The Role of Palliative Surgery for Malignant Bowel Obstruction and Perforation in Advanced Microsatellite Instability-High Colorectal Carcinoma in the Era of Immunotherapy: Case Report.

The role of palliative surgery in the management of acute complications in patients with disseminated malignancy remains controversial given the complexity of assessing acute surgical risk and long-term oncologic outcome. With the emergence of checkpoint blockade immunotherapy, there appears to be an increasing role for historically palliative procedures as a bridge to systemic immunotherapy. This is especially evident in advanced microsatellite instability-high (MSI-H) colorectal cancer where malignant obstruction and fistula formation are more common and where immunotherapy with checkpoint blockade (anti-PD-1/PD-L1, anti-CTLA-4) has a high response rate with potential for favorable oncologic outcomes. We present a series of three patients with MSI-H metastatic colorectal cancer complicated by malignant bowel obstruction and fistula formation, who having progressed on standard chemotherapy, underwent palliative intervention as a bridge to immune checkpoint blockade with durable and clinically meaningful anti-cancer responses. These cases highlight the need to re-evaluate the role of historically palliative operations in the setting of disease progression for immunotherapy-responsive tumors

Metastatic pattern is a prognostic factor in BRAFV600E mutant colorectal cancer

Background: Despite recent advancements in the treatment of metastatic BRAFV600E colorectal cancer (CRC), prognosis remains poor. However, a some patients with BRAFV600E disease have superior outcomes compared to the overall cohort and the prognostic factors associated with this improved survival are not well understood. Methods: We conducted a single center retrospective review of patients with metastatic CRC and available next generation sequencing data. Patients with confirmed BRAFV600E disease were selected for the final analysis. We collected baseline demographic characteristics, concurrent mutations, and metastatic pattern. The primary endpoint was overall survival (OS). Univariate and multivariable logistic regression was used to examine the association between baseline concurrent somatic mutations and sites of metastatic disease with survival. Results: Of 466 patients with metastatic CRC, 50 harbored BRAFV600E disease and 42 were included in the final analysis. The median OS in this cohort was 18.7 months (95% CI: 5.55–31.8). There was no association between baseline concurrent somatic mutations and OS. On univariate analysis, patients with lymph node only disease at the time of metastatic disease were more likely to have longer OS (hazard ratio [HR] = 0.30, 95% CI: 0.09–0.98, p = 0.047) and patients with peritoneal disease were more likely to have shorter OS (HR = 2.78, 95% CI: 1.12–6.88, p = 0.03). However, these associations did not retain statistical significance on multivariable analysis. Conclusions: The pattern of metastatic disease in BRAFV600E CRC may be a prognostic factor and future studies are needed to better understand the underlying mechanisms and potentially change clinical practice for a select patient population. MicroAbstract: Select patients with metastatic BRAFV600E colorectal cancer may have better than expected survival but are not well characterized. We conducted a retrospective review of 42 patients with metastatic BRAFV600E colorectal cancer and showed that lymph node only disease at the time of metastatic disease was associated with superior survival

Photosynthetic characteristics of the subtending leaf of cotton boll at different fruiting branch nodes and their relationships with lint yield and fiber quality

To investigate photosynthetic characteristics of the subtending leaf at the 2-3rd and 10-11th fruiting branch (FBN, FB2-3 and FB10-11), and their relationship with cotton yield and quality, field experiments were conducted using two cotton cultivars, Kemian 1 and Sumian 15. The results showed that with FBN increasing, chlorophyll (Chl) components, Pn and non-photochemical quenching (NPQ) in the subtending leaf significantly declined, while soluble sugar, amino acid and their ratio (CSS/CAA) as well as Fv/Fm increased. These results indicated that 1) non-radiative dissipation of excess light energy at FB2-3 was reduced to improve solar energy utilization efficiency to compensate for lower Pn, 2) higher NPQ at FB10-11 played a role in leaf photo-damage avoidance, 3) boll weight was related to the CSS/CAA ratio rather than carbohydrates content alone, 4) with FBN increasing, lint biomass and lint/seed ratio increased significantly, but lint yield decreased due to lower relative amount of bolls, and 5) the decreases in Pn, sucrose content and CSS/CAA in the subtending leaf at FB2-3 resulted in lower boll weight and fiber strength

The effects of fruiting positions on cellulose synthesis and sucrose metabolism during cotton (Gossypium hirsutum L.) fiber development.

Cotton (Gossypium hirsutum L.) boll positions on a fruiting branch vary in their contribution to yield and fiber quality. Fiber properties are dependent on deposition of cellulose in the fiber cell wall, but information about the enzymatic differences in sucrose metabolism between these fruiting positions is lacking. Therefore, two cotton cultivars with different sensitivities to low temperature were tested in 2010 and 2011 to quantify the effect of fruit positions (FPs) on fiber quality in relation to sucrose content, enzymatic activities and sucrose metabolism. The indices including sucrose content, sucrose transformation rate, cellulose content, and the activities of the key enzymes, sucrose phosphate synthase (SPS), acid invertase (AI) and sucrose synthase (SuSy) which inhibit cellulose synthesis and eventually affect fiber quality traits in cotton fiber, were determined. Results showed that as compared with those of FP1, cellulose content, sucrose content, and sucrose transformation rate of FP3 were all decreased, and the variations of cellulose content and sucrose transformation rate caused by FPs in Sumian 15 were larger than those in Kemian 1. Under FP effect, activities of SPS and AI in sucrose regulation were decreased, while SuSy activity in sucrose degradation was increased. The changes in activities of SuSy and SPS in response to FP effect displayed different and large change ranges between the two cultivars. These results indicate that restrained cellulose synthesis and sucrose metabolism in distal FPs are mainly attributed to the changes in the activities of these enzymes. The difference in fiber quality, cellulose synthesis and sucrose metabolism in response to FPs in fiber cells for the two cotton cultivars was mainly determined by the activities of both SuSy and SPS

Recent Advances in Targeted Therapies for Advanced Gastrointestinal Malignancies.

The treatment of advanced gastrointestinal (GI) cancers has become increasingly molecularly driven. Molecular profiling for HER2 and PD-L1 status is standard for metastatic gastroesophageal (GEJ) cancers to predict benefits from trastuzumab (HER2-targeted therapy) and pembrolizumab (anti-PD-1 therapy), while extended RAS and BRAF testing is standard in metastatic colorectal cancer to predict benefits from epidermal growth factor receptor (EGFR)-targeted therapies. Mismatch repair (MMR) or microsatellite instability (MSI) testing is standard for all advanced GI cancers to predict benefits from pembrolizumab and in metastatic colorectal cancer, nivolumab with or without ipilimumab. Here we review recent seminal trials that have further advanced targeted therapies in these cancers including Poly (adenosine diphosphate-ribose) polymerases (PARP) inhibition in pancreas cancer, BRAF inhibition in colon cancer, and isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) inhibition in biliary tract cancer. Targeted therapies in GI malignancies constitute an integral component of the treatment paradigm in these advanced cancers and have widely established the need for standard molecular profiling to identify candidates

Variability in multimodality treatment influences survival in non- metastatic gastric cancer patients

BackgroundWhile gastric cancer is a leading cause of cancer-related mortality in Eastern Europe and Asia, it is less common in the USA. Recommendations regarding optimal treatment of non-metastatic gastric cancer (nmGC) with regard to type and extent of surgery, choice and sequence of chemotherapeutic agents, and use of radiation therapy vary across geographic locations. To determine how variability in treatment practices affects patient outcomes, we conducted a retrospective study to evaluate clinical outcomes in nmGC patients treated at four high-volume academic institutions.MethodsCalifornia Cancer Registry data were collected for nmGC patients who underwent gastrectomy with curative intent from 2010 to 2018. We conducted chart reviews of the patients' electronic health records to validate clinical factors and outcomes. We performed multivariable Cox regressions to determine prognostic factors for outcomes.ResultsDemographics of study cohort (n=326): mean age 66 years; 64% male; 44% Caucasian, 35% Asian, 16% Latino. Tumor stage: 48% loco-regional (pT4 or pN1+) vs. 52% localized (pT1-3, pN0). Histology: 47% intestinal, 30% diffuse, 8% mixed, 15% unknown. Surgery: 34% open gastrectomy, 48% laparoscopic, 18% unknown; number of recovered lymph nodes varied from 0 to 60 in any tumor stage. Chemotherapy: 20% neoadjuvant alone, 25% adjuvant alone, 16% perioperative, 39% none. Multimodality therapy: 44% surgery only, 31% chemotherapy, 25% chemotherapy and radiation. With a median post-surgical follow-up of 6 years, 24% of patients developed recurrence and 40% had died. Compared to open surgery, laparoscopic surgeries were associated with fewer recovered lymph nodes (mean =18 vs. 25, P=0.0042). Fewer recovered lymph nodes were associated with a significant decrease in 5-year overall survival [hazard ratio (HR) =1.9, 95% confidence interval (CI): 1.3-2.8]. Timing of chemotherapy and addition of radiation therapy to chemotherapy did not confer further improvements in survival; in contrast, greater lymph node recovery plus chemotherapy were associated with a significant increase in survival (HR =0.3, 95% CI: 0.1-0.6).ConclusionsThis study highlights major practice differences in the management of nmGC patients across providers and institutions. Further efforts should be made to standardize the use of chemotherapy and adequate recovery and assessment of lymph nodes in this patient population

Effect of late planting and shading on cellulose synthesis during cotton fiber secondary wall development.

Cotton-rapeseed or cotton-wheat double cropping systems are popular in the Yangtze River Valley and Yellow River Valley of China. Due to the competition of temperature and light resources during the growing season of double cropping system, cotton is generally late-germinating and late-maturing and has to suffer from the coupling of declining temperature and low light especially in the late growth stage. In this study, late planting (LP) and shading were used to fit the coupling stress, and the coupling effect on fiber cellulose synthesis was investigated. Two cotton (Gossypium hirsutum L.) cultivars were grown in the field in 2010 and 2011 at three planting dates (25 April, 25 May and 10 June) each with three shading levels (normal light, declined 20% and 40% PAR). Mean daily minimum temperature was the primary environmental factor affected by LP. The coupling of LP and shading (decreased cellulose content by 7.8%-25.5%) produced more severe impacts on cellulose synthesis than either stress alone, and the effect of LP (decreased cellulose content by 6.7%-20.9%) was greater than shading (decreased cellulose content by 0.7%-5.6%). The coupling of LP and shading hindered the flux from sucrose to cellulose by affecting the activities of related cellulose synthesis enzymes. Fiber cellulose synthase genes expression were delayed under not only LP but shading, and the coupling of LP and shading markedly postponed and even restrained its expression. The decline of sucrose-phosphate synthase activity and its peak delay may cause cellulose synthesis being more sensitive to the coupling stress during the later stage of fiber secondary wall development (38-45 days post-anthesis). The sensitive difference of cellulose synthesis between two cultivars in response to the coupling of LP and shading may be mainly determined by the sensitiveness of invertase, sucrose-phosphate synthase and cellulose synthase

Correlation coefficients among parameters in fibers on FP1 and FP3 of two cultivars during 2010–2011.

<p>The coefficient between UHM and <i>CEL</i>max (A), ST and <i>CEL</i>max (B), MIC and <i>CEL</i>max (C), UHM and <i>Tr</i> (D), ST and <i>Tr</i> (E), and MIC and <i>Tr</i> (F) in fibers on FP1 and FP3 of two cultivars. UHML-fiber upper-half mean length, MIC-micronaire value, ST-fiber strength, <i>CEL</i>max-maximum cellulose content, <i>Tr</i>-sucrose transformation rate. * and **, significant differences at <i>P</i> = 0.01 and <i>P</i> = 0.05 probability levels, respectively. n = 12, <i>R</i>_0.05 = 0.576, <i>R</i>_0.01 = 0.707.</p

Short term exposure to polystyrene nanoplastics in mice evokes self-regulation of glycolipid metabolism

With the detection of nano-plastics (NPs) in daily essentials and drinking water, the potential harm of NPs to human health has become the focus of global attention. Studies have shown that long term exposure to NPs can lead to disorders of glucose and lipid metabolism in organisms, while the effects of short term exposure are rarely reported. Moreover, environmental factors cause the aging of NPs, and it is unclear whether this has an effect on their toxicity. In this study, we use 100 nm polystyrene (PS) NPs and ultraviolet (UV) aging PS (aPS) NPs to gavage mice for 7 days at an exposure dose of 50 mg/kg/day. To evaluate the effects of exposure on mice hepatic glucose lipid metabolism, we performed blood biochemical, pathological and metabolomic analyses. The results showed that exposure to PS NPs and aPS NPs increased serum glucose, disrupted serum lipoprotein levels, and up-regulated the expression levels of phosphatidylinositol 3-kinase (PI3K)/ phosphoprotein kinase B (p-AKT)/Glucose transporter 4 (GLUT4) proteins in the glucose metabolism pathway. The expression levels of key proteins sterol regulatory element binding protein-1 (SREBP-1)/peroxisome proliferator-activated receptor-γ (PPARγ)/adipose triglyceride lipase (ATGL) in the lipid metabolism signaling pathway were significantly increased. These findings suggest that short term exposure to PS NPs and aPS NPs induces glycolipid metabolism disturbance in mice, which may subsequently awaken the mice to self-regulate the serum levels of various lipoproteins and the expression of related key proteins. Compared with PS NPs, the aPS NPs interfered more strongly with glucose metabolism, and the corresponding self-regulation in mice was also more obvious. These findings not only provide a basis for environmental factors to increase the health risk of NPs but also provided a reference for the selection of test substances for further studies on the toxicity of NPs

Correlation coefficients between cellulose content and sucrose transformation rate in fibers during 2010–2011.

<p>The coefficient between <i>CEL</i>max and <i>Tr</i> in fibers on FP1 and FP3 of Kemian 1 (A), <i>CEL</i>max and <i>Tr</i> in fibers on FP1 and FP3 of Sumian 15 (B). <i>CEL</i>max-maximum cellulose content, <i>Tr-</i>sucrose transformation rate. * and **, significant differences at <i>P</i> = 0.01 and <i>P</i> = 0.05 probability levels, respectively. n = 12, <i>R</i>_0.05 = 0.576, <i>R</i>_0.01 = 0.707.</p