Cation-eutaxy-enabled III-V-derived van der Waals crystals as memristive semiconductors.

Novel two-dimensional semiconductor crystals can exhibit diverse physical properties beyond their inherent semiconducting attributes, making their pursuit paramount. Memristive properties, as exemplars of these attributes, are predominantly manifested in wide-bandgap materials. However, simultaneously harnessing semiconductor properties alongside memristive characteristics to produce memtransistors is challenging. Herein we prepared a class of semiconducting III-V-derived van der Waals crystals, specifically the HxA1-xBX form, exhibiting memristive characteristics. To identify candidates for the material synthesis, we conducted a systematic high-throughput screening, leading us to 44 prospective III-V candidates; of these, we successfully synthesized ten, including nitrides, phosphides, arsenides and antimonides. These materials exhibited intriguing characteristics such as electrochemical polarization and memristive phenomena while retaining their semiconductive attributes. We demonstrated the gate-tunable synaptic and logic functions within single-gate memtransistors, capitalizing on the synergistic interplay between the semiconducting and memristive properties of our two-dimensional crystals. Our approach guides the discovery of van der Waals materials with unique properties from unconventional crystal symmetries.

Phase 2 trial of avelumab in combination with gemcitabine in advanced leiomyosarcoma as a second-line treatment (EAGLES, Korean Cancer Study Group UN18-09).

BACKGROUND: In this single-arm, multicenter, phase 2 trial, the authors evaluated the efficacy and safety of avelumab plus gemcitabine in patients with leiomyosarcoma (LMS) who failed on first-line chemotherapy. METHODS: Patients with advanced LMS received avelumab 10 mg/kg on days 1 and 15 (for up to 24 months) plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle until they developed disease progression or intolerable toxicity. The primary end point was the objective response rate (ORR). RESULTS: In total, 38 patients were enrolled. Of these, 35 patients were evaluable, and the ORR was 20% (95% confidence interval; [CI], 8%-37%). The disease control rate was 71%, and the median duration of response was 21.8 months (range, 7.6 to ≥43.3 months). The median progression free-survival was 5.6 months (95% CI, 4.5-6.8 months), and the median overall survival was 27.5 months (95% CI, 20.4-34.6 months). Grade 3-4 adverse events occurred in 70% of patients, of which neutropenia was the most common (54%). Immune-mediated adverse events occurred in five patients (14%; hypothyroidism, n = 3; hepatitis, n = 2). Patients who had a higher density of tumor-infiltrating lymphocytes (greater than the median) exhibited better ORR (35% vs. 8%; p = .104), progression-free survival (median, 7.3 vs. 3.3 months; p = .024), and overall survival (median, not reached vs. 21.5 months; p = .027). CONCLUSIONS: The combination of avelumab and gemcitabine demonstrated promising efficacy and manageable safety in patients with advanced LMS who progressed on first-line therapy. Tumor-infiltrating lymphocyte density may be an important factor in predicting the response to combining immunotherapy with chemotherapy.

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

Experiences and Perceptions of Social Connection Among Minoritized Older Adults With HIV During the COVID-19 Pandemic.

PURPOSE: Older people with HIV (OPWH; aged ≥50 years) have unique vulnerabilities to intersecting risks for marginalization and isolation. The current qualitative study explored perceptions of social connection during the coronavirus disease 2019 (COVID-19) pandemic. METHOD: Purposive sampling was used to recruit participants from two local community-based organizations (CBOs) in the Greater Boston area. Recruitment occurred through dissemination of flyers by staff of the CBOs. Semi-structured interviews were conducted between October 2021 and March 2022. Data were analyzed using thematic analysis. RESULTS: Of 22 participants, most were women (63.6%) and Hispanic/Latinx or African American/Black (86.4%). Participants viewed social connection as an important aspect of well-being, but acknowledged that COVID-19 induced social isolation. There were gender differences in social connection. Technology was adopted by all participants that allowed connection to others. Pre-existing relationships with support groups and CBOs facilitated improved social connection and well-being. CONCLUSION: Focused attention should be on individuals not linked to CBOs or social services and those who lack access or have barriers to technology use, as they may be at the most significant risk for isolation. [Journal of Gerontological Nursing, xx(xx), xx-xx.].

The Effect of Mesenchymal Stem Cells on Dry Eye in Sjogren Syndrome Mouse Model.

Sjögren's syndrome (SS) is a systemic autoimmune disease delineated by chronic lymphocytic infiltrates into the lacrimal or salivary glands, leading to severe dry eye and dry mouth. Mesenchymal stem cells have been shown to be effective in treating numerous autoimmune diseases. This study aimed to illustrate the effects of mesenchymal stem cells on the attenuation of dry eyes (DE) through the inhibition of autophagy markers in a SS mouse model. NOD/ShiLtJ female mice with developed DE were treated with either subconjunctival or lacrimal gland injections of hMSCs (Catholic MASTER Cells). After maintenance for 14 days, clinical DE markers such as tear secretion and corneal staining were observed, as well as goblet cell counts in the conjunctiva, infiltration of inflammatory foci, B and T cells, and autophagy markers in the lacrimal glands. Proinflammatory cytokine expressions of the cornea and conjunctiva, as well as the lacrimal glands, were examined. Clinical markers, such as tear secretion and corneal stain scores, goblet cell counts in the conjunctiva, and foci infiltrations in the lacrimal glands were attenuated in mice treated with subconjunctival or lacrimal gland injections of hMSCs compared to the PBS-treated control group. B cell marker B220 decreased in the lacrimal glands of hMSCs-treated mice, as well as reduced proinflammatory cytokine expressions in the lacrimal glands and cornea. Notably, expression of autophagy markers ATG5 and LC3B-II, as well as HIF-1α and mTOR which play roles in the pathways of autophagy modulation, were shown to be attenuated in the lacrimal glands of hMSCs-treated mice compared to the PBS-treated control mice. Treatment with hMSCs by lacrimal gland or subconjunctival injection demonstrated the alleviation of DE through the repression of autophagy markers, suggesting the therapeutic potentials of hMSCs in a SS mouse model.

CRISPR-Cas9-Based Gene Knockout of Immune Checkpoints in Expanded NK Cells.

Natural killer (NK) cell immunotherapy has emerged as a novel treatment modality for various cancer types, including leukemia. The modulation of inhibitory signaling pathways in T cells and NK cells has been the subject of extensive investigation in both preclinical and clinical settings in recent years. Nonetheless, further research is imperative to optimize antileukemic activities, especially regarding NK-cell-based immunotherapies. The central scientific question of this study pertains to the potential for boosting cytotoxicity in expanded and activated NK cells through the inhibition of inhibitory receptors. To address this question, we employed the CRISPR-Cas9 system to target three distinct inhibitory signaling pathways in NK cells. Specifically, we examined the roles of A2AR within the metabolic purinergic signaling pathway, CBLB as an intracellular regulator in NK cells, and the surface receptors NKG2A and CD96 in enhancing the antileukemic efficacy of NK cells. Following the successful expansion of NK cells, they were transfected with Cas9+sgRNA RNP to knockout A2AR, CBLB, NKG2A, and CD96. The analysis of indel frequencies for all four targets revealed good knockout efficiencies in expanded NK cells, resulting in diminished protein expression as confirmed by flow cytometry and Western blot analysis. Our in vitro killing assays demonstrated that NKG2A and CBLB knockout led to only a marginal improvement in the cytotoxicity of NK cells against AML and B-ALL cells. Furthermore, the antileukemic activity of CD96 knockout NK cells did not yield significant enhancements, and the blockade of A2AR did not result in significant improvement in killing efficiency. In conclusion, our findings suggest that CRISPR-Cas9-based knockout strategies for immune checkpoints might not be sufficient to efficiently boost the antileukemic functions of expanded (and activated) NK cells and, at the same time, point to the need for strong cellular activating signals, as this can be achieved, for example, via transgenic chimeric antigen receptor expression.

Long-term outcomes in patients with advanced and/or metastatic non-small cell lung cancer who completed 2 years of immune checkpoint inhibitors or achieved a durable response after discontinuation without disease progression: Multicenter, real-world data (KCSG LU20-11).

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown significant improvements in patients with advanced non-small cell lung cancer (NSCLC). One of the major issues with ICIs is determining the optimal treatment duration. METHODS: This multicenter, retrospective study analyzed clinical outcomes in patients with NSCLC who completed 2 years of ICI therapy or were treated for more than 6 months and then discontinued ICIs without disease progression at 11 medical centers in Korea between August 2017 and December 2020. RESULTS: Ninety-six patients who completed 2 years of ICIs were reviewed. The median durations of treatment and follow-up were 24.0 and 33.9 months, respectively. The objective response rate (ORR) was 85.4%. The median progression-free survival (PFS) and overall survival (OS) periods were not reached. After completion, the PFS and OS rates were 81.1% and 96.4%, respectively, at 12 months. Forty-three patients were identified who discontinued ICIs without disease progression: 26 (60.5%) for adverse events and 17 (39.5%) for other causes. The median durations of treatment and follow-up were 10.5 and 21.2 months, respectively. The ORR was 90.7%. The median PFS and OS periods were not reached. After discontinuation, the PFS and OS rates were 71.0% and 90.0%, respectively, at 12 months. CONCLUSIONS: A significantly high proportion of patients who completed 2 years of ICI therapy continued to experience long-term PFS. Even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long-term survival. LAY SUMMARY: The optimal treatment duration for immune checkpoint inhibitors (ICIs) remains to be determined. This study reports the long-term outcomes of patients with non-small cell lung cancer who completed 2 years of ICI therapy or achieved a durable response after the discontinuation of ICIs without disease progression in real-world practice. A significantly high proportion of patients who completed 2 years of ICIs continued to experience long-term progression-free survival. In addition, even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long-term survival.

Prognostic role of tumor subtype and germline BRCA mutation in advanced breast cancer patients treated with palbociclib plus endocrine therapy.

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor which shows promising effect in hormone receptor-positive breast cancer. The purpose of this study is to evaluate the real-world efficacy and toxicity of palbociclib plus endocrine therapy. METHODS: This is a retrospective study performed in two tertiary referral hospitals in Korea. Advanced breast cancer patients who were treated with 1st-line palbociclib plus endocrine therapy were enrolled. RESULTS: A total of 216 patients were included between August 2016 and May 2019. Median age was 56 (29-89) years old and 75 patients (34.7%) were premenopausal. Median progression-free survival (PFS) was 33.0 months [95% confidence interval (CI) 24.7 to 41.3] and objective response rate was 59.3%. Luminal B patients had shorter PFS (33.0 months vs. Not reached, p = 0.019) and tendency of lower ORR (58.3 vs. 62.0%, p = 0.19) compared to luminal A patients. Multivariate analysis revealed luminal B (adjusted hazard ratio 1.90, p = 0.038) and germline BRCA mutation (adjusted hazard ratio 5.57, p = 0.002) as an independent poor prognostic factor for PFS. The most common grade 3 or 4 adverse event was neutropenia (86.7%). CONCLUSION: The efficacy and toxicity of palbociclib in the real world were comparable to those of clinical trials. In addition, palbociclib with endocrine therapy was an effective treatment option for young patients. Luminal B and germline BRCA mutation were associated with inferior outcome.

Ambient Humidity-Induced Phase Separation for Fiber Morphology Engineering toward Piezoelectric Self-Powered Sensing.

Electrospun polymeric piezoelectric fibers have a considerable potential for shape-adaptive mechanical energy harvesting and self-powered sensing in biomedical, wearable, and industrial applications. However, their unsatisfactory piezoelectric performance remains an issue to be overcome. While strategies for increasing the crystallinity of electroactive ß phases have thus far been the major focus in realizing enhanced piezoelectric performance, tailoring the fiber morphology can also be a promising alternative. Herein, a design strategy that combines the nonsolvent-induced phase separation of a polymer/solvent/water ternary system and electrospinning for fabricating piezoelectric poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE) fibers with surface porosity under ambient humidity is presented. Notably, electrospun P(VDF-TrFE) fibers with higher surface porosity outperform their smooth-surfaced counterparts with a higher ß phase content in terms of output voltage and power generation. Theoretical and numerical studies also underpin the contribution of the structural porosity to the harvesting performance, which is attributable to local stress concentration and reduced dielectric constant due to the air in the pores. This porous fiber design can broaden the application prospects of shape-adaptive energy harvesting and self-powered sensing based on piezoelectric polymer fibers with enhanced voltage and power performance, as successfully demonstrated in this work by developing a communication system based on self-powered motion sensing.

High tumor hexokinase-2 expression promotes a pro-tumorigenic immune microenvironment by modulating CD8+/regulatory T-cell infiltration.

BACKGROUND: Relationship between cancer cell glycolysis and the landscape of tumor immune microenvironment in human cancers was investigated. METHODS: Forty-one fresh lung adenocarcinoma (ADC) tissues were analyzed using flow cytometry for comprehensive immunoprofiling. Formalin-fixed tissues were immunostained for hexokinase-2 (HK2) to assess cancer cell glycolysis. For validation, formalin-fixed tissues from 375 lung ADC, 118 lung squamous cell carcinoma (SqCC), 338 colon ADC, and 78 lung cancer patients treated with anti-PD-1/PD-L1 immunotherapy were immunostained for HK2, CD8, and FOXP3. RESULTS: Based on immunoprofiling of lung ADC, HK2 tumor expression was associated with the composition of lymphoid cells rather than myeloid cells. High HK2 tumor expression was associated with immunosuppressive/pro-tumorigenic features, especially decreased ratio of CD8 + T-cells to Tregs (rho = -0.415, P = 0.012). This correlation was also confirmed in four different cohorts including lung ADC and SqCC, colon ADC, and the immunotherapy cohort (rho = -0.175~-0.335, all P < 0.05). A low CD8 + T-cell to Treg ratio was associated with poor progression-free survival and overall survival in lung SqCC patients, and a shorter overall survival in the immunotherapy cohort (all, P < 0.05). CONCLUSION: An increase in HK2 expression may contribute to shaping the immunosuppressive/pro-tumorigenic tumor microenvironment by modulating the CD8 + T-cell to Treg ratio. Targeting tumor HK2 expression might be a potential strategy for enhancing anti-tumor immunity.

First-line pembrolizumab versus dabrafenib/trametinib treatment for BRAF V600-mutant advanced melanoma.

BACKGROUND: Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma. OBJECTIVE: To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation. METHODS: Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n = 40) or dabrafenib/trametinib (n = 32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed. RESULTS: A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio = 2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P = .375) and response rate (P = .123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8+ T cells. LIMITATIONS: Analysis was conducted in a retrospective manner. CONCLUSION: Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

Discovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues.

BACKGROUND: Immune checkpoint inhibitor (ICI) has an emerging role in several types of cancer. However, the mechanisms of acquired resistance (AR) to ICI have not been elucidated yet. To identify these mechanisms, we analyzed the pre- and post-ICI paired tumor samples in patients with AR. METHODS: Six patients with renal cell carcinoma, urothelial cell carcinoma, or head and neck cancer, who showed an initial response to ICI followed by progression and had available paired tissue samples, were retrospectively analyzed. Whole exome sequencing, RNA sequencing, and multiplex immunohistochemistry were performed on pre-treatment and resistant tumor samples. RESULTS: The median time to AR was 370 days (range, 210 to 739). Increased expression of alternative immune checkpoints including TIM3, LAG3, and PD-1 as well as increased CD8+ tumor-infiltrating lymphocytes were observed in post-treatment tumor than in pre-treatment tumor of a renal cell carcinoma patient. In contrast, CD8+ T cells and immunosuppressive markers were all decreased at AR in another patient with human papillomavirus-positive head and neck squamous cell carcinoma. This patient had an evident APOBEC-associated signature, and the tumor mutation burden increased at AR. Resistant tumor tissue of this patient harbored a missense mutation (E542K) in PIK3CA. No significant aberrations of antigen-presenting machinery or IFN-γ pathway were detected in any patient. CONCLUSIONS: Our study findings suggest that the observed increase in immunosuppressive markers after ICI might contribute to AR. Moreover, APOBEC-mediated PIK3CA mutagenesis might be an AR mechanism. To validate these mechanisms of AR, further studies with enough sample size are required.

Pan-cancer methylation analysis reveals an inverse correlation of tumor immunogenicity with methylation aberrancy.

Tumor immunogenicity is driven by various genomic and transcriptomic factors but the association with the overall status of methylation aberrancy is not well established. We analyzed The Cancer Genome Atlas pan-cancer database to investigate whether the overall methylation aberrancy links to the immune evasion of tumor. We created the definitions of hypermethylation burden, hypomethylation burden and methylation burden to establish the values that represent the degree of methylation aberrancy from human methylation 450 K array data. Both hypermethylation burden and hypomethylation burden significantly correlated with global methylation level as well as methylation subtypes defined in previous literatures. Then we evaluated whether methylation burden correlates with tumor immunogenicity and found that methylation burden showed a significant negative correlation with cytolytic activity score, which represent cytotoxic T cell activity, in pan-cancer (Spearman rho = - 0.37, p < 0.001) and 30 of 33 individual cancer types. Furthermore, this correlation was independent of mutation burden and chromosomal instability in multivariate regression analysis. We validated the findings in the external cohorts and outcomes of patients who were treated with immune checkpoint inhibitors, which showed that high methylation burden group had significantly poor progression-free survival (Hazard ratio 1.74, p = 0.038). Overall, the degree of methylation aberrancy negatively correlated with tumor immunogenicity. These findings emphasize the importance of methylation aberrancy for tumors to evade immune surveillance and warrant further development of methylation biomarker.

Immunogenicity of Influenza Vaccination in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

Among prospectively enrolled adult patients with cancer receiving immune checkpoint inhibitors (ICIs; n = 46) or cytotoxic agents (n = 90), seroprotection and seroconversion rates after seasonal quadrivalent influenza vaccinations were higher with ICI than with cytotoxic chemotherapy. These results support annual influenza vaccinations for cancer patients receiving ICIs. Clinical Trials Registration clinicaltrials.gov (NCT03590808).

Prediction of pathologic complete response using image-guided biopsy after neoadjuvant chemotherapy in breast cancer patients selected based on MRI findings: a prospective feasibility trial.

PURPOSE: Accurate prediction of pathologic complete response (pCR) in breast cancer using magnetic resonance imaging (MRI) and ultrasound (US)-guided biopsy may aid in selecting patients who forego surgery for breast cancer. We evaluated the accuracy of US-guided biopsy aided by MRI in predicting pCR in the breast after neoadjuvant chemotherapy (NAC). METHODS: After completion of NAC, 40 patients with near pCR (either tumor size ≤ 0.5 cm or lesion-to-background signal enhancement ratio (L-to-B SER) ≤ 1.6 on MRI) and no diffused residual microcalcifications were prospectively enrolled at a single institution. US-guided multiple core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) of the tumor bed, followed by standard surgical excision, was performed. Matched biopsy and surgical specimens were compared to assess pCR. The negative predictive value (NPV), accuracy, and false-negative rate (FNR) were analyzed. RESULTS: pCR was confirmed in 27 (67.5%) surgical specimens. Preoperative biopsy had an NPV, accuracy, and FNR of 87.1%, 90.0%, and 30.8%, respectively. NPV for hormone receptor-negative and hormone receptor-positive tumors were 83.3% and 100%, respectively. Obtaining at least 5 biopsy cores based on tumor size ≤ 0.5 cm and an L-to-B SER of ≤ 1.6 on MRI (27 patients) resulted in 100% NPV and accuracy. No differences in accuracy were noted between CNB and VAB (90% vs. 90%). CONCLUSIONS: Investigation using stringent MRI criteria and ultrasound-guided biopsy could accurately predict patients with pCR after NAC. A larger prospective clinical trial evaluating the clinical safety of breast surgery omission after NAC in selected patients will be conducted based on these findings.

A Phase II Trial of Pazopanib in Patients with Metastatic Alveolar Soft Part Sarcoma.

LESSONS LEARNED: Pazopanib shows a modest efficacy in metastatic alveolar soft part sarcoma.Clinical outcomes were comparable to those in previous studies using antiangiogenic drugs.Further prospective studies evaluating the benefit of pazopanib in alveolar soft part sarcoma with a larger sample are warranted to validate results. BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignant tumor characterized by an unbalanced translocation, t(X;17)(p11.2;q25), which leads to the fusion of ASPSCR1 to the TFE3 transcription factor. Because this results in the upregulation of angiogenesis-related transcripts, antiangiogenic drugs have been used in ASPS patients. METHODS: This open-label, single-arm, multicenter, investigator-initiated phase II trial was designed to evaluate efficacy and safety of pazopanib 800 mg once daily in patients with metastatic ASPS. The primary endpoint was investigator-assessed overall response rate (ORR), and secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS). 68Ga-RGD (Arg-Gly-Asp) positron emission tomography (PET) scan and gene expression profiling using NanoString platform were performed for biomarker analysis. RESULTS: Six patients with histologically confirmed metastatic ASPS were enrolled between December 2013 and November 2014. Among six patients, one achieved a partial response (PR) (ORR 16.7%) and five patients showed stable disease (SD). With a median follow-up of 33 months (range 18.7-39.3 months), median PFS was 5.5 months (95% confidence interval [CI] 3.4-7.6 months), and median OS was not reached. There were no severe toxicities except one patient with grade 3 diarrhea. CONCLUSION: Pazopanib showed modest antitumor activity with manageable toxicities for patients with metastatic ASPS.

Prognostic Impact of Pregnancy in Korean Patients with Breast Cancer.

BACKGROUND: Pregnancy concurrent with, shortly before, or after breast cancer poses unique challenges because hormonal changes in pregnancy potentially interact with breast cancer outcomes. MATERIALS AND METHODS: We studied a cohort of 3,687 female patients of reproductive age (<50 years) with breast cancer, linking a large institutional database and the nationwide claims database to comprehensively capture exposure status and tumor characteristics. Exposures included breast cancer during pregnancy, postpartum breast cancer (<12 months after delivery), and pregnancy after breast cancer. RESULTS: Forty-five patients with postpartum breast cancer were significantly more likely to have advanced stage, hormone receptor-negative tumor and to be younger than 35 years at diagnosis than those without postpartum breast cancer. This trend was not observed with 18 patients with breast cancer during pregnancy. The unadjusted 5-year survival rates were 77% versus 96% for patients with postpartum breast cancer versus their counterparts, 89% versus 96% for patients with breast cancer during pregnancy versus their counterparts, and 98% versus 96% for patients with pregnancy after breast cancer versus their counterparts, respectively. In the multivariable analyses, postpartum breast cancer exhibited hazard ratios for death of 1.57 (95% confidence interval [CI], 0.82-2.99), whereas those for breast cancer during pregnancy and pregnancy after breast cancer were 1.09 (95% CI, 0.15-7.91) and 0.86 (95% CI, 0.26-2.83), respectively. CONCLUSION: Postpartum breast cancer, but not breast cancer during pregnancy, was associated with advanced stage, younger age at diagnosis (<35 years), hormone receptor-negative disease, and poorer survival. Pregnancy after breast cancer did not compromise overall survival. IMPLICATIONS FOR PRACTICE: Although pregnancy around the time of diagnosis of breast cancer is expected to become increasingly common with maternal age at first childbirth on the rise, data on the prognostic impact of pregnancy have been inconsistent and rare from Asian populations. In this investigation of a Korean patient cohort with breast cancer, pregnancy-associated breast cancer was associated with advanced stage, younger age at diagnosis (<35 years), hormone receptor-negative disease, and poorer survival. This adverse impact of pregnancy on the prognosis was apparent with postpartum breast cancer but not observed with breast cancer during pregnancy. Pregnancy after breast cancer did not compromise overall survival.

Safety and efficacy of immune checkpoint inhibitors for end-stage renal disease patients undergoing dialysis: a retrospective case series and literature review.

Despite the lack of safety and efficacy data regarding immune checkpoint inhibitors (ICIs) for renal dysfunction, they have been approved to treat even in the patients with end-stage renal disease (ESRD). We report our experience with ICI administration to three ESRD patients undergoing hemodialysis. One of the patients had a partial response for several months; however, the other patients had a stable disease while undergoing dialysis. The toxicity was tolerable; however, one patient developed grade 2 pneumonitis. A literature review of other rarely reported cases of hemodialysis revealed that 10 out of 13 patients had a partial response or complete response; in addition, grade 3 or grade 4 immune-related adverse events occurred in 3 patients. ESRD combined with dialysis may not be a contraindication for the use of ICIs. ICIs can be beneficial to ESRD patients undergoing dialysis. However, caution is needed regarding immune-related adverse events. Further prospective studies involving pharmacokinetic analyses are necessary to obtain reliable safety and efficacy data.

NK92-CD16 cells are cytotoxic to non-small cell lung cancer cell lines that have acquired resistance to tyrosine kinase inhibitors.

BACKGROUND: Treatment with tyrosine kinase inhibitors (TKIs) has improved the outcomes for patients with non-small cell lung cancer (NSCLC) harboring targetable driver mutations. However, acquired resistance to TKIs invariably develops within approximately 1 year of treatment by various mechanisms, including gatekeeper mutations, alternative pathway activation and histological transformations. Because immunotherapy is an option for patients with drug-resistant cancers, we generated several TKI-resistant NSCLC cell lines in vitro, and then evaluated the cytotoxicity of NK92-CD16 cells to these resistant cells. MATERIALS AND METHODS: TKI-resistant NSCLC cells (H3122CR1, H3122LR1, H3122CR1LR1, PC-9GR, PC-9ER, EBC-CR1 and EBC-CR2) were established from NCI-H3122 (EML4-ALK fusion), PC-9 (EGFR exon19 deletion) and EBC-1 (MET amplification) after continuous exposure to crizotinib, ceritinib, gefitinib, erlotinib and capmatinib. Expression of ligands for natural killer (NK) cell receptors and total EGFR were analyzed using flow cytometry. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) using anti-EGFR monoclonal antibody (mAb) cetuximab were measured using NK92-CD16 as effectors and detected using the 51Chromium-release assay. RESULTS: We found that NK92-CD16 cells preferentially killed TKI-resistant NSCLC cells when compared with their parental NSCLC cells. Mechanistically, intracellular adhesion molecule 1 (ICAM-1) was up-regulated in the TKI-resistant NSCLC cells and patients' tumors, and the ICAM-1 up-regulated cancer cells lines were less susceptible to NK cytotoxicity by blocking ICAM-1. Moreover, NK92-CD16 cell-induced cytotoxicity toward TKI-resistant NSCLC cells was enhanced in the presence of cetuximab, an EGFR-targeting mAb. CONCLUSION: These data suggest that combinational treatment with NK cell-based immunotherapy and cetuximab may be promising for patients with TKI-resistant NSCLC.

Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.

BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway. METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells. RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs. CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.