Citations

Objectives Important findings can be masked in gene expression studies of mixed cell populations. We examined single-cell gene expression in SLE patient monocytes in the context of clinical and immunological features. Methods Monocytes were purified from patients with SLE and controls, and individually isolated for single-cell gene expression measurement. A panel of monocyte-related transcripts were measured in individual classical (CL) and non-classical (NCL) monocytes. Results Analyses of both CL and NCL monocytes demonstrated that many genes had a lower expression rate in SLE monocytes than in controls. Unsupervised hierarchical clustering of the CL and NCL data sets demonstrated independent clusters of cells from the patients with SLE that were related to disease activity, type I interferon (IFN) and medication use. Thus, each of these factors exerted a different impact on monocyte gene expression that could be identified separately, and a number of genes correlated uniquely with disease activity. We found within-cell correlations between genes directly induced by type I IFN-induced and other non–IFN-induced genes, suggesting the downstream biological effects of type I IFN in individual human SLE monocytes which differed between CLs and NCLs. Conclusions In summary, single-cell gene expression in monocytes was associated with a wide range of clinical and biological features in SLE, providing much greater detail and insight into the cellular biology underlying the disease than previous mixed-cell population studies.

ABSTRACTIntroduction: In polyradiculoneuropathy‐organomegaly‐endocrinopathy‐monoclonal protein‐skin changes (POEMS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), limb nerve conduction studies (NCSs) are limited in identifying demyelination and in detecting treatment effects in severely affected patients. Blink R1 latency may improve these assessments. Methods: POEMS and CIDP patients who had undergone NCS and blink reflex were identified. Correlations among R1 latency, limb NCS, and neuropathy impairment scores (NIS) were compared. Results: Among 182 patients (124 POEMS, 58 CIDP) who were identified, R1 prolongation (>13 ms) occurred in 64.3% (65.3% POEMS, 62.1% CIDP). R1 prolongation correlated with more severely affected NCS in both POEMS (ulnar CMAP 2.6 mV vs. 4.5 mV, P = 0.001) and CIDP (2.0 mV vs. 6.1 mV, P < 0.001). In severely affected patients (ulnar CMAP ≤0.5 mV [10%:18/182]), R1 (>13 ms) helped establish demyelination. In 31 patients (16 POEMS, 15 CIDP), the R1 latency changes were concordant with NIS changes in 94% of patients with POEMS and 60% of patients with CIDP. Discussion: Blink R1 latencies are valuable in defining demyelination and detecting improvement in severely affected POEMS and CIDP patients. Muscle Nerve 57: E8–E13, 2018

Vascularized lymph node (VLN) transfer has been of high interest in the past decade for the treatment of lymphedema, since it has been shown to be effective in reducing limb volumes, decreasing infectious episodes and improving quality of life. Multiple donor sites have been described in the quest for the optimal one. Herein, we describe a novel lymph node flap option based on the ileocolic artery and vein. The ileocecal vascularized lymph node (IC‐VLN) flap was used in the management of a 33‐year‐old male patient with lower extremity lymphedema secondary to left inguinal trauma. The patient had previously underwent a pedicled omentum flap transposition with minimal improvement in limb size and persistent episodes of infection. At 15 month follow‐up, the IC‐VLN flap improved the lymphatic drainage in the affected limb with a mean limb circumference reduction rate of 26.3%. No donor site complications or further episodes of infection were noted. According to our findings, the IC‐VLN flap may be another option for VLN transfer in very selected cases. Nevertheless, larger series with a longer follow‐up are required to analyze the efficacy and long‐term results of this flap.

AbstractThis work is to show which is more relevant to cause local failures (LFs) due to patient setup uncertainty between the planning target volume (PTV) underdosage and the potential target underdosage subject to patient setup uncertainties in head and neck (H&N) cancer treated with volumetric‐modulated arc therapy (VMAT). Thirteen LFs in 10 H&N patients treated by VMAT were analyzed. Measures have been taken to minimize the chances of insufficient target delineation for these patients and the patients were clinically determined to have LF based on the PET/CT scan results by an experienced radiologist and then reviewed by a second experienced radiation oncologist. Two methods were used to identify the possible locations of LF due to underdosage: (a) examining the standard VMAT plan, in which the underdosed volume in the nominal dose distribution (UVN) was generated by subtracting the volumes receiving the prescription doses from PTVs, and (b) plan robustness analysis, in which in addition to the nominal dose distribution, six perturbed dose distributions were created by translating the CT iso‐center in three cardinal directions by the PTV margin. The coldest dose distribution was represented by the minimum of the seven doses in each voxel. The underdosed volume in the coldest dose distribution (UVC) was generated by subtracting the volumes receiving the prescription doses in the coldest dose distribution from the volumes receiving the prescription doses in the nominal dose distribution. UVN and UVC were subsequently examined for spatial association with the locations of LF. The association was tested using the binominal distribution and the Fisher's exact test of independence. We found that of 13 LFs, 11 were associated with UVCs (P = 0.011), while three were associated with UVNs (P = 0.99). We concluded that the possible target underdosage due to patient setup uncertainties appeared to be a more relevant factor associated with LF in VMAT for H&N cancer than the compromised PTV coverage at least for the patients included in this study.

Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty‐eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL‐6], IL‐8, interferon gamma–induced protein 10, IL‐4, IL‐9, IL‐10, fibroblast growth factor 2, IL‐7, IL‐15, and transforming growth factor alpha) but lower levels of the anti‐inflammatory macrophage‐derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon‐gamma in response to T‐cell stimulation. Up‐regulated IL‐6, IL‐8, CD38, and CD69 and down‐regulated macrophage‐derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL‐6, IL‐8, CD38, and CD69 were reduced, whereas levels of macrophage‐derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL‐8, IL‐10, fibroblast growth factor 2, and IL‐7 remained higher. Conclusion: AH patients were in a highly immune‐dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575–590).

Pancreatic cancer has one of the lowest survival rates of all cancers. The mechanism underlying chemo-resistance of pancreatic cancer is not well understood. Our previous article reported that small molecule YM155 induced apoptosis in pancreatic cancer cells via activation of death receptor 5. In this study, we aim to continuously address death receptor 5–mediated apoptosis in chemo-resistant pancreatic carcinoma. We found that in comparison to paired pancreatic cancer tissues and adjacent normal tissues, five of the six cancer tissues had downregulated death receptor 5 and upregulated Bcl-xL. Mono treatment with lexatumumab was not sufficient to induce apoptosis in pancreatic cancer cells, whereas focal adhesion kinase inhibitor PF573228 significantly sensitized lexatumumab-induced apoptosis. Western blotting analysis revealed that lexatumumab and PF573228 combination treatment increased death receptor 5 but decreased Bcl-xL expression. Interestingly, pre-treatment with Bcl-xL inhibitor ABT263 reversed the insensitivity of panc-1 cells to lexatumumab or PF573228-induced apoptosis. Specific small interfering RNA-mediated gene silencing of Bcl-xL effectively sensitized pancreatic cancer cells to lexatumumab or PF573228-induced apoptosis. Furthermore, lexatumumab and PF573228 combination was shown to exhibit significant xenograft pancreatic tumor growth inhibition in SCID mice. Our data provide fundamental evidence to support the notion that lexatumumab and PF573228 co-treatment could be a potentially effective regime for patients with pancreatic cancer.

Abstract Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Cancer Res; 77(13); 3655–65. ©2017 AACR.

Key Points Pembrolizumab was first shown to be clinically active in CLL patients with RT. PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select RT patients for PD-1 blockade.

Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK‐2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK‐2206 in combination with BR in relapsed CLL. Single‐agent MK‐2206 (weekly dosed) was administered one‐week in advance before BR on cycle 1 and subsequently was given with BR at the same time for cycle 2‐6. Phase II employed the MTD of MK‐2206 with BR to evaluate safety and efficacy of this study combination. Thirteen relapsed/refractory CLL were treated for maximal 6‐cycle of therapy. The maximum tolerated dose of MK‐2206 was 90 mg by mouth once weekly. The most common grade 3/4 adverse events were neutropenia (46%), febrile neutropenia (23%), rash (15%), diarrhea (15%), and thrombocytopenia (15%). Overall response rate was 92% with a median progression free survival and treatment free survival of 16 and 24 months, respectively. Five patients (38%) achieved complete remission or complete remission with incomplete count recovery, two of whom were MRD negative. The efficacy and tolerability of this combination indicates that Akt inhibition combined with chemoimmunotherapy is a promising novel treatment combination in CLL and deserves further prospective clinical trial.