Murine cytotoxic CD4+ T cells in the tumor microenvironment are at a hyper-maturation stage of Th1 CD4+ T cells sustained by IL-12.

The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model featuring subcutaneous murine colon cancer and analyzed the dynamic changes of phenotype and function of the tumor-associated CD4+ T-cell response. We found that, even at a late stage of tumor growth, the tumor-infiltrating CD4+Foxp3- T cells still expressed effector molecules, inflammatory cytokines and molecules that are expressed at reduced levels in exhausted cells. We used microarrays to examine the gene-expression profiles of different subsets of CD4+ T cells and revealed that the tumor-infiltrating CD4+Foxp3- T cells expressed not only type 1 helper (Th1) cytokines, but also cytolytic granules such as those encoded by Gzmb and Prf1. In contrast to CD4+ regulatory T cells, these cells exclusively co-expressed natural killer receptor markers and cytolytic molecules as shown by flow-cytometry studies. We used an ex vivo killing assay and proved that they could directly suppress CT26 tumor cells through granzyme B and perforin. Finally, we used pathway analysis and ex vivo stimulation to confirm that the CD4+Foxp3- T cells expressed higher levels of IL12rb1 genes and were activated by the IL-12/IL-27 pathway. In conclusion, this work finds that, in late-stage tumors, the tumor-infiltrating lymphocyte population of CD4+ cells harbored a sustained, hyper-maturated Th1 status with cytotoxic function supported by IL-12.

Innate-like bystander-activated CD38+ HLA-DR+ CD8+ T cells play a pathogenic role in patients with chronic hepatitis C.

BACKGROUND AND AIMS: HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38-positive (CD38+ ) human leukocyte antigen DR-positive (HLA-DR+ ) CD8+ T cells are regarded as bystander CD8+ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8+ T cells play a pathogenic role in CHC. METHODS: Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38+ HLA-DR+ CD8+ T cells were studied. RESULTS: The percentage of CD38+ HLA-DR+ CD8+ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38- HLA-DR- CD8 T cells. They were largely composed of non-HCV-specific CD8+ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38+ HLA-DR+ CD8+ T cells had strong cytotoxicity, which could be inhibited by anti-DNAX accessory molecule 1, anti-NKG2 family member D, and anti-natural killer NKp30 antibodies. Lastly, the percentage of CD38+ HLA-DR+ CD8+ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. CONCLUSIONS: The TCR-independent, cytokine-responsive bystander CD38+ HLA-DR+ CD8+ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.

The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies.

BACKGROUND: The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. METHODS: We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, the patients who experienced grade 1-2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27-0.98; p = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24-1.02; p = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21-0.74; p = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17-0.69, p = 0.003) than patients without any of these irAEs. CONCLUSIONS: Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1-2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

Prognostic value of lymph node to primary tumor standardized uptake value ratio in unresectable esophageal cancer.

BACKGROUND: Unresectable esophageal cancer harbors high mortality despite chemoradiotherapy. Better patient selection for more personalized management may result in better treatment outcomes. We presume the ratio of maximum standardized uptake value (SUV) of metastatic lymph nodes to primary tumor (NTR) in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT) may provide prognostic information and further stratification of these patients. METHODS: The patients with non-metastatic and unresectable esophageal squamous cell carcinoma (SCC) receiving FDG PET/CT staging and treated by chemoradiotherapy were retrospectively reviewed. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cut-off value for NTR. Kaplan-Meier method and Cox regression model were used for survival analyses and multivariable analyses, respectively. RESULTS: From 2010 to 2016, 96 eligible patients were analyzed. The median follow-up time was 10.2 months (range 1.6 to 83.6 months). Using ROC analysis, the best NTR cut-off value was 0.46 for prediction of distant metastasis. The median distant metastasis-free survival (DMFS) was significantly lower in the high-NTR group (9.5 vs. 22.2 months, p = 0.002) and median overall survival (OS) (9.5 vs. 11.6 months, p = 0.013) was also significantly worse. Multivariable analysis revealed that NTR was an independent prognostic factor for DMFS (hazard ratio [HR] 1.81, p = 0.023) and OS (HR 1.77, p = 0.014). CONCLUSIONS: High pretreatment NTR predicts worse treatment outcomes and could be an easy-to-use and helpful prognostic factor to provide more personalized treatment for patients with non-metastatic and unresectable esophageal SCC.

The association between acute myocardial infarction and subsequent diagnosis of breast cancer: a nationwide, population-based cohort study.

Coronary artery disease (CAD) such as acute myocardial infarction (MI) share several common risk factors with cancers, and each disease may influence the prognosis of the other. Recently, acute MI was demonstrated to accelerate the outgrowth of preexisting breast cancer cells but the risk of breast cancer after MI remains unclear. This study aimed to investigate the association between acute MI and a subsequent diagnosis of breast cancer. Female patients with and without a history of acute MI were identified from nationwide databases in Taiwan. Patients with a diagnosis of cancer, MI or CAD prior to the study period were excluded. After reducing confounding through inverse probability of treatment weighting, we compared the incidence of newly diagnosed breast cancer between patients with a history of acute MI and those without. As a result, a total of 66,445 female patients were obtained, including 15,263 patients with a history of acute MI and 51,182 patients without. The incidences of breast cancer during follow-up were 1.93 (95% confidence interval [CI] 1.78-2.09) and 1.80 (95% CI 1.67-1.93) per 1,000 person-years for patients with and without a history of acute MI, respectively. The hazard ratio (HR) was 1.05 (95% CI 0.78-1.41, P = 0.756). In subgroup analysis, breast cancer risk was significantly associated with acute MI in patients using antidiabetic drugs (HR 1.27; 95% CI 1.02-1.58) and in low to moderate urbanization levels (HR 1.28; 95% CI 1.06-1.53). In conclusion, the risk of newly diagnosed breast cancer was not increased in patients with acute MI when compared to general population without MI or CAD.

Immunophenotype and antitumor activity of cytokine-induced killer cells from patients with hepatocellular carcinoma.

BACKGROUND: Cytokine-induced killer (CIK) cells are heterogeneous lymphocytes from human peripheral blood mononucleated cells (PBMCs) co-cultured with several cytokines. The main purpose of this study is to evaluate the functional characteristics and anticancer ability of CIK cells from hepatocarcinoma (HCC) patients. METHODS: CIK cells were activated ex-vivo and expanded from PBMCs from HCC patients. The immunophenotype and the ex-vivo killing ability of CIK cells were evaluated. Human CIK cells were intravenously injected into NOD/SCID mice to evaluate the in vivo anticancer ability. RESULTS: More than 70% of CIK cells were CD3+CD8+, and 15%-30% were CD3+CD56+. These cells expressed an increased number of activated natural killer (NK) receptors, such as DNAM1 and NKG2D, and expressed low-immune checkpoint molecules, including PD-1, CTLA-4, and LAG-3. Among the chemokine receptors expressed by CIKs, CXCR3 and CD62L were elevated in CD8+ T cells, representing the trafficking ability to inflamed tumor sites. CIK cells possess the ex-vivo anticancer activity to different cell lines. To demonstrate in vivo antitumor ability, human CIK cells could significantly suppress the tumor of J7 bearing NOD/SCID mice. Furthermore, human immune cells could be detected in the peripheral blood and on the tumors after CIK injection. CONCLUSIONS: This study revealed that CIK cells from HCC patients possess cytotoxic properties, and express increased levels of effector NK receptors and chemokine molecules and lower levels of suppressive checkpoint receptors. CIK cells can suppress human HCC ex-vivo and in vivo. Future clinical trials of human CIK cell therapy for HCC are warranted.

Sex disparities in the association between acute myocardial infarction and colon cancer risk.

BACKGROUND: Acute myocardial infarction (AMI) and colon cancer share similar risk factors. Studies have suggested an association between AMI and colon cancer; however, evidence is conflicting. Whether sex disparities exist in this association in the real world remains unknown. METHODS: In this population-based retrospective cohort study, 94,780 and 97,987 male patients and 38,697 and 72,007 female patients with and without new-onset AMI, respectively, from January 1, 2001, to December 31, 2012, were enrolled from Taiwan's National Health Insurance Research Database. Inverse probability of treatment weighting (IPTW) was used to balance covariates across study groups. The primary outcome was a new diagnosis of colon cancer. RESULTS: The incidence rate of colon cancer was 1.54 (95% confidence interval [CI] = 1.46-1.62) and 1.40 (95% CI = 1.32-1.48) per 1000 person-years in the male patients and 1.62 (95% CI = 1.50-1.74) and 1.22 (95% CI = 1.13-1.32) in the female patients, in the AMI and non-AMI groups, respectively. AMI was associated with a significantly higher risk of colon cancer in the female patients (hazard ratio [HR] = 1.31, 95% CI = 1.06-1.61) but not in the male patients (HR = 1.09, 95% CI = 0.95-1.26). In the subgroup analysis, the association between AMI and colon cancer in the female patients was stronger in those aged ≥65 years (HR = 1.28, 95% CI = 1.13-1.44). CONCLUSIONS: An increased risk of colon cancer was observed only in the female patients with AMI. The association between AMI and colon cancer in the female patients was the most evident in those aged ≥65 years.

A Radiotherapy Dose Map-Guided Deep Learning Method for Predicting Pathological Complete Response in Esophageal Cancer Patients after Neoadjuvant Chemoradiotherapy Followed by Surgery.

Esophageal cancer is a deadly disease, and neoadjuvant chemoradiotherapy can improve patient survival, particularly for patients achieving a pathological complete response (ypCR). However, existing imaging methods struggle to accurately predict ypCR. This study explores computer-aided detection methods, considering both imaging data and radiotherapy dose variations to enhance prediction accuracy. It involved patients with node-positive esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiotherapy and surgery, with data collected from 2014 to 2017, randomly split into five subsets for 5-fold cross-validation. The algorithm DCRNet, an advanced version of OCRNet, integrates RT dose distribution into dose contextual representations (DCR), combining dose and pixel representation with ten soft regions. Among the 80 enrolled patients (mean age 55.68 years, primarily male, with stage III disease and middle-part lesions), the ypCR rate was 28.75%, showing no significant demographic or disease differences between the ypCR and non-ypCR groups. Among the three summarization methods, the maximum value across the CTV method produced the best results with an AUC of 0.928. The HRNetV2p model with DCR performed the best among the four backbone models tested, with an AUC of 0.928 (95% CI, 0.884-0.972) based on 5-fold cross-validation, showing significant improvement compared to other models. This underscores DCR-equipped models' superior AUC outcomes. The study highlights the potential of dose-guided deep learning in ypCR prediction, necessitating larger, multicenter studies to validate the results.

Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer.

Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.

EV-miRome-wide profiling uncovers miR-320c for detecting metastatic colorectal cancer and monitoring the therapeutic response.

PURPOSE: Molecular composition of circulating small extracellular vesicles (EVs) does not merely reflect the cells of origin, but also is enriched in specific biomolecules directly associated with the cellular transformation. However, while most of the currently identified EV-miRs are only geared towards one-dimensional disease detection, their application for long-term tracking and treatment response monitoring has been largely elusive. METHODS: We established and optimized a rapid, sensitive and robust liquid biopsy sampling method, and further used small RNA sequencing to comprehensively catalogue EV-miRomes in association with the progression and outcome of metastatic colorectal cancer (mCRC). RESULTS: By cross-comparison of EV-miRomes (n = 290) from multi-stage and longitudinal cohorts, we uncovered a 15-EV-miR signature with dual detection and long-term monitoring of tumor size progression for mCRC. From this panel, EV-miR-320c was uncovered as a strong clinical marker - aside from its diagnostic power and a therapeutic monitoring performance superior to carcinoembryonic antigen (CEA), its high expression has also been linked to lower overall survival and a greater likelihood of disease recurrence. Further, integrative analyses of tissue transcriptomic and liquid biopsy implicated this 15-EV-miR signature in programming the mesenchymal-epithelial transition (MET) for distant localization of the metastasized cells and also in creating a tumor-favoring metastatic niche. CONCLUSION: Our clinically-oriented delineation of the mCRC-associated circulating EV-miRomes systematically revealed the functional significance of these liquid biopsy markers and further strengthen their translational potential in mCRC therapeutic monitoring.

Therapeutic Role of Inducible Nitric Oxide Synthase Expressing Myeloid-Derived Suppressor Cells in Acetaminophen-Induced Murine Liver Failure.

Background: Acetaminophen (APAP) overdose is one of the major etiologies of liver failure. Hepatocyte necrosis induced by toxic metabolites of APAP can activate proinflammatory responses, including elastase-expressing neutrophils, to exacerbate liver injury. Myeloid-derived suppressor cells (MDSCs) increased in inflammation can inhibit proinflammatory responses. Our aim is to investigate the role of MDSC in APAP-induced liver failure and the possible therapeutic application. Methods: BLAB/c mice were injected with a sublethal/lethal dose of APAP as the murine model of liver failure. MDSCs were defined as CD11b+Gr-1+ cells with the ability of T-cell suppression. Results: A sublethal challenge of APAP could increase the intrahepatic MDSC and protect mice against subsequent lethal challenge of APAP, lipopolysaccharide (LPS)/D-galatosamine or concanavalin A. This protection was lost if MDSCs were depleted and inducible nitric oxide synthase (iNOS) was the key molecule in this MDSC-mediated protection. Taking advantage of these observations, different bone marrow-derived MDSCs (BM-MDSCs) were generated. Among different cytokine-treated BM-MDSCs, tumor necrosis factor alpha/LPS-primed MDSCs (TNF-α/LPS MDSCs) had the strongest liver-protection ability after adoptive transfer. Further mechanistic explorations showed, iNOS-expressing TNF-α/LPS MDSCs induced the apoptosis of activated neutrophil and decreased the intrahepatic infiltration of elastase-expressing neutrophil. Moreover, we generated MDSCs from human peripheral blood mononuclear cells (PBMCs) with similar phenotype. Conclusion: We demonstrated the protective role of MDSCs and therapeutic effect of TNF-α/LPS MDSCs in APAP-induced liver failure. MDSC might protect against the APAP-induced liver failure by reducing the intrahepatic infiltration of activated neutrophil to limit inflammation. Therefore, a therapeutic role of MDSCs for APAP-induced liver failure was proposed.

Prognostic Value of Lymph Node-To-Primary Tumor Standardized Uptake Value Ratio in Esophageal Squamous Cell Carcinoma Treated with Definitive Chemoradiotherapy.

We aimed to investigate the prognostic value of the relative maximum standardized uptake value (SUV) of metastatic lymph node (LN) compared with that of primary tumor (SUVLN / SUVTumor) based on a pretreatment [18F]-FDG PET/CT scan in patients with clinically node-positive esophageal squamous cell carcinoma (cN+ ESCC) treated with definitive chemoradiotherapy (dCRT). We retrospectively evaluated cN+ ESCC patients who underwent a PET/CT scan before dCRT. Time-dependent receiver operating characteristics analysis was performed to identify the optimal cutoff value for SUVLN / SUVTumor. Prognostic influences of SUVLN / SUVTumor on distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated using the Kaplan-Meier method and log-rank test for univariate analysis and Cox's proportional hazards regression model for multivariate analysis. We identified 112 patients with newly diagnosed cN+ ESCC. After a median follow-up of 32.0 months, 50 (44.6%) patients had distant failure and 84 (75.0%) patients died. Patients with high SUVLN / SUVTumor (≥ 0.39) experienced worse outcomes than low SUVLN / SUVTumor (< 0.39) (two-year DMFS: 26% vs. 70%, p < 0.001; two-year OS: 21% vs. 48%, p = 0.001). Multivariate analysis showed that SUVLN / SUVTumor was an independent prognostic factor for both DMFS (adjusted HR 2.24, 95% CI 1.34-3.75, p = 0.002) and OS (adjusted HR 1.61, 95% CI 1.03-2.53, p = 0.037). Pretreatment of SUVLN / SUVTumor is a simple and useful marker for prognosticating DMFS and OS in cN+ ESCC patients treated with dCRT, which may help in tailoring treatment and designing future clinical trials.

Immune Checkpoint Inhibitors for Advanced Melanoma: Experience at a Single Institution in Taiwan.

Background: Immune checkpoint inhibitors (ICIs) have significantly changed the current approach to cancer treatment. Although the use of ICIs has become the standard of care for advanced melanoma, reports of ICI use among Asian populations with melanoma are limited. Therefore, we conducted this retrospective study to assess the efficacy and safety of ICI use in Taiwanese patients. Patients: Patients with histologically confirmed melanoma treated with ICIs at Linkou Chang Gung Memorial Hospital from January 2014 to July 2019 were retrospectively reviewed. Univariant and multivariant analyses were performed to identify possible prognostic factors. Results: Among 80 patients, 45 were treatment-naïve (56.3%), and 35 received prior systemic drugs other than ICIs. Regarding treatment regimens, patients were treated with ipilimumab (n = 9), nivolumab (n = 33), pembrolizumab (n = 16), or combination drugs (n = 22). Nine patients achieved either a complete (n = 2) or partial (n = 7) response and 13 patients were stable, with a resulting response rate of 11.3% and disease control rate of 27.5%. As of the last follow-up in January 2020, patients treated with combination drugs had longer median progression-free survival (PFS) of 5.6 (95% confidence interval [CI]: 1.6-9.6) months than nivolumab (2.9 months, 95% CI: 1.9-3.9 months), pembrolizumab (3.2 months, 95% CI: 2.6-3.8 months), and ipilimumab (2.6 months, 95% CI: 2.4-2.8 months; p = 0.011). No significant differences in overall survival (OS) among the four regimens (p = 0.891) were noted. In the multivariate analysis, combination treatment, disease control, and performance ≤ 1 were independent prognostic factors for PFS. Liver metastases and no disease control were independent unfavorable prognostic factors for OS. The most common factor was skin toxicity (45%), followed by endocrine toxicity (18.8%). Patients undergoing combination treatment experienced more frequent and serious adverse events than patients undergoing monotherapy. Conclusion: ICIs demonstrated efficacy and safety in Taiwanese patients with melanoma. Combination treatment showed the greatest efficacy, but this was also accompanied by greater toxicity among the four regimens. In addition, we identified important prognostic factors, such as liver metastases, performance status, and tumor response, for both PFS and OS. These findings could provide physicians with more information to justify clinical outcomes observed in Asian patients with advanced melanoma.

Induction of liver-specific intrahepatic myeloid cells aggregation expands CD8 T cell and inhibits growth of murine hepatoma.

Toll-Like Receptor 9 (TLR9) stimulation selectively triggers the formation of a cell cluster termed intrahepatic myeloid aggregation for T cell expansion" (iMATE) in a mouse chronic viral hepatitis model. iMATE expands cytotoxic T cells and controls viral hepatitis infection. The liver-specific immune response prompted this investigation of whether the effect could control tumor growth in the murine hepatic tumor model. Murine hepatic BNL cells were used to establish an orthotropic liver tumor model. We found that intravenous infusion of TLR 9 agonist, CpG oligodeoxynucleotide (ODN) induced iMATE formation in non-tumor parts of liver and suppressed the murine BNL tumor growth. The ratio of intra-tumor CD8+ T cells have increased after CpG ODN. These cells expressed higher levels of effector and checkpoint molecules, and produce more Th1 cytokine upon ex vivo stimulation. The CD11b+Ly6ChiLy6G - subset of CD11b+ myeloid cells in the tumor microenvironment has increased. Both CD11b+Ly6ChiLy6G - and CD11b+Ly6CloLy6G+ subsets expressed higher level of interferon-gamma post CpG ODN treatment, although still presented a suppressive phenotype. Their suppressive ability was decreased, instead, the targeted CD8+ T cell proliferation was promoted at a higher dose of CD11b+Ly6ChiLy6G- cells. The phenomenon was further proven in DEN induced liver tumor model. In conclusion, systemic CpG ODN treatment induced iMATE formation that expanded effector CD8+ T cells to control tumor growth in the mouse hepatic tumor model. This novel strategy provides a new rationale for liver-specific tumor immunotherapy.

Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies.

With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5-91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management.

Impact of Detection Method and Accompanying Ductal Carcinoma in Situ on Prognosis of T1a,bN0 Breast Cancer.

Background: T1a,bN0 breast cancer is not easily detected. Before mammography became widespread, most cases were discovered only after the development of symptoms. The presence of ductal carcinoma in situ (DCIS) affects the detectability of associated invasive cancer; however, the prognostic value of concomitant DCIS is controversial. This study compared the characteristics of screening-detected and symptom-detected T1a,bN0 breast cancer, and investigated the impact of accompanying DCIS on detection and prognosis. Patients and Methods: Data were collected from a single hospital between 2000 and 2009. Of 5,690 primary breast cancers patients, 438 met the criteria for T1a,bN0M0. Logistic regression models were used to identify prognostic indicators and their association with the detection method. Survival analyses were performed to estimate distant relapse-free survival (DRFS) and breast cancer-specific survival (BCSS). Results: Tumors in 79 and 359 patients were detected by screening and development of symptoms, respectively. Symptomatic cancer patients were younger, more likely to receive a mastectomy, and had larger accompanying DCIS lesions; their 10-year DRFS rates were worse than those of patients with screening-detected tumors (91.1% vs. 100% respectively, p=0.049). Patients with large accompanying DCIS (≥2 cm) had markedly worse 10-year DRFS (77.1% vs. 97.4%, p<0.001) and BCSS (94.3% vs. 98.9%, p<0.001). Conclusion: T1a,bN0 breast cancers detected owing to symptoms are more likely to have larger accompanying DCIS. T1a,bN0 patients with large accompanying DCIS have worse DRFS and BCSS. It is important to consider associated DCIS size when evaluating prognosis in T1a,bN0 breast cancer patients.

Combination of palonosetron, aprepitant, and dexamethasone as primary antiemetic prophylaxis for cisplatin-based chemotherapy.

BACKGROUND: The purpose of this study was to evaluate the efficacy of combined treatment with the long-acting 5-hydroxytryptamine receptor-3 antagonist, palonosetron, the neurokinin-1 receptor antagonist, oral aprepitant, and dexamethasone as primary antiemetic prophylaxis for cancer patients receiving highly emetogenic cisplatin-based chemotherapy. METHODS: Chemotherapy-naïve patients received the triple combination of palonosetron (0.25 mg), aprepitant (125 mg on day 1 and 80 mg on days 2 and 3), and dexamethasone (20 mg) from the beginning of highly emetogenic chemotherapy with cisplatin-based (≥50 mg/m(2)) regimens. The primary endpoint was a complete response (no emetic episodes and no rescue antiemetics) during the days 1-6. RESULTS: Sixty-nine hospitalized patients receiving chemotherapy from September 2012 to October 2014 were analyzed. Complete response of vomiting and nausea-free was achieved in 97.1% and 85.5% of patients in the first cycle, respectively, and 96.7% and 83.6% of patients in the second cycle, respectively. Common adverse events in all 69 patients included constipation (43%), hiccup (26%), and headache (4%). CONCLUSION: The combination of palonosetron, aprepitant, and dexamethasone as primary antiemetic prophylaxis for cancer patients with highly emetogenic cisplatin-based chemotherapy is effective.

A Simple Risk Model to Predict Survival in Patients With Carcinoma of Unknown Primary Origin.

Carcinoma of unknown primary origin (CUP) is characterized by diverse histological subtypes and clinical presentations, ranging from clinically indolent to frankly aggressive behaviors. This study aimed to identify prognostic factors of CUP and to develop a simple risk model to predict survival in a cohort of Asian patients.We retrospectively reviewed 190 patients diagnosed with CUP between 2007 and 2012 at a single medical center in Taiwan. The clinicopathological parameters and outcomes of our cohort were analyzed. A risk model was developed using multivariate logistic regression and a prognostic score was generated.The prognostic score was calculated based on 3 independent prognostic variables: the Eastern Cooperative Oncology Group (ECOG) scale (0 points if the score was 1, 2 points if it was 2-4), visceral organ involvement (0 points if no involvement, 1 point if involved), and the neutrophil-to-lymphocyte ratio (0 points if ≤3, 1 point if >3). Patients were stratified into good (score 0), intermediate (score 1-2), and poor (score 3-4) prognostic groups based on the risk model. The median survival (95% confidence interval) was 1086 days (500-1617, n = 42), 305 days (237-372, n = 75), and 64 days (44-84, n = 73) for the good, intermediate, and poor prognostic groups, respectively. The c-statistics using the risk model and ECOG scale for the outcome of 1-year mortality were 0.80 and 0.70 (P = 0.038), respectively.In this study, we developed a simple risk model that accurately predicted survival in patients with CUP. This scoring system may be used to help patients and clinicians determine appropriate treatments.