20.17% (24/119, 95% CI, 13.370%-28.506%) based on both independent review committee (IRC) and the investigator's assessment per RECIST v1.1. The median PFS were 2.89 (95% CI, 2.037-4.074) months and 2.46 (95% CI, 2.004-4.008) months based on IRC and investigator's assessment, respectively, per RECIST v1.1. The median OS was 16.59 (95% CI, 13.963-26.973) months. Treatment-related adverse events (TRAEs) occurred in 77.3% (92/119) of the patients. The incidence of Grade ≥ 3 TRAEs was 15.1% (18/119). In addition, none of the patients died because of TRAEs. As for biomarker analysis, Eotaxin (CCL11) and MCP-1 (CCL2) were related to treatment response, while TNF-α and VEGF were related to treatment failure. CONCLUSIONS: Pucotenlimab as a ≥ 2nd line therapy showed promising efficacy and tolerable toxicity for patients with locally advanced or metastatic melanoma. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04749485 (registered retrospectively on 11/02/2021).

First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations.

BACKGROUND: HL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations. METHODS: This was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5-18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D. RESULTS: Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months. CONCLUSIONS: The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations. TRIAL REGISTRATION: Trial registration ClinicalTrials.gov number: NCT03973151.

Impact of response patterns for patients with advanced acral melanoma treated with anti-programmed death-1 monotherapy.

BACKGROUND: Acral melanoma (AM) is less responsive to immunotherapy than nonacral cutaneous melanoma. Variable responses are seen during immunotherapy, including pseudoprogression, hyperprogressive disease (HPD) and heterogeneous responses. There are currently no studies on the response patterns of patients with AM treated with immunotherapy and the impact on the outcome. OBJECTIVES: To evaluate the response patterns and prognosis of patients with AM treated with anti-programmed death (PD)-1 antibodies. METHODS: Patients with advanced AM treated prospectively in five clinical trials of anti-PD-1 monotherapy at Peking University Cancer Hospital were included. Responses of individual metastases and heterogeneous responses were evaluated during immunotherapy. Cox proportional hazards regression analysis was conducted to identify the possible predictive factors and generate a nomogram to predict the risk of 1-year and 2-year mortality. RESULTS: The overall response rate was 18·0%, the disease control rate was 36·1%, median progression-free survival was 3·5 months [95% confidence interval (CI) 1·7-5·3] and median overall survival was 17·5 months (95% CI 15·1-19·9) for anti-PD-1 monotherapy. Overall, 9·8% of patients met the criteria of HPD, and displayed a dramatically worse outcome than patients without HPD. In total, 369 metastatic lesions were assessed, with the highest response rate in lymph nodes (20·4%) and the lowest in the liver (5·6%). Homogeneous response, heterogeneous response and heterogeneous or homogeneous progression had different prognoses from the best to the worst. A predictive model was constructed and achieved good accuracy with a C-index of 0·73 (95% CI 0·63-0·84) in the training set and 0·74 (95% CI 0·61-0·86) in the validation set. CONCLUSIONS: HPD during immunotherapy serves as an essential biomarker of poor prognosis in advanced AM. Metastases in different sites respond distinctively to immunotherapy. Clinically heterogeneous responses to immunotherapy affect the outcome of patients. A predictive model was built to distinguish the prognosis of acral melanoma under immunotherapy.

Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy.

BACKGROUND: Accumulating data suggest that mucosal melanoma, well known for its poor response to immune checkpoint blockade (ICB) and abysmal prognosis, is a heterogeneous subtype of melanoma with distinct genomic and clinical characteristics between different anatomic locations of the primary lesions. Primary malignant melanoma of the esophagus (PMME) is a rare, highly aggressive disease with a poorer prognosis compared with that of non-esophageal mucosal melanoma (NEMM). In this study, we retrospectively analyzed the efficacy of anti-programmed death (PD)-1 in patients with PMME and explored its molecular basis. METHODS: The response and survival of patients with PMME and NEMM under anti-PD-1 monotherapy were retrospectively analyzed. To explore the molecular mechanisms of the difference in therapeutic efficacy between PMME and NEMM, we performed genomic analysis, bulk RNA sequencing, and multiplex immunohistochemistry staining. RESULTS: We found that PMME (n=28) responded better to anti-PD-1 treatment than NEMM (n=64), with a significantly higher objective response rate (33.3% (95% CI 14.3% to 52.3%) vs 6.6% (95% CI 0.2% to 12.9%)) and disease control rate (74.1% (95% CI 56.4% to 91.7%) vs 37.7% (95% CI 25.2% to 50.2%)). Genomic sequencing analysis revealed that the genomic aberration landscape of PMME predominated in classical cancer driver genes, with approximately half of PMME cases harboring mutations in BRAF, N/KRAS, and NF1. In contrast, most NEMM cases were triple wild-type. Transcriptome analysis revealed that, compared with NEMM, PMME displayed more significant proliferation and inflammatory features with higher expression of genes related to antigen presentation and differentiation, and a less immunosuppressive signature with lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. The multiplex immunohistochemical analysis also demonstrated higher CD8+ T-cell infiltration in PMME than in NEMM. CONCLUSIONS: PMME is an outlier of mucosal melanoma showing a malicious phenotype but a particularly high response rate to ICB because of its distinct molecular characteristics. Patient stratification based on anatomic origin can facilitate clinical decision-making in patients with mucosal melanoma following the verification of our results in future prospective studies.

YAP Activation in Promoting Negative Durotaxis and Acral Melanoma Progression.

Directed cell migration towards a softer environment is called negative durotaxis. The mechanism and pathological relevance of negative durotaxis in tumor progression still requires in-depth investigation. Here, we report that YAP promotes the negative durotaxis of melanoma. We uncovered that the RhoA-myosin II pathway may underlie the YAP enhanced negative durotaxis of melanoma cells. Acral melanoma is the most common subtype of melanoma in non-Caucasians and tends to develop in a stress-bearing area. We report that acral melanoma patients exhibit YAP amplification and increased YAP activity. We detected a decreasing stiffness gradient from the tumor to the surrounding area in the acral melanoma microenvironment. We further identified that this stiffness gradient could facilitate the negative durotaxis of melanoma cells. Our study advanced the understanding of mechanical force and YAP in acral melanoma and we proposed negative durotaxis as a new mechanism for melanoma dissemination.

Efficacy and safety of PD-1/PD-L1 inhibitors plus chemotherapy for triple-negative breast cancer: a systematic review and meta-analysis.

OBJECTIVE: The results of PD-1/PD-L1 inhibitor combined with chemotherapy for TNBC are controversial. Therefore, a meta-analysis was conducted to evaluate the efficacy and safety after PD-1/PD-L1 inhibitors plus chemotherapy in TNBC patients. METHODS: We systematically searched seven databases and several mainly oncology conferences for prospective clinical trials of chemotherapy combined with immunotherapy to treat TNBC, and we included pathologic complete response (PCR), progression-free survival (PFS), overall survival (OS) and adverse effects as outcome indicators of the study. RESULTS: We analyzed data from six studies involving 4,187 patients. The efficacy analysis indicated that PD1/PD-L1 inhibitor combined with chemotherapy significantly increased PCR rates in neoadjuvant patients (OR: 1.60; 95% CI: 1.18-2.17; p=0.003). There was no correlation between increases in PCR rates and the expression of PD-L1, but the PCR rate was higher in PD-L1+ patients. Subgroup analysis suggested that the lymph node-positive (OR: 2.52; 95% CI: 1.69-3.77; p<0.001) and ECOG PS 0 (OR: 1.9; 95% CI: 1.42-2.53; p<0.001) subgroups benefited from the combination of PD-1/PD-L1 inhibitor plus chemotherapy. In TNBC receiving advanced rescue treatment, PFS was higher in the group receiving PD-1/PD-L1 inhibitor plus chemotherapy than in the group receiving chemotherapy alone (HR: 0.78; 95% CI: 0.70-0.86; p<0.001). Compared with chemotherapy alone, PD-1/PD-L1 inhibitors combined with chemotherapy did not increase the OS of patients (HR=0.88, 95% CI: 0.76~1.03, p=0.12). In addition, the toxicity analysis showed that more grade 3-4 adverse effects and severe adverse effects occurred in the PD-1/PD-L1 inhibitor combined with chemotherapy group. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with chemotherapy can improve the PCR and PFS rate of TNBC patients, but did not improve the OS, and had a higher risk of AEs.

Phaeosphaeridiols A-C: Three New Compounds from Undescribed Phaeosphaeriaceae sp. SGSF723.

Fungi in forest litter are diverse as decomposers but natural products from these fungi are rarely investigated, especially for their antimicrobial activities against crop diseases. In this study, fungal isolate SGSF723 with antimicrobial activities was cultured. A multi-gene phylogenetic analysis showed SGSF723 was an undescribed species in the family Phaeosphaeriaceae. By bio-guided assay, three new compounds (Phaeosphaeridiols A-C) and two known compounds were purified from the ethyl acetate extract. The structures of Phaeosphaeridiols A-C were elucidated as 2-(2'-butenyl)-5 (3″-pentene)-1,3-benzenediol (1), 2-(2'-butenyl)-5-(3″S,4″S-pentane diol)-1,3-benzenediol (2), and 3-(4'-(2″-butenyl)-3',5'-benzenediol phenol)-2-acrylic acid (3) by 2D NMR, HRESIMS, and Mosher's method. Phaeosphaeridiols A-C exhibited moderate or weak antimicrobial activities against plant pathogens by 96-well plate and spore germination assays.

Phase I pharmacokinetic study of an oral, small-molecule MEK inhibitor tunlametinib in patients with advanced NRAS mutant melanoma.

Background: Malignant melanoma is an aggressive disease. Tunlametinib (HL-085) is a potent, selective, and orally bioavailable MEK1/2 inhibitor. The objective of this study was to determine the pharmacokinetics (PK) of tunlametinib and its main metabolite M8 in patients with NRAS-mutant melanoma following a single dose and multiple doses in a phase I safety and PK study. Methods: A multiple-center phase I study was performed in patients with melanoma including dose-escalation phase and dose-expansion phase. PK following a single oral dose and multiple doses of 0.5-18 mg twice daily was assessed. Results: A total of 30 participants were included in the dose escalation phase and then 11 patients were included in the dose-expansion phase (12 mg twice daily). Tunlametinib plasma concentration rapidly increased after dosing, with a Tmax of 0.5-1 h. Mean elimination half-life (t1/2) was dose-independent and had a range from 21.84 to 34.41 h. Mean apparent clearance (CL/F) and distribution volume (V/F) were 28.44-51.93 L/h and 1199.36-2009.26 L, respectively. The average accumulation ratios of AUC and Cmax after the multiple administration of tunlametinib were 1.64-2.73 and 0.82-2.49, respectively. Tunlametinib was rapidly transformed into the main metabolite M8 and M8 reached the peak concentration about 1 h after administration. Mean t1/2 of M8 was 6.1-33.54 h. The body exposure of M8 in plasma was 36%-67% of that of tunlametinib. There were general dose-proportional increases in maximum concentration (Cmax) and area under the curve (AUC) of tunlametinib and M8 both in the single dose phase and in the multiple doses phase. Conclusion: Tunlametinib was absorbed rapidly and eliminated at a medium speed after drug withdrawal. Pharmacokinetic body exposure increased in general dose-proportional manner from 0.5 mg up to 18 mg. Slight accumulation was found after multiple oral doses. The pharmacokinetics of tunlametinib and its metabolite suggest that twice daily dosing is appropriate for tunlametinib.

Generation of 99.8 fs, 25 kW Peak-Power, Dispersion-Managed Pulses Directly from an Yb-Doped Figure-of-9 Fiber Laser.

We reported on the generation of 99.8 fs, 25 kW peak-power, dispersion-managed pulses directly from a passively mode-locked Yb-fiber laser oscillator with a figure-of-9 configuration. The introduction of strongly injected pump power and optical components with a high damage threshold enables high-power operation, while the polarization-maintaining (PM) fiber supports environmentally stable self-started mode-locking. Mode-locking in the soliton-like and negative-dispersion regime is characterized by the dispersion management via tuning the separation distances between a pair of gratings inside the cavity. The oscillator generates stable pulses with up to 40.10 mW average power at a 16.03 MHz repetition rate, corresponding to a pulse energy of 2.5 nJ. To the best of our knowledge, it is the highest peak-power directly obtained by a laser oscillator with a figure-of-9 configuration.

Pembrolizumab in Chinese patients with advanced melanoma: 3-year follow-up of the KEYNOTE-151 study.

Survival is generally poor for Chinese patients with advanced melanoma because of high rates of acral and mucosal melanoma and limited therapeutic options. The first analysis of the phase 1b KEYNOTE-151 study showed second-line pembrolizumab was well tolerated and had clinically meaningful antitumor activity in Chinese patients with advanced melanoma. Three-year follow-up is presented. Eligible patients were of Chinese descent and had unresectable stage III/IV melanoma that progressed after first-line therapy. Patients received pembrolizumab 2 mg/kg every 3 weeks for ≤35 cycles. Primary end points were safety and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Response was assessed per RECIST v1.1 by blinded independent central review. Subgroup analyses were conducted by melanoma subtype and BRAF and PD-L1 status (acral melanoma only). 103 patients were enrolled; median follow-up duration (time from first dose to data cutoff [July 13, 2020]) was 44.6 months (IQR, 39.1-46.2). Any-grade treatment-related adverse events (TRAEs) occurred in 85.4% of patients, and grade 3/4 TRAEs in 12.6%. No grade 5 TRAEs occurred. Three patients discontinued pembrolizumab because of TRAEs (immune-mediated hepatitis, pneumonia, and arthritis). Immune-mediated AEs and infusion reactions occurred in 34.0% (grade 3/4, 2.9%). ORR was 17.6% (95% CI, 10.8-26.4; 1 complete response/17 partial responses), and median DOR was 13.8 months (range, 2.7-37.4+). Median PFS was 2.8 months (95% CI, 2.7-3.5) and 36-month PFS rate was 5.0%. Median OS was 13.2 months (95% CI, 10.4-16.5) and 36-month OS rate was 22.3%. Median OS for patients with known melanoma subtype was 14.8 months for acral, 13.5 months for nonacral cutaneous, and 7.4 months for mucosal melanoma. Among the acral subgroup, median OS was 22.8 months for PD-L1-positive disease, 8.4 months for PD-L1-negative disease, 18.5 months for BRAF wild-type disease, and 5.8 months for BRAF-mutant disease. Over 3 years' follow-up, second-line pembrolizumab continued to show manageable safety, clinically meaningful antitumor activity, and durable responses in Chinese patients with advanced melanoma. Subgroup analysis suggested particular benefit in PD-L1-positive and BRAF wild-type acral melanoma, although small subgroup sizes preclude definitive conclusions. Clinical trial registration: https://clinicaltrials.gov, identifier NCT02821000.

[Bifidobacterium bifidum TMC3115 Promotes Early Life Intestinal Microbiota Building to Alleviate Symptoms of Inflammatory Bowel Disease].

Objective: To investigate the effects of using Bifidobacterium bifidum TMC3115 in early life on intestinal microbiota and immune functions and the long-term impact on inflammatory bowel disease. Methods: Fourteen pregnant BALB/c mice were purchased and 84 newborn BALB/c mice were subsequently obtained. Then, the newborn mice were randomly assigned to a normal saline (NS) group and a TMC3115 group, given via oral gavage normal saline and TMC3115, respectively, at a daily volume of 0.2 mL for each mouse. About 42 mice were assigned to each group. The gavage was stopped after 3 weeks. At this point, half of the mice in each group were sacrificed, and then the remaining mice in each group were randomly divided into NS-water group, NS-DSS group, TMC3115-water group, and TMC3115-DSS group, with about 10 mice in each group. The mice were given regular feed until the end of week 6 when they were given 3% dextran sulphate sodium (DSS) ad libitum for 4 days to establish the enteritis model, while the non-modeling groups were given pure water ad libitum. The experiment ended after 6 weeks and 4 days. The weekly body mass changes of the mice were documented. The intestinal tissue at the end of the experiment and the fecal samples, spleen and serum of the mice at 3 weeks and at the end of the experiment were collected to determine the pathology scores of colonic inflammation, the composition of fecal gut microbiota, spleen organ index and the mass concentration of serum cytokines. Results: 1) At the end of the experiment, the inflammatory pathology score was significantly lower in the TMC3115-DSS group compared with that of the Saline-DSS group ( P<0.05), with less disruption of colonic crypt structures and other structures, less inflammatory infiltration, and more intact epithelial structures. 2) At 3 weeks, in comparison with those of the NS group, the relative abundance of Bifidobacteriumwas significantly higher in the feces of the TMC3115 ( P<0.05), the relative abundance of both Enterococcusand Staphylococcuswas lower ( P<0.05), the splenic organ index was significantly higher ( P<0.05), and interleukin (IL)-10 was significantly decreased ( P<0.05), while there was no significant change in IL-6 or TNF-α ( P>0.05). At the end of the experiment, in comparison with those of the NS-DSS group that undergone DSS induction, the TMC3115-DSS group had reduced relative abundance of Staphylococcus, Staphylococcus tumefaciens and Escherichia/ Shigellain the feces ( P<0.05), while the splenic organ index was significantly higher ( P<0.05), and there were no significant changes in IL-6 or TNF-α ( P>0.05). Conclusion: The use of TMC3115 in early life promotes the construction of gut microbiota in neonatal mice, thereby producing a long-term effect that alleviates colitis in mice, but the mechanisms involved are still not fully understood.

Prognostic impact of Breslow thickness in acral melanoma: A retrospective analysis.

BACKGROUND: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited. OBJECTIVE: The objective of the study was to determine the prognostic impact of Breslow thickness in AM. METHODS: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression. RESULTS: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The median follow-up time was 60.1 months. The median MSS in patients with T1-T4 disease was not reached, 111.0, 92.8, and 67.1 months, respectively. MSS differed significantly among cN0 patients with T1-T3 AM (log-rank P = .004, .012, <0.001 for T1 vs T2, T2 vs T3, and T1 vs T3, respectively); however, there was no significant difference between T3 and T4 AM (hazard ratio = 0.82, 95% CI, 0.62-1.09). Six-subgroup analyses confirmed that survival outcomes were similar between different subgroups with tumor thickness >2 mm. LIMITATIONS: The limitations were retrospective design and some missing variables. CONCLUSIONS: There was no association between tumor thickness and survival in AM patients with a Breslow thickness >2 mm.

Cumulative incidence and risk factors of brain metastasis for acral and mucosal melanoma patients with stages I-III.

PURPOSE: Few studies focused on the incidence of brain metastasis in patients with acral and mucosal melanoma, and a better understanding of the incidences and predictors of brain metastasis is needed in these patients. METHOD: A prospectively accrued cohort of 799 patients with acral and mucosal melanoma in stages I-III from July 2011 to December 2015 at Peking University Cancer Hospital were included in this study. Competing risk models (Fine and Gray) were used to estimate the cumulative incidence of brain metastasis and compare the differences in cumulative incidence curves between different primary lesions, stages, and molecular types. RESULTS: At a median follow-up time of 68.0 months, 60 of the 779 patients (7.7%) developed brain metastasis, and 261 (33.5%) patients developed extracranial metastasis. Considering the risk of competition, the cumulative incidence of brain metastasis at one year, two years, and five years after diagnosis were 5.1%, 10.2%, and 19.5%, respectively. Stage III, BRAF mutations, and NRAS mutations were associated with a high risk of brain metastasis in univariable analysis. Multivariate analysis showed BRAF mutations, and NRAS mutations had statistically correlated with an increased cumulative incidence of brain metastasis at diagnosis and all-time point of one year and two years after diagnosis. CONCLUSION: This study is the first to report the cumulative incidence and risk factors of brain metastasis for patients with acral and mucosal melanoma in stages I-III. Patients with BRAF and NRAS mutations had a higher incidence at diagnosis and all-time point, providing the basis for surveillance guidelines and further mechanic exploration.

A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma.

BACKGROUND: A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma. PATIENTS AND METHODS: Patients received a single FCN-159 dose at assigned levels, proceeding to continuous dosing (once daily [QD] for 28-day cycles) if no dose-limiting toxicities (DLTs) occurred within the next 3 days. Dose escalation was initiated after review of data for the previous dose level. The primary end-point was incidence of DLTs after the first dose. RESULTS: Thirty-three patients were enrolled across nine FCN-159 dose groups (0.2-15 mg QD). One DLT occurred: grade 3 folliculitis in the 15-mg group. There was one grade >3 treatment-emergent adverse event (TEAE), death of unknown aetiology (not FCN-159 related). The most common FCN-159-related TEAE was rash (36.4%), and the incidence of grade ≥3 FCN-159-related TEAEs was 15.2%. Antitumour activity at QD doses <6 mg was limited; therefore, efficacy data are presented only for doses ≥6 mg (n = 21). The objective response and clinical benefit rates were 19.0% (four partial responses) and 52.4%, respectively. Median (95% confidence interval) duration of response and progression-free survival were 4.8 months (2.8-not reached) and 3.8 months (1.8-5.6), respectively. FCN-159 exposure increased dose-proportionately; geometric mean terminal half-life was 29.9-56.9 h. CONCLUSIONS: FCN-159 was well tolerated and demonstrated promising antitumour activity at doses ≥6 mg QD in patients with advanced, NRAS-mutant melanoma. The recommended phase 2 dose was 12 mg QD. GOV IDENTIFIER: NCT03932253. https://clinicaltrials.gov/ct2/show/NCT03932253.

Expert consensus on the diagnosis and treatment of NTRK gene fusion solid tumors in China.

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Dual Polarization Modality Fusion Network for Assisting Pathological Diagnosis.

Polarization imaging is sensitive to sub-wavelength microstructures of various cancer tissues, providing abundant optical characteristics and microstructure information of complex pathological specimens. However, how to reasonably utilize polarization information to strengthen pathological diagnosis ability remains a challenging issue. In order to take full advantage of pathological image information and polarization features of samples, we propose a dual polarization modality fusion network (DPMFNet), which consists of a multi-stream CNN structure and a switched attention fusion module for complementarily aggregating the features from different modality images. Our proposed switched attention mechanism could obtain the joint feature embeddings by switching the attention map of different modality images to improve their semantic relatedness. By including a dual-polarization contrastive training scheme, our method can synthesize and align the interaction and representation of two polarization features. Experimental evaluations on three cancer datasets show the superiority of our method in assisting pathological diagnosis, especially in small datasets and low imaging resolution cases. Grad-CAM visualizes the important regions of the pathological images and the polarization images, indicating that the two modalities play different roles and allow us to give insightful corresponding explanations and analysis on cancer diagnosis conducted by the DPMFNet. This technique has potential to facilitate the performance of pathological aided diagnosis and broaden the current digital pathology boundary based on pathological image features.

Atezolizumab plus Bevacizumab in Patients with Unresectable or Metastatic Mucosal Melanoma: A Multicenter, Open-Label, Single-Arm Phase II Study.

PURPOSE: Anti-programmed cell death-1 monotherapy is part of standard therapy for cutaneous melanoma but has low efficacy in mucosal melanoma. We evaluated the efficacy and safety of atezolizumab plus bevacizumab as first-line therapy for advanced mucosal melanoma. PATIENTS AND METHODS: This multicenter, open-label, single-arm, phase II study used a Simon's two-stage design. Atezolizumab (fixed-dose, 1,200 mg) and bevacizumab (7.5 mg/kg) were administered by intravenous infusion every 3 weeks. The primary endpoint was objective response rate (ORR), determined per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety, with adverse events (AE) summarized using NCI-CTCAE v5.0. RESULTS: Overall, 43 patients were enrolled, including 20 (46.5%) with unresectable and 23 (53.5%) with metastatic mucosal melanoma. Median follow-up was 13.4 months at data cutoff (July 30, 2021). Forty patients were evaluable for response: ORR was 45.0% [95% confidence interval (CI), 29.3%-61.5%; one complete response, 17 partial responses]. Median PFS was 8.2 months (95% CI, 2.7-9.6); 6- and 12-month PFS rates were 53.4% (95% CI, 36.6%-67.6%) and 28.1% (95% CI, 14.2%-43.9%), respectively. Median OS was not reached (NR; 95% CI, 14.4-NR). Six- and 12-month OS rates were 92.5% (95% CI, 78.5%-97.5%) and 76.0% (95% CI, 57.1%-87.5%), respectively. Median DOR was 12.5 months (95% CI, 5.5-NR). Overall, 90.7% (39/43) of patients experienced treatment-related AEs; 25.6% (11/43) experienced grade ≥3 events. CONCLUSIONS: Atezolizumab in combination with bevacizumab showed promising efficacy and manageable safety in patients with advanced mucosal melanoma.