Thromboembolic events in patients who received adjuvant chemotherapy for gastric cancer: a single-center retrospective study.

BACKGROUND: Thromboembolic events (TEEs) are significant adverse events that can cause serious morbidities and mortality in cancer patients receiving chemotherapy. Patients with gastric cancer (GC) treated with palliative chemotherapy have been reported to experience a TEE incidence of 5-27%. However, very few reports have addressed TEEs in adjuvant chemotherapy (AC) for GC. METHODS: This study retrospectively analyzed 611 GC patients (stage II: 309, III: 302) who started AC with capecitabine/oxaliplatin (167 patients) or S-1 (444 patients) after undergoing curative resection between January 2013 and June 2020 at a single center. The incidence of TEEs during AC or within 1 year after AC completion was investigated, while analyzing the factors that influenced the TEEs' occurrence. RESULTS: TEEs were confirmed in 20 patients (3.3%), and TEEs occurred in almost all patients in the S-1 group (19 patients). The most common TEE types were cerebral infarction and pulmonary thromboembolism (five patients each). Although old age (≥ 70 years, p < 0.0001), S-1 treatment (p = 0.021), and hypertension (p = 0.017) were identified as significant risk factors for TEEs in univariate analysis, only old age showed a statistically significant correlation with TEEs' occurrence in multivariate analysis (odds ratio: 3.07; 95% confidence interval 1.11-8.48; p = 0.031). CONCLUSIONS: TEEs occurred in fewer patients with GC who had been treated with AC than patients who had received palliative chemotherapy in previous reports. However, elderly GC patients who are undergoing AC require more careful surveillance for possible TEEs, considering relatively higher incidence of them.

Atypical occurrence of anti-Ma2-associated encephalitis after breast cancer surgery and COVID-19.

In this report, we present a rare case of anti-Ma2-associated encephalitis concurrent with coronavirus disease 2019 (COVID-19) following breast cancer surgery. The patient exhibited minimal clinical symptoms of COVID-19 infection but developed seizures and altered mental status after surgery, leading to diagnosis of a classic paraneoplastic syndrome. This case highlights the possibility of paraneoplastic neurological syndrome even after cancer surgery and the need for careful consideration of post-acute infection syndromes when neurological symptoms occur following an infection.

Smooth, Chemically Altered Nucleating Platform for Abrupt Performance Enhancement of Ultrathin Cu-Layer-Based Transparent Electrodes.

Rapid advances in flexible optoelectronic devices necessitate the concomitant development of high-performance, cost-efficient, and flexible transparent conductive electrodes (TCEs). This Letter reports an abrupt enhancement in the optoelectronic characteristics of ultrathin Cu-layer-based TCEs via Ar+-mediated modulation of the chemical and physical states of a ZnO support surface. This approach strongly regulates the growth mode for the subsequently deposited Cu layer, in addition to marked alteration to the ZnO/Cu interface states, resulting in exceptional TCE performance in the form of ZnO/Cu/ZnO TCEs. The resultant Haacke figure of merit (T10/Rs) of 0.063 Ω-1, 53% greater than that of the unaltered, otherwise identical structure, corresponds to a record-high value for Cu-layer-based TCEs. Moreover, the enhanced TCE performance in this approach is shown to be highly sustainable under severe simultaneous loadings of electrical, thermal, and mechanical stresses.

Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response.

PURPOSE: Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy. Materials and Methods: We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA. RESULTS: Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10-4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker. CONCLUSION: Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer.

BACKGROUND: Targeting the DNA damage repair (DDR) pathways is an attractive strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral kinase inhibitor of ataxia telangiectasia and Rad3 related protein, which is a master regulator of DDR. We conducted a phase II trial of ceralasertib plus durvalumab in patients with previously treated advanced gastric cancer (AGC) to demonstrate the safety, tolerability, and clinical activity of the combination. METHODS: This phase II, open-label, single-center, non-randomized study was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with AGC. The study drug regimen was ceralasertib (240 mg two times a day) days 15-28 in a 28-day cycle in combination with durvalumab (1500 mg) at day 1 every 4 weeks. The primary end point was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (V.1.1). Exploratory biomarker analysis was performed using fresh tumor biopsies in all enrolled patients. RESULTS: Among 31 patients, the ORR, disease control rate, median progression-free survival (PFS), and overall survival were 22.6% (95% CI 9.6% to 41.1%), 58.1% (95% CI 39.1% to 75.5%), 3.0 (95% CI 2.1 to 3.9) months, and 6.7 (95% CI 3.8 to 9.6) months, respectively. Common adverse events were manageable with dose modification. A subgroup of patients with a loss of ataxia telangiectasia mutated (ATM) expression and/or high proportion of mutational signature attributable to homologous repair deficiency (sig. HRD) demonstrated a significantly longer PFS than those with intact ATM and low sig. HRD (5.60 vs 1.65 months; HR 0.13, 95% CI 0.045 to 0.39; long-rank p<0.001). During the study treatment, upregulation of the innate immune response by cytosolic DNA, activation of intratumoral lymphocytes, and expansion of circulating tumor-reactive CD8 +T cell clones were identified in responders. Enrichment of the tumor vasculature signature was associated with treatment resistance. CONCLUSIONS: Ceralasertib plus durvalumab has promising antitumor activity, with durable responses in patients with refractory AGC. Thus, a biomarker-driven trial is required. TRIAL REGISTRATION: NCT03780608.

Longitudinal monitoring by next-generation sequencing of plasma cell-free DNA in ALK rearranged NSCLC patients treated with ALK tyrosine kinase inhibitors.

BACKGROUND: Patients with ALK-rearranged non-small cell lung cancer (ALK+ NSCLC) inevitably acquire resistance to ALK inhibitors. Longitudinal monitoring of cell-free plasma DNA (cfDNA) next-generation sequencing (NGS) could predict the response and resistance to tyrosine kinase inhibitor (TKI) therapy in ALK+ NSCLC. METHODS: Patients with ALK+ NSCLC determined by standard tissue testing and planned to undergo TKI therapy were prospectively recruited. Plasma was collected at pretreatment, 2 months-post therapy, and at progression for cfDNA-NGS analysis, Guardant 360. RESULTS: Among 92 patients enrolled, circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%): 43 ALK fusions (62.3%) and two ALK mutations without fusion (2.8%). Two patients showed ALK-resistance mutations after ceritinib; G1202R, and co-occurring G1202R and T1151R. Eight patients developed ALK resistance mutations after crizotinib therapy; L1196M (n = 5), G1269A (n = 1), G1202R (n = 1), and co-occurring F1174L, G1202R, and G1269A (n = 1). Absence of ctDNA at baseline was significantly associated with longer progression-free survival (PFS; median 36.1 vs. 11.4 months, p = 0.0049) and overall survival (OS; not reached vs. 29.3 months, p = 0.0200). ctDNA clearance at 2 months (n = 29) was associated with significantly longer PFS (25.4 vs. 11.6 months, p = 0.0012) and OS (not reached vs. 26.1 months, p = 0.0307) than those without clearance (n = 22). Patients with co-occurring TP53 alterations and ALK fusions at baseline (n = 16) showed significantly shorter PFS (7.28 vs. 13.0 months, p = 0.0307) than those without TP53 alterations (n = 25). CONCLUSIONS: cfDNA-NGS facilitates detection of ALK fusions and resistance mutations, assessment of prognosis, and monitoring dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK-TKI.

Spatial immune heterogeneity of hypoxia-induced exhausted features in high-grade glioma.

The tumor immune microenvironment (TIME) in high-grade glioma (HGG) exhibits high spatial heterogeneity. Though the tumor core and peripheral regions have different biological features, the cause of this spatial heterogeneity has not been clearly elucidated. Here, we examined the spatial heterogeneity of HGG using core and peripheral regions obtained separately from the patients with HGG. We analyzed infiltrating immune cells by flow cytometry from 34 patients with HGG and the transcriptomes by RNA-seq analysis from 18 patients with HGG. Peripheral region-infiltrating immune cells were in vitro cultured in hypoxic conditions and their immunophenotypes analyzed. We analyzed whether the frequencies of exhausted CD8+ T cells and immunosuppressive cells in the core or peripheral regions are associated with the survival of patients with HGG. We found that terminally exhausted CD8+ T cells and immunosuppressive cells, including regulatory T (TREG) cells and M2 tumor-associated macrophages (TAMs), are more enriched in the core regions than the peripheral regions. Terminally exhausted and immunosuppressive profiles in the core region significantly correlated with the hypoxia signature, which was enriched in the core region. Importantly, in vitro culture of peripheral region-infiltrating immune cells in hypoxic conditions resulted in an increase in terminally exhausted CD8+ T cells, CTLA-4+ TREG cells, and M2 TAMs. Finally, we found that a high frequency of PD-1+CTLA-4+CD8+ T cells in the core regions was significantly associated with decreased progression-free survival of patients with HGG. The hypoxic condition in the core region of HGG directly induces an immunosuppressive TIME, which is associated with patient survival.

When to apply immune checkpoint inhibitor in patients with refractory advanced gastric cancer.

Background: Immune checkpoint inhibitors (ICIs) show clinical benefit in patients with refractory advanced gastric cancer (GC). The ICIs in routine clinical practice have been used in various treatment lines. Therefore, we investigated the timing for application of ICI in patients with refractory advanced GC. Methods: We analyzed 187 patients with refractory advanced or recurrent GC who received ICIS as a 3rd- or 4th-line treatment between September 2015 and October 2020. Clinical outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were evaluated. Results: Among 187 patients, 105 received ICIs as a 3rd-line treatment and 82 as a 4th line. The ORR for ICIs was 10.5% (11/105) in 3rd line and 8.5% (7/82) in 4th line. The DCR for ICIs was 36.2% (38/105) in 3rd-line treatment and 31.7% (26/82) in 4th line. There was no significant difference for ORR (P = 0.819) or DCR (P = 0.870). The median PFS and OS to ICIs was 1.4 months (95% CI, 1.1 to 1.8 months) and 4.4 months (95% CI, 1.6 to 7.2 months) in 3rd line and 1.8 months (95% CI, 1.4 to 2.3 months) and 2.8 months (95% CI, 2.2 to 3.4 months) in 4th line. The median PFS and OS to ICIs was not different between 3rd line and 4th line (P = 0.495 and P=0.208, respectively). There were also no significant difference for PFS and OS between PD-L1-positive tumors (CPS≥1) and PD-L1-negative tumors (P = 0.910 and P=0.931, respectively). Conclusions: ICIs showed similar clinical benefits in the 3rd-line and 4th-line settings. ICIs might be a reasonable approach for patients with refractory GC in the setting of 3rd-line or 4th-line treatment options.

Expanded natural killer cells augment the antimyeloma effect of daratumumab, bortezomib, and dexamethasone in a mouse model.

The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.

Association between non-alcoholic fatty liver disease and the risk of biliary tract cancers: A South Korean nationwide cohort study.

AIMS: The association between non-alcoholic fatty liver disease (NAFLD) and cholangiocarcinoma has been previously reported only in case-control studies. Therefore, we conducted this nationwide cohort study to evaluate the longitudinal association between NAFLD and the risk of biliary tract cancer (BTC), including cholangiocarcinoma and gallbladder cancer. METHODS: We included 8,120,674 adults who underwent national health screening in 2009 based on the Korean National Health Insurance Service data. NAFLD was determined using the fatty liver index: ≥60, NAFLD; 30-59, intermediate score; <30, no NAFLD. The exclusion criteria were baseline clinical liver disease, heavy alcohol consumption and cancer. Participants were followed up until December 2017 for the development of BTC. Cox proportional hazards regression models were performed. RESULTS: During the median follow-up period of 7.2 years, 13,043 patients were with newly diagnosed BTC. NAFLD was associated with an increased risk of BTC (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.20-1.37) compared with no NAFLD. The aHRs for the association of cholangiocarcinoma and gallbladder cancer with NAFLD were 1.33 (95% CI, 1.23-1.43) and 1.14 (95% CI, 1.003-1.29), respectively. Overall, the aHR for BTC tended to increase with the increasing fatty liver index (P for trend < 0.001). Concomitant NAFLD and diabetes were associated with an increased risk of BTC by 47% (aHR, 1.47; 95% CI, 1.35-1.60). CONCLUSION: In this nationwide cohort study, NAFLD was associated with an increased risk of cholangiocarcinoma and gallbladder cancer. This finding suggests that NAFLD is a potentially modifiable risk factor for BTC.

Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer.

Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti-PD-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1+ CD8+ T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. SIGNIFICANCE: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features.See related commentary by Fontana and Smyth, p. 2126.This article is highlighted in the In This Issue feature, p. 2113.

Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea.

Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline BRCA (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.'s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline BRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. "Discordant: Opposite classification" was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. "Discordant: Laboratory's uncertain classification" was found in 22.2% of the sample (six patients). All discrepancies were generated during interpretation of BRCA 2 gene sequencing. Further studies and standardization of genetic testing for BRCA 1/2 genes are required.

Chromatin accessibility of circulating CD8+ T cells predicts treatment response to PD-1 blockade in patients with gastric cancer.

Although tumor genomic profiling has identified small subsets of gastric cancer (GC) patients with clinical benefit from anti-PD-1 treatment, not all responses can be explained by tumor sequencing alone. We investigate epigenetic elements responsible for the differential response to anti-PD-1 therapy by quantitatively assessing the genome-wide chromatin accessibility of circulating CD8+ T cells in patients' peripheral blood. Using an assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify unique open regions of chromatin that significantly distinguish anti-PD-1 therapy responders from non-responders. GC patients with high chromatin openness of circulating CD8+ T cells are significantly enriched in the responder group. Concordantly, patients with high chromatin openness at specific genomic positions of their circulating CD8+ T cells demonstrate significantly better survival than those with closed chromatin. Here we reveal that epigenetic characteristics of baseline CD8+ T cells can be used to identify metastatic GC patients who may benefit from anti-PD-1 therapy.

Prevalence and Predictive Factors for Upfront Dose Reduction of the First Cycle of First-Line Chemotherapy in Older Adults with Metastatic Solid Cancer: Korean Cancer Study Group (KCSG) Multicenter Study.

Old age alone does not reflect an intolerability to chemotherapy. However, upfront dose reduction (UDR) of the first cycle of first-line palliative chemotherapy has sometimes been chosen by physicians for older adults with metastatic cancer due to concerns regarding adverse events. The development of predictive factors for UDR of palliative chemotherapy would be helpful for treatment planning among older adults. This was a secondary analysis of a study on predicting adverse events of first-line palliative chemotherapy in 296 patients (≥70 years) with solid cancer. We assessed the prevalence of UDR of the first cycle of first-line chemotherapy and the association of UDR with the variables of geriatric assessment (GA) and chemotherapy compliance. Among the 296 patients, 177 (59.8%) patients were treated with UDR. The mean percentage of UDR for the total patient group was 19.2% (range: 4-47%) of the standard dose. In a multivariate analysis, poor performance status (PS) and living without a spouse were independent predictive factors of UDR of first-line palliative chemotherapy in older adults. Patients with UDR showed fewer grade 3-5 adverse events versus the standard dose group. Study completion as planned was significantly higher in the UDR group versus the standard dose group. Older adults with UDR better tolerated chemotherapy than patients with a standard dose.

A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.

We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.

TOX-expressing terminally exhausted tumor-infiltrating CD8+ T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer.

Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8+ tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8+ TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer. We also evaluated the reinvigoration of exhausted CD8+ TILs upon ex vivo treatment with inhibitory checkpoint blockers. TOX-expressing PD-1highCD8+ TILs had the highest expression of immune checkpoint receptors (ICRs), the most terminally exhausted features, and the highest tumor antigen reactivity among PD-1+CD8+ TILs. Bladder cancer patients with a high percentage of PD-1highTOX+CD8+ TILs had more progressed T-cell exhaustion features and higher programmed death-ligand 1 expression in tumor tissues. TIGIT was the most frequent co-expressed ICR on PD-1+CD8+ TILs, and TIGIT blockade enhanced the PD-1 blockade-mediated cytokine production by CD8+ TILs from bladder cancer patients. Our findings provide an improved understanding of the heterogeneous exhaustion status of CD8+ TILs and additional immunotherapy strategies to improve outcomes of bladder cancer patients.

Tumor-promoting macrophages prevail in malignant ascites of advanced gastric cancer.

Gastric cancer (GC) patients develop malignant ascites as the disease progresses owing to peritoneal metastasis. GC patients with malignant ascites have a rapidly deteriorating clinical course with short survival following the onset of malignant ascites. Better optimized treatment strategies for this subset of patients are needed. To define the cellular characteristics of malignant ascites of GC, we used single-cell RNA sequencing to characterize tumor cells and tumor-associated macrophages (TAMs) from four samples of malignant ascites and one sample of cerebrospinal fluid. Reference transcriptomes for M1 and M2 macrophages were generated by in vitro differentiation of healthy blood-derived monocytes and applied to assess the inflammatory properties of TAMs. We analyzed 180 cells, including tumor cells, macrophages, and mesothelial cells. Dynamic exchange of tumor-promoting signals, including the CCL3-CCR1 or IL1B-IL1R2 interactions, suggests macrophage recruitment and anti-inflammatory tuning by tumor cells. By comparing these data with reference transcriptomes for M1-type and M2-type macrophages, we found noninflammatory characteristics in macrophages recovered from the malignant ascites of GC. Using public datasets, we demonstrated that the single-cell transcriptome-driven M2-specific signature was associated with poor prognosis in GC. Our data indicate that the anti-inflammatory characteristics of TAMs are controlled by tumor cells and present implications for treatment strategies for GC patients in which combination treatment targeting cancer cells and macrophages may have a reciprocal synergistic effect.

Docetaxel rechallenge in metastatic castration-resistant prostate cancer: A retrospective, single-center study.

PURPOSE: To assess the efficacy and safety of docetaxel rechallenge in the salvage setting in metastatic castration-resistant prostate cancer (mCRPC) patients. MATERIALS AND METHODS: Clinicopathologic data from patients treated with docetaxel rechallenge were collected from a single-center cancer registry. Among 227 patients who received first-line docetaxel for mCRPC between January 2011 and June 2019, 23 undergo rechallenge docetaxel after failure to androgen receptor targeting agents and/or cabazitaxel treatment. Endpoints included radiologic progression-free survival (PFS), treatment duration, and prostate-specific antigen (PSA) response and safety. RESULTS: Overall, 30%, 44%, 13%, and 13% of patients received docetaxel rechallenge as either the third, fourth, fifth, or sixth-line therapy, respectively, at a median of 23.6 months after stopping first-line docetaxel. With first-line docetaxel and rechallenge, median treatment duration was 6.4 and 3.3 months, respectively. With docetaxel rechallenge, PSA response was 35% (95% confidence interval [CI], 15% to 54%) and median PFS was 4.5 months (95% CI, 1.9 to 7.1 months). The median OS was 24.3 months (95% CI, 4.6 to 44.0 months). There were 7 severe adverse events (grade 3 or more) including anemia (8.7%), neutropenia, thrombocytopenia, leukopenia, diarrhea, and nausea (4.3% each). CONCLUSIONS: Docetaxel rechallenge showed meaningful anti-tumor activity with acceptable toxicity in heavily pretreated patients with mCRPC.

Distinct tumor immune microenvironments in primary and metastatic lesions in gastric cancer patients.

This study compared the tumor immune microenvironments (TIMEs) of primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). CD4+ and CD8+ T-cell density and PD-L1 expression were evaluated by multiplex immunohistochemistry, DNA mismatch repair (MMR) by immunohistochemistry, and immune-related genes by RNA sequencing. Twenty-three patients who underwent surgical treatment for PGC and MGC were enrolled in this study. CD8+ T-cell, PD-L1+ cell, and PD-L1+CK+ cell densities were significantly lower in MGC than PGC. PD-L1 positivity using a combined positive score (≥ 1%) and deficient MMR were observed in 52.2% and 8.7% of PGC samples, respectively, whereas both occurred in only 4.3% of MGC samples. The most frequent TIME types were inflamed (34.8%) and adaptive immune resistance (34.8%) in PGC, and immune desert (65.2%) and immunological ignorance (73.9%) in MGC. In transcriptome analysis, the expression of the T-cell inflamed gene set and co-stimulatory gene module was down-regulated in MGC compared to PGC. The total CD8+ T-cell density was an independent prognostic marker in both PGC and MGC (univariate P = 0.002, multivariate P = 0.006). Our result suggest that the TIME of metastatic tumors was less immunologically active compared to that of primary tumors in gastric cancer patients.

Clinical outcomes of immune checkpoint inhibitors for patients with recurrent or metastatic head and neck cancer: real-world data in Korea.

BACKGROUND: Anti-PD1 inhibitors have been approved for the treatment of recurrent or metastatic head and neck cancer (HNC), as a result of Global Phase III trials. However, the clinical outcomes of immune checkpoint inhibitors in patients who are not eligible for clinical trials or have various medical conditions have not been fully elucidated. METHODS: We retrospectively reviewed 46 patients with recurrent or metastatic HNC who received pembrolizumab or nivolumab between June 2016 and June 2019. RESULTS: Thirty-five patients had head and neck squamous cell carcinoma (HNSCC) affecting the oropharynx, oral cavity, hypopharynx, larynx, nasal cavity, or paranasal sinuses, and eleven patients had nasopharyngeal cancer (NPC). The median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.8 months, respectively, for patients with HNSCC, and 4.3 months and 11.8 months, respectively, for patients with NPC. The objective response rate (ORR) in all patients was 21%. Of 30 patients with HNSCC, 5 patients achieved complete response and 2 achieved partial response (ORR 23%); 1 of 8 NPC patients achieved partial response (13%). Patients who previously underwent radiotherapy had better OS than those who did not (median OS, 7.6 months vs. 2.3 months, p = 0.006). OS was longer in patients treated with pembrolizumab than in those treated with nivolumab (median OS, 11.8 months vs. 6.8 months, p = 0.017). CONCLUSION: Consistent with previous reports, immune checkpoint inhibitors showed promising efficacy in patients with previously treated recurrent or metastatic HNC in a real-world setting.