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Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti–programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti–PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS P = 0.12; CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02–1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. Cancer Immunol Res; 4(7); 569–73. ©2016 AACR.

Progression free survival and overall survival using alternate cutoffs for prolonged benefit ({greater than or equal to} 120 days) and rapid progression (< 60 days).

Progression free survival and overall survival using alternate cutoffs for prolonged benefit ({greater than or equal to} 67% percentile) and rapid progression (< 33 percentile).

Legends for supplementary figures 1-3

GSEA analysis of mobocertinib and T-DM1 treated tumors versus mobocertinib-only treated tumors Genes involved in "INTERFERON ALPHA RESPONSE", "INFLAMMATORY RESPONSE", "INTERFERON GAMMA RESPONSE", "IL2 STAT5 SIGNALING", "TNFA SIGNALING VIA NFKB" and "IL6 JAK STAT3 SIGNALING" pathways of HALLMARK gene sets.

No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients.Significance:This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Figure S1

Damage is a common condition in ancient timber structures, whose influence on the mechanical properties of structures cannot be ignored. To study the mechanical properties of damaged hoop head mortise-tenon joint, four specimens with shrinkage gauge, including one intact joint specimen and three artificial simulated damaged joint specimens, are designed, and fabricated in this paper by regarding the global damage degree and column axial force as the variation of parameters. The failure mode, hysteresis curve, skeleton curve, ductility, and energy dissipation capacity of the specimens are studied by low-cyclic reversed loading tests. The results show that the failure pattern is randomly manifested as parallel-to-grain tensile cracking failure or vertical splitting failure of the beam tenon. When the global damage degree increases, the two types of damage are more likely to appear simultaneously. The global damage degree has a significant influence on the ultimate bending moment and energy dissipation capacity of hoop head mortise-tenon joints, and 2.4% of the global damage degree can lead to a significant decrease in both. The column axial force can affect the ultimate bending moment, ductility, and energy dissipation capacity of hoop head mortise-tenon joints. When the column axial force increases, the ultimate bending moment and energy dissipation capacity will increase, while the ductility will decrease.

No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients. Significance: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

BackgroundSmall cell lung cancer (SCLC) is a deadly disease with a 5-year survival of less than 7%. The addition of immunotherapy to chemotherapy was recently approved as first-line treatment; however, the improved clinical benefit is modest, highlighting an urgent need for new treatment strategies. Nemvaleukin alfa, a novel engineered interleukin-2 fusion protein currently in phase I–III studies, is designed to selectively expand cytotoxic natural killer (NK) cells and CD8+ T cells. Here, using a novel SCLC murine model, we investigated the effects of a mouse version of nemvaleukin (mNemvaleukin) on tumor growth and antitumor immunity.MethodsA novel Rb1−/−p53−/−p130−/− SCLC model that mimics human disease was generated. After confirming tumor burden by MRI, mice were randomized into four treatment groups: vehicle, mNemvaleukin alone, chemotherapy (cisplatin+etoposide) alone, or the combination of mNemvaleukin and chemotherapy. Tumor growth was measured by MRI and survival was recorded. Tumor-infiltrating lymphocytes and peripheral blood immune cells were analyzed by flow cytometry. Cytokine and chemokine secretion were quantified and transcriptomic analysis was performed to characterize the immune gene signatures.ResultsmNemvaleukin significantly inhibited SCLC tumor growth, which was further enhanced by the addition of chemotherapy. Combining mNemvaleukin with chemotherapy provided the most significant survival benefit. Profiling of tumor-infiltrating lymphocytes revealed mNemvaleukin expanded the total number of tumor-infiltrating NK and CD8+ T cells. Furthermore, mNemvaleukin increased the frequencies of activated and proliferating NK and CD8+ T cells in tumors. Similar immune alterations were observed in the peripheral blood of mNemvaleukin-treated mice. Of note, combining mNemvaleukin with chemotherapy had the strongest effects in activating effector and cytotoxic CD8+ T cells. mNemvaleukin alone, and in combination with chemotherapy, promoted proinflammatory cytokine and chemokine production, which was further confirmed by transcriptomic analysis.ConclusionsmNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.

BACKGROUND. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths in the United States. Although management strategies have evolved, there are continued controversies about the use of neoadjuvant chemotherapy (NAC) and pretreatment biliary drainage (PBD) in patients with resectable and potentially-resectable disease. AIMS. We aimed to characterize the practice trends and outcomes for NAC and PBD. METHODS. A single-center cohort study was performed. Electronic medical records were reviewed between 2011 and 2019, and 140 patients who had pancreaticoduodenectomy for PDAC were included. Diagnosis, treatment, and outcome data were captured. RESULTS. There were no statistically significant temporal trends relating to the use of chemotherapy and PBD. Overall, 41% of patients received NAC and had improved survival, independent of other factors. Of the 71% who received PBD, only 40% had appropriate indications; 30% experienced post-procedure complications and 34% required reintervention. Factors associated with the application of PBD included preoperative jaundice (OR 70.5, 95% CI 21.4–306.6) and evaluation by non-tertiary therapeutic endoscopists (OR 3.9, 95% CI 1.3–13.6). PBD was associated with a 12-day delay in surgery among those who did not receive NAC (p = 0.005), but there were no differences in surgical complications or mortality. CONCLUSIONS. Our findings suggest that (1) NAC may confer a survival benefit and (2) PBD should be reserved for individuals with jaundice requiring NAC. Implementation of guidelines by North American gastroenterology societies, multidisciplinary treatment models, and delivery of care at high-volume tertiary centers may help optimize management.

Person re-identification (re-ID) aims to match person images under different cameras with disjoint views. Although supervised re-ID has achieved great progress, unsupervised cross-domain re-ID remains a challenging work due to domain bias. In this work, we divide cross-domain re-ID task into two phases: domain-invariant features learning and domain-specific features learning. Our contributions are twofold. (i) To achieve domain-invariant features learning, a novel model called Pedestrian General Similarity (PGS) is proposed, which can eliminate two main factors that cause domain bias: image style and background. Compared with the existing re-ID models, PGS has better generalization ability. (ii) A novel pseudo label assignment method named Mutual Nearest Neighbors Pseudo Labeling (MNNPL) is proposed, which calculates pseudo labels based on the similarity between samples in the target domain, and the resulting pseudo labels are used to guide domain-specific feature learning. Extensive experiments are conducted on several large scale datasets, the results show that our method outperforms most published unsupervised cross-domain methods by a large margin.

Person re-identification (Re-ID) is aimed to identify the same person under different cameras with disjoint views. With the development of deep learning, supervised Re-ID has made great progress. However, most methods fail to be generalized to new domains due to the potential image distinctions between different domains, making it difficult to be applied in practical use. We propose an unsupervised domain-adaptive person re-identification method based on style transfer (STReID) to improve model cross-domain capability. In this work, a novel style transfer framework is proposed for Re-ID, which allows us to change the style of images while retaining content information. Specifically, STReID mainly includes two steps: first, each image in the source domain is converted into the target domain style and the identity (ID) information remains unchanged. Then the source domain images and style transferred images are combined to train a style-independent Re-ID model. Experiments show that our method achieves higher performance of unsupervised cross-domain person Re-ID.

Isocitrate dehydrogenase (IDH) mutations in low-grade gliomas (LGG) result in improved survival and DNA hypermethylation compared with IDH wild-type LGGs. IDH-mutant LGGs become hypomethylated during progression. It is uncertain whether methylation changes occur during IDH wild-type GBM progression and whether the methylome can be reprogrammed. This phase I study evaluated the safety, tolerability, efficacy, and methylome changes after l-methylfolate (LMF) treatment, in combination with temozolomide and bevacizumab in patients with recurrent high-grade glioma. Fourteen patients total, 13 with GBM, one with anaplastic astrocytoma, all IDH wild-type were enrolled in the study. All patients received LMF at either 15, 30, 60, or 90 mg daily plus temozolomide (75 mg/m2 5 days per month) and bevacizumab (10 mg/kg every two weeks).No MTD was identified. LMF-treated patients had median overall survival of 9.5 months [95% confidence interval (CI), 9.1–35.4] comparable with bevacizumab historical control 8.6 months (95% CI, 6.8–10.8). Six patients treated with LMF survived more than 650 days. Across all treatment doses, the most adverse events were diarrhea (7%, 1 patient, grade 2), reflux (7%, 1 patient, grade 2), and dysgeusia (7%, 1 patient, grade 2). In the six brains donated at death, there was a 25% increase in DNA methylated CpGs compared with the paired initial tumor. LMF in combination with temozolomide and bevacizumab was well tolerated in patients with recurrent IDH wild-type high-grade glioma. This small study did not establish a superior efficacy with addition of LMF compared with standard bevacizumab therapy; however, this study did show methylome reprogramming in high-grade glioma. Significance: Glioblastoma (GBM) is a primary brain tumor with a poor prognosis. Therapies to date have failed to improve survival. LGGs, with IDH mutations, have increased global DNA methylation and increased survival compared with GBMs. GBMs lack this mutation and have less DNA methylation. Here we show that the DNA methylome can be modified in GBM with LMF. Such treatment might be useful in methylome priming prior to immunotherapy.

Esophageal squamous cancer remains an important cause of mortality worldwide with two new immunotherapy drugs recently approved for metastatic disease.The authors review the epidemiology and genomics of esophageal squamous cell carcinoma. They also examine prior trials involving targeted agents under investigation as well immunotherapies that have been approved and novel combinations.Great advances have been made in characterizing the molecular changes in esophageal carcinoma. However, relatively few drugs have shown benefit in this disease. Targeted therapies have not shown to improve survival although many of these trials did not explore potential biomarkers. Pembrolizumab and nivolumab are now approved for esophageal squamous carcinoma but much more data are needed to understand how these agents may be used in non-metastatic settings. Novel treatments are still required as overall prognosis remains poor.

59 Background: 5-Fluorouracil (5-FU) is a component of first-line treatment regimens for metastatic colorectal cancer (mCRC). Historically, 5-FU is administered as a bolus followed by an infusion. However, the bolus dose adds substantial toxicity and is often withheld in patients with limited functional status or high-risk comorbidities, but its impact on treatment outcomes remains unclear. Small studies suggest that it may be omitted. The aim of this study was to determine whether omission of the 5-FU bolus is associated with a difference in overall survival (OS). Methods: An electronic health record-derived national multicenter oncology database from Flatiron Health was queried to select patients with mCRC who received a first-line 5-FU-containing regimen. Demographics, relevant labs, treatment details, and survival outcomes were collected. Propensity score (PrS) matching and OS analysis were performed incorporating age, race, sex, ECOG score, combination drug regimen, and baseline creatinine and bilirubin. Variables with p < 0.10 in univariable Cox proportional hazards models were included in the multivariable analysis. Results: We included 9741 patients with mCRC who received 5-FU-based regimens. All individuals received a 5-FU infusion, and 7901 (81%) also received a 5-FU bolus. Among our entire cohort, 43% were female, 23% were > 70 years, 66% were white, and 89% had ECOG ≤ 1. Over a median follow-up time of 19 months, 5847 patients (60%) died. In the unmatched univariable (HR 0.94, 95% CI 0.88-1.00, p = 0.06) and multivariable (aHR 0.85, 95% CI 0.93-1.06, p = 0.85) analyses, there was no association between the use of bolus 5-FU and OS. A number of factors were associated with an increased risk of death, including older age, high ECOG scores, and elevated bilirubin or creatinine levels. Similarly, in our PrS-matched dataset (n = 6126), the use of a 5-FU bolus was not associated with OS (HR 0.98; 95% CI 0.91-1.06; p = 0.64). Conclusions: The findings of our PrS-matched multicenter cohort study indicate that, after adjusting for host and treatment factors, 5-FU bolus dosing was not associated with an overall survival benefit among patients with mCRC. These results suggest that, in mCRC, the addition of a 5-FU bolus does not appear to add efficacy to regimens utilizing infusional 5-FU. Future work is necessary to determine the role of bolus dosing in the adjuvant setting and its impact on other clinically-relevant outcomes.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of pre-clinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion mutant cell lines, the IC(50) of mobocertinib was higher than poziotinib and comparable or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC(50) / WT EGFR IC(50) ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20(YVMA) allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20(G776>VC) lung tumors exhibited a sustained complete response to mobocertinib, while HER2 exon 20(YVMA) tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1) synergized with mobocertinib in HER2 exon 20(YVMA) tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4(+) T cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20(YVMA) insertion-mutant lung adenocarcinoma patients.

Neuropathic pain is a most challenging diseases worldwide, caused by the injury of nerve system. CircularRNAs (circRNAs) are revealed to be involved in various diseases, includingneuropathic pain. However, the waycircRNAsparticipate in the progress ofneuropathic painstill needs further study. Identifyingthe possible circRNAexpression patterns of neuropathic painis of great significance to understand its underlying mechanism. Previously, circ_0005075 has been regarded as an important oncogene in multiple cancers and it has been characterized as an inflammation‑associated circRNA in various processes. Nevertheless, the functional role of circ_0005075 in neuropathic pain development is still poorly known. In our present study, we observed circ_0005075 was obviously increased in CCI rat models. Knockdown of circ_0005075 repressed thebehaviors of neuropathic pain including mechanical and thermal hyperalgesia. Moreover, loss of circ_0005075 could repress the neuroinflammation via targeting COX-2, IL-6 and TNF-α whereas inducing IL-10 in vivo. Additionally, we predicted miR-151a-3p as the potential target of circ_0005075 using bioinformatics analysis. We displayed that miR-151a-3p was greatly reduced in CCI rats and circ_0005075 reversed the repressive effect of miR-151a-3p on neuropathic pain. For another, NOTCH2 has been shown to induce a variety of intracellular responses correlated withneuropathic pain. Here, we found NOTCH2 expression was strongly induced in CCI rats and miR-151a-3p. In addition, circ_0005075 significantly rescued NOTCH2 expression, which could be repressed by miR-151a-3p. To sum up, we indicated that loss ofcirc_0005075relieved neuropathic pain progression by inducement of miR-151a-3p and inactivation of NOTCH2 signaling.

Neuropathic pain caused by somatosensory nervous system dysfunction is a serious public health problem. Some long noncoding RNAs (lncRNAs) can participate in physiological processes involved in neuropathic pain. However, the effects of lncRNA DGCR5 in neuropathic pain have not been explored. Therefore, in our current study, we concentrated on the biological roles of DGCR5 in neuropathic pain. Here, it was observed that DGCR5 was significantly decreased in chronic sciatic nerve injury (CCI) rat models. DGCR5 overexpression was able to alleviate neuropathic pain development including mechanical and thermal hyperalgesia. In addition, the current understanding of miR-330-3p function in neuropathic pain remains largely incomplete. Here, we found that miR-330-3p was greatly increased in CCI rats and DGCR5 can modulate miR-330-3p expression negatively. Upregulation of DGCR5 repressed inflammation-correlated biomarkers including interleukin 6 (IL-6), tumor necrosis factor α, and IL-1β in CCI rats by sponging miR-330-3p. The negative correlation between DGCR5 and miR-330-3p was confirmed in our current study. Inhibition of miR-330-3p suppressed neuropathic pain progression by restraining neuroinflammation in vivo. In addition, PDCD4 was predicted as a downstream target of miR-330-3p. Furthermore, PDCD4 was significantly increased in CCI rats and DGCR5 regulated PDCD4 expression through sponging miR-330-3p in CCI rat models. Taken these together, it was implied that DGCR5/miR-330-3p/PDCD4 axis participated in neuropathic pain treatment.

Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation but can rarely occur after solid organ transplants. Small bowel and liver transplants are typically implicated, but solid organ transplant-associated GVHD has also been associated with other organs. We present a 40-year-old diabetic woman who underwent renal followed by pancreatic transplantation over a span of 21 months and ultimately developed acute classic GVHD. The diagnosis proved to be challenging in the context of confounding infections and inconclusive bone marrow and skin biopsy findings. She had multiorgan failure at the time of endoscopic confirmation and died after having minimal response to aggressive immunosuppression.

Malicious domains are key components to a variety of illicit online activities. We propose MalShoot, a graph embedding technique for detecting malicious domains using passive DNS database. We base its design on the intuition that a group of domains that share similar resolution information would have the same property, namely malicious or benign. MalShoot represents every domain as a low-dimensional vector according to its DNS resolution information. It automatically maps the domains that share similar resolution information to similar vectors while unrelated domains to distant vectors. Based on the vectorized representation of each domain, a machine-learning classifier is trained over a labeled dataset and is further applied to detect other malicious domains. We evaluate MalShoot using real-world DNS traffic collected from three ISP networks in China over two months. The experimental results show our approach can effectively detect malicious domains with a 96.08% true positive rate and a 0.1% false positive rate. Moreover, MalShoot scales well even in large datasets.

Person re-identification (person Re-ID) is mostly viewed as an image retrieval problem across different cameras. Most of existing models have achieved significant improvement on single-domain setting but failed to generalize to new domain due to the image style variations between domains. In this work, we aim to adapt a model trained on source domain to unlabeled target domain without significant performance drop. Thus, a novel style transfer framework that allows us to separate image style from content is proposed in Re-ID. Firstly, the source domain image is transferred to the target style while retaining the ID information. Then the source domain images and transferred images are combined to train a style-independent Re-ID model. Experiments show that we achieved higher performance of unsupervised cross-domain person Re-ID on the Market-1501 and DukeMTMC-reID datasets.

e24047 Background: The incidence of colorectal cancer in patients younger than 50 has been increasing over the past 2 decades. This demographic shift has important implications for survivorship care, in particular regarding issues of future fertility especially in light of USPSTF’s recommendation for colorectal cancer screening to begin at 45. Although ASCO has longstanding recommendations for fertility counseling in patients with cancer, the rates of fertility counseling in younger patients with colorectal cancer are unknown. Methods: Records for new patient visits for colorectal cancer in patients younger than age 55 in a large academic cancer center between 2012 and 2019 were queried for patient demographics, disease characteristics, and documentation of fertility counseling. Associations between demographic/clinical characteristics and fertility counseling were explored. Univariate and multivariable logistical regression analyses were performed using SAS v9.4. Results: Among 194 patients who met inclusion criteria, 39.2% of patients were female, 10.4% were African American, 31.4% had rectal cancer, and 69.6% were treated with curative intent. Approximately 14.5% of patients had Medicaid insurance. Age ranged from 22-55. The overall rate of fertility counseling among all patients was 15.5%. Of these patients, 43.3% were male. In univariate analysis, age less than or equal to 40 (p < 0.01), female gender (p = 0.03) and curative intent therapy (p = 0.03) were associated with fertility counseling. These factors were again statistically significant in multivariate analysis: age < 40, female, and curative intent therapy (Table). Race, stage of cancer, insurance status, prior exposure to chemotherapy, year of diagnosis and colon vs rectal cancer were not associated with counseling. Conclusions: The rate of fertility counseling was very low among patients with colorectal cancer, and exceptionally low among men. Despite changes in the demographics of colorectal cancer, it does not appear that appropriate changes have been made in fertility counseling. Increases in fertility counseling were not seen in more recent years despite recognition of increasing incidence in younger patients. Additional studies to identify barriers to counseling and strategies to improve survivorship care are urgently needed.[Table: see text]

Prolonged treatment with adjuvant valganciclovir has been shown in one retrospective study to exert a significant effect on overall survival (OS) in newly diagnosed patients with glioblastoma multiforme (GBM). However, studies evaluating the effectiveness of valganciclovir in the treatment of recurrent GBM have not been performed. We evaluated the effect of valganciclovir in the recurrent setting in combination with bevacizumab therapy. A retrospective analysis was performed on patients treated for recurrent GBM with off-label valganciclovir and bevacizumab at Vanderbilt University. We identified 13 patients who received valganciclovir plus bevacizumab at some point during their treatment, 8 of whom were started on valganciclovir and bevacizumab concurrently upon first recurrence, whereas 5 had valganciclovir added to their bevacizumab regimen prior to a second recurrence. of these patients, 12 were pathologically confirmed to have GBM, and 1 patient was diagnosed with gliosarcoma. We also identified an institutional cohort of 50 patients who had not been exposed to valganciclovir, but were treated with bevacizumab for first recurrence. The progression-free survival (PFS) at 6 months (PF6) and median OS (mOS) in the valganciclovir plus bevacizumab group was 62% and 13.1 months, respectively, for all 13 patients, and 50% and 11.3 months, respectively, for the 8 concurrently treated patients. In the institutional bevacizumab cohort, the PF6 and mOS were 34% and 8.7 months, respectively. In this retrospective analysis, valganciclovir in combination with bevacizumab exhibited a trend toward improved survival in patients with recurrent GBM. However, given the small sample size and the retrospective nature of this study, a larger prospective study is required to confirm these results.

e24081 Background: The incidence of colorectal cancer in patients younger than 50 has been increasing over the past two decades. This demographic shift has important implications for survivorship care, in particular regarding issues of future fertility. Although ASCO has a longstanding recommendation for fertility counseling in patients with cancer, the rates of fertility counseling in younger patients with colorectal cancer are unknown. Methods: Records for new patient visits for colorectal cancer in patients younger than age 55 in a large academic cancer center between 2016 and 2019 were retrospectively queried for patient demographics, disease characteristics, and documentation of fertility counseling. Associations between patient demographic/clinical characteristics and receipt of fertility counseling were explored. Univariate analyses and multivariable logistical regression analyses were performed using SAS v9.4. Results: Among the 136 patients who met inclusion criteria, 37.5% of patients were female, 16.2% were African American, 31.6% had rectal cancer, 20.7% of patients had Medicaid insurance. 63.7% were treated with curative intent. Age ranged from 22-55 (median = 46). Among all patients, 21/136 (15.4%) had documented fertility counseling. Of these, 11/51 (21.6%) patients were female and 10/85 (11.8%) were men. In univariate chi-square analysis, age less than or equal to 40 was associated with fertility counseling (p < 0.001) and curative intent therapy was numerically but not statistically associated with fertility counseling (p = 0.07). In multivariable analysis with logistical regression, age less than 40 (OR = 3.90, 95% CI [1.95, 7.81]), female gender (OR = 2.37, 95% CI [1.16, 4.84]), and curative intent therapy (OR = 3.26, 95% CI [1.14, 9.35]) were associated with fertility counseling. Race, stage of cancer, insurance status, prior exposure to chemotherapy, and colon vs rectal cancer were not associated with fertility counseling. Conclusions: The rate of fertility counseling was very low among patients with colorectal cancer, and exceptionally low among men with colorectal cancer. Despite changes in the demographics of colorectal cancer, it does not appear that appropriate changes have been made in fertility counseling. Additional studies to identify barriers and implementation strategies for fertility counseling are urgently needed in a disease that affects more young patients each year.

Domain names have been abused for illicit online activities for decades. A wealth of effort has been devoted to detect malicious domains in the past. However, these works primarily identify suspicious DNS behaviors (e.g., lookup patterns, resolution graphs) to distinguish legitimate domains from malicious ones. Whereas, these behaviors can only be observed after malicious activity is already underway, thus are often too late to prevent miscreants from reaping benefits of the attacks, delaying detection. In this paper, we propose MalHunter, a timely detection technique that determines a domain’s reputation via only a single DNS query. We base it on the insight that miscreants need to host malicious domains on IPs that they control, which makes different malicious domains are commonly hosted on the same IPs and creates intrinsic associations. To capture these inherent associations, we employ a deep neural network architecture based method, thus making it possible for detecting malicious domains via only a single DNS query. We evaluate MalHunter using real-world DNS traffic collected from three large ISP networks in China over two months. Compared to previous approaches, our method significantly reduces the time delay of detection from days or weeks to approximate ten microseconds while maintaining as high detection accuracy.

Protocol fingerprinting (PF) focuses on the capability to derive a series of distinguishable features for recognizing which protocol or application generated the network traffic. Unfortunately, deep packet inspection (DPI), a widely adopted method for PF, requires significant expert effort to develop and maintain protocol signatures. Additionally, the new solution paradigm, deep flow inspection (DFI) using machine learning for PF, also relies on hand-designed features. In this paper, we present ProNet, a payload based approach to protocol fingerprinting, which overcomes the limitation of artificial feature engineering. The key novelty of ProNet is two-fold: (i) it takes generic, raw short packet payloads as input, instead of the typical flow-statistical-features (e.g., port, packet size, packet-interval); (ii) it learns to simultaneously extract features via convolutional operations on the byte-level embeddings and ngram-level embeddings. We implement and evaluate ProNet on real-world traces, including DNS, QQLive, PPLive, PPStream, SopCast, DHCP, NBNS, HTTP, SMTP and SMB. Our experiment results show that ProNet achieves over 99% precision and recall with low false-positives (less than 1%) and nearly no false-negatives.

Background. Ipilimumab improves overall survival (OS) in advanced melanoma. Acral melanoma is an uncommon clinical subtype of this disease associated with poor prognosis. The clinical activity of ipilimumab has not been well-defined in advanced acral melanoma. Methods. We retrospectively reviewed the demographics, treatment history, and clinical outcomes for all patients with acral melanoma treated with ipilimumab from two academic centers between February 2006 and June 2013. Using Cox proportional hazards models, we assessed for factors that correlated with OS. Results. A total of 35 patients with acral melanoma received ipilimumab. Melanomas arose on volar surfaces (n = 28) and subungual sites (n = 7); stage M1c disease was present in 54%, and 45% had elevated serum lactate dehydrogenase (LDH). Best response by RECIST 1.1 criteria was complete response in 1 patient, partial response in 3, and stable disease (SD) in 4 for an objective response rate (ORR) of 11.4% and a clinical benefit rate (ORR + SD) at 24 weeks of 22.9%. Median progression-free survival was 2.5 months (95% confidence interval [CI]: 2.3–2.7 months); median OS was 16.7 months (95% CI: 10.9–22.5 months). Normal LDH and absolute lymphocyte count ≥1,000 at 7 weeks predicted longer OS. Immune-related adverse events (irAEs) were noted in 16 patients including 7 with grade 3/4 irAEs (20%). Conclusion. Ipilimumab is clinically active in acral melanoma with similar ORR and OS compared with unselected melanoma populations. Ipilimumab remains a viable therapeutic option for patients with advanced acral melanoma. Implications for Practice: Ipilimumab is a commonly used immune therapy that improves survival in metastatic melanoma. The clinical activity of ipilimumab in certain rare melanoma subtypes, such as uveal or mucosal melanomas, is suboptimal. Acral melanoma is another unusual subtype of this disease that arises on the palms, soles, and nailbeds. In this study of 35 patients with acral melanoma from 2 centers, ipilimumab was found to have activity that appears equivalent to unselected melanoma (response rate of 11.4%, median overall survival of 16.7 months). Ipilimumab remains a viable treatment option for this melanoma subpopulation.

Malicious domains play a vital component in various cyber crimes. Most of the prior works depend on DNS A (address) records to detect the malicious domains, which are directly resolved to IP addresses. In this paper, we propose a malicious domain detection method focusing on the domains that are not resolved to IP addresses directly but only appear in DNS CNAME (canonical name) records. This kind of domains occupy 18.39% of the total domains in our 1530-days-long DNS traffic dataset collected from 217 DNS servers. In addition, the real-world dataset shows that domains connected with malicious ones through DNS CNAME records tend to be malicious too. Based on this observation, our proposal can identify the illegal domains by computing their maliciousness probabilities. The experiments demonstrate the high detection performance of our solution. It achieves the accuracy, on average, over 97.25% true positive rate with less than 0.027% false positive rate. Moreover, the proposal performs near real time detections. Our work can help network attack defenders to build a more robust domain monitoring system.