Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Resource Warfare, Pacification and the Spectacle of ‘Green’ Development: Logics of Violence in Engineering Extraction in Southern Madagascar

Bringing political ecology's concern with the critical politics of nature and resource violence into dialogue with key debates in political geography, critical security studies and research on the geographies and phenomenology of violence and warfare, this paper explores strategies ‘from above’ in relation to the establishment and operation of the Rio Tinto QIT-Madagascar Minerals (QMM) ilmenite mine in southeast Madagascar. While QMM claims to be a responsible ‘green’ self-regulator and sustainable development actor, it has triggered serious social, environmental and legal conflicts since its inception, including allegations of a ‘double land grab’ to accommodate mining activities and compensatory biodiversity offsetting. We argue that ‘pacification’, theorised as a productive form of violence that works through the re-ordering of socio-nature, underwrites the forms of ‘security’, ‘stability’ and even ‘sustainability’ that facilitate multiple and overlapping strategies of value extraction in the territorial and extra-territorial spaces occupied by the QMM mine partnership. By situating these dynamics historically, we identify ways in which pacification draws upon sedimented and evolving logics of racialised violence to facilitate operations and silence opposition

Updates in pancreatic cancer: Modest gains and hopeful targets

Pancreatic cancer is the twelfth most common cancer in the United States, representing 3.2% of all new cancer cases. While composing a small percentage of cancer diagnoses, pancreatic cancer is amongst the most lethal carcinomas, with an overall 5-year survival of 8.2% and incidence rates almost equivocal to death rates. By the time of diagnosis, a majority of patients will present with advanced stage disease. For patients with resectable disease, the estimated overall survival (OS) remains low at 20% as most will develop metastatic disease within 5 years. The lethality of this cancer is attributed to several factors including delayed presentation, lack of effective screening, and complex tumor biology and genetics. Data also suggest that even upon early presentation, pancreatic cancer is a systemic disease with micrometastasis present in the early stages. Traditional cytotoxic therapies have not been clinically impactful in pancreatic cancer, especially in advanced stages, and very little headway has been made in the development of new targeted therapies. As such, this review will discuss current advances in standard of care treatments and novel drug targets being researched. </jats:p

Retrospective study evaluating the safety of administering pegfilgrastim on the final day of 5-fluorouracil continuous intravenous infusion

Background Pegfilgrastim, a long-acting granulocyte-colony-stimulating factor used to prevent neutropenia, is not indicated for administration within 24 h of completion of chemotherapy. The safety of administering pegfilgrastim in gastrointestinal cancer chemotherapy regimens containing continuous intravenous infusion of 5-fluorouracil (5-FUCI) on the day of completion of 5-fluorouracil has not been adequately studied. Methods An institutional review board-approved retrospective analysis of patients with a gastrointestinal malignancy receiving pegfilgrastim on the final day of 5-FUCI was conducted. The primary end point was to determine the incidence of grade 3 and grade 4 neutropenia and febrile neutropenia when pegfilgrastim was administered on the final day of 5-FUCI. The secondary endpoint was to determine rate of dose reductions and treatment delays. Results A total of 300 patients were reviewed from January 2010 to May 2017. The most common cancers were colorectal (25%) and pancreatic (60%), with 77% of patients having late stage disease. The risk of a patient developing grade 3 neutropenia was 0.010 (95% CI 0.002–0.029) and grade 4 neutropenia was 0.007 (95% CI 0.001–0.024). The risk of febrile neutropenia was 0.007 (95% CI 0.001–0.024). The risks of treatment delay and treatment reduction were 0.013 (95% CI 0.004–0.034) and 0.010 (95% CI 0.002–0.029), respectively. Conclusion The low risk of grade 3 and grade 4 neutropenia, febrile neutropenia, as well as dose delays and/or reduction suggests that pegfilgrastim can be administered on the final day of 5-FUCI. Limitations of this study were that it was retrospective in nature and was conducted at a single institution. </jats:sec

Poorly differentiated histology as a predictive biomarker in patients with advanced gastrointestinal (GI) cancers treated with immunotherapy.

664 Background: Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have showed a correlation between immune cell infiltration and poorly differentiated cancers. We evaluated the impact of poorly differentiated histology on survival in patients with advanced GI malignancies treated with immunotherapy. Methods: We performed a retrospective, single institution analysis of patients with poorly differentiated GI tumors treated with CPI between 2016 and 2021. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor/patient characteristics, progression free survival (PFS) and overall survival (OS). Results: A total of 123 patients were included. Median age was 66years. Majority had stage IV disease (88.2%), were White (65.5%) and male (64.5%). Most common diagnoses were HCC (28.5%), gastric (15.4%) and esophageal (14.6%) adenocarcinomas. About 32% were MSI-H, with 10% BRAF mutation rate. About 25% received CPI as initial treatment and 35.5% received 2 or more prior lines of therapy. Compared with well and moderately differentiated histology, poorly differentiated tumors had shorter mPFS (3.4 vs 2.5 vs. 2.2months; p = 0.29) and mOS (not reached [NR] vs. 20.9 vs. 14.2 months; p = 0.14) respectively. On UVA, the degree of tumor differentiation did not correlate with mPFS or mOS. Female patients (HR: 0.55, CI: 0.34-0.90, p = 0.018) and ECOG of 1 vs. ≥2 had significantly longer mPFS (HR: 0.58, CI: 0.35-0.97, p = 0.036). ECOG 1 correlated with better mOS (HR: 0.47, CI: 0.23-0.94, p = 0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, CI: 2.41-13.63, p &lt; 0.001) and mOS (HR: 5.45, CI: 1.64-18.12, p = 0.006). Number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, CI: 1.03-1.39, p = 0.022) and mOS (HR: 1.23, CI: 1.01-1.50, p = 0.045). On MVA, ECOG status of 0/1 vs. ≥2 and MSI-H vs. MSS remained significantly associated with longer mPFS and mOS. There was no correlation with race or mutations such as BRAF or KRAS. Conclusions: Poorly differentiated histology did not predict for PFS or OS. Treatment naïve patients, female gender, ECOG 1 and MSI-H were most likely to benefit from CPI. </jats:p

Successful Liver Transplantation of Recurrent Fibrolamellar Carcinoma following Clinical and Pathologic Complete Response to Triple Immunochemotherapy: A Case Report

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Fibrolamellar carcinoma (FLC) is a rare liver cancer that predominantly affects younger patients without a history of liver disease. Surgical resection is the cornerstone of therapy and represents the best potentially curative treatment option. Modest objective responses with cytotoxic chemotherapy alone or combined with immune checkpoint inhibitors (ICIs) have been reported; however, there are no established systemic therapy regimens for unresectable or metastatic FLC. &lt;b&gt;&lt;i&gt;Case Presentation:&lt;/i&gt;&lt;/b&gt; We report a case of a 23-year-old woman with FLC who presented with a 11.5 × 8.3 cm left liver mass and subsequently underwent resection as initial therapy. Molecular analysis of her surgical tissue revealed a &lt;i&gt;DNAJB1-PRKACA&lt;/i&gt; fusion gene. The patient developed biopsy-proven recurrent FLC with multiple liver lesions but without any distant metastatic disease only 3 months after initial resection. In light of emerging data, the patient was treated with a novel triple therapy regimen including 5-fluorouracil (5-FU), interferon (IFN) alfa-2b, and nivolumab. Partial radiographic response was achieved after 4 treatments and complete response was achieved after 12 cycles with the combination. The patient received 2 more doses of 5-FU/IFN alfa-2b without nivolumab and underwent orthotopic liver transplantation (OLT) 6 months after the last dose of ICI. Pathological examination of the explanted liver remarkably confirmed pathologic complete response. She remains recurrence-free and is on active surveillance. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; For patients with unresectable/recurrent FLC with no distant disease, the combination of 5-FU, IFN alfa-2b, and nivolumab could be an effective systemic therapy option. The use of this chemoimmunotherapy regimen to downstage FLC prior to OLT may be worth investigating further. </jats:p

The impact of body mass index (BMI) on the safety and outcomes of small molecule inhibitors (SMI) in gastrointestinal cancer.

144 Background: A number of studies have demonstrated that overweight and early obese states are associated with improved survival in renal and melanoma cancer patients. The purpose of this study was to investigate the impact of BMI on outcomes of GI cancers treated with SMIs. Methods: A retrospective chart review was conducted to compare outcomes between patients with BMIs ≥ 25 and &lt; 25 who received treatment at Winship between 1/2010-8/2019. The primary objective was to determine the PFS, OS, and ADR rates of patients with BMI ≥ 25 treated with SMIs compared to patients with BMIs &lt; 25. PFS and OS rates were estimated with the Kaplan-Meier method and compared between the groups using the log-rank test. The incidence of adverse events was estimated as frequency and percentage and logistic regression was used to estimate the impact of BMI on adverse effects. Results: 269 patients were included in analysis for PFS, 61 for OS and 281 for ADR rate analysis. Diagnoses included HCC (n = 123, 44%) and CRC (n = 158, 56%). There was no significant difference seen in PFS and OS between the BMI &lt; 25 and BMI ≥ 25 groups (HR 1.17 (0.87-1.56), p = 0.291, HR 1.10 (0.66-1.84), p = 0.713, respectively). A significant difference was demonstrated in the rates of adverse reactions between the two groups (OR 0.31 (0.19-0.52), p&lt;.001) with BMI &lt; 25 having a lower rate of ADRs. After adjusting for covariates, HCC vs CRC diagnosis (p = 0.002) and not requiring dose reduction or delay due to toxicity (p&lt;0.001) were significantly associated with better PFS. Conclusions: Based on the multiple regression analysis, patients with a BMI ≥ 25 do not have improved outcomes over those with a BMI &lt; 25 when taking SMIs for their GI malignancies. Patients with BMI &lt; 25 experienced less drug toxicity that required dose reduction, discontinuation, or treatment delays. [Table: see text] </jats:p

Impact of metformin on clinical outcomes in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.

4118 Background: Non-alcoholic steatohepatitis (NASH) is an emerging etiology for hepatocellular carcinoma (HCC) and contributes to the increasing incidence of HCC worldwide. Patients with NASH often have risk factors of metabolic syndrome including hypertension, obesity, and type 2 diabetes (T2DM). NASH induced HCC has been shown to be associated with less response to immune check point inhibitors (ICIs) in HCC. Anti-diabetic agent metformin has been shown to be associated with improved outcomes in patients treated with ICIs in melanoma and non-small cell lung cancer. However, the impact of metformin on the efficacy of ICIs is not well defined in HCC. The main purpose of this study was to examine the effect of metformin on clinical outcomes in patients with advanced HCC treated with ICIs. Methods: We performed a retrospective analysis of patients with advanced HCC treated with ICIs in first and later-line settings between 2015 and 2021. The primary endpoints were overall survival (OS), progression free survival (PFS), and objective response rate (ORR) as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients were stratified based on their usage of metformin. OS and PFS were analyzed using Cox proportional hazard models and Kaplan-Meier analysis with log-rank test. Results: A total of 111 patients met inclusion criteria, 18 patients in the metformin group and 93 patients in the non-metformin group. Most common cause of HCC was viral hepatitis (52%), followed by NASH (29%), alcohol (8%) and other (11%). Baseline characteristics between the two groups were similar except all patients in the metformin group had a diagnosis of T2DM. ORR was 5.6%. (1 partial response) in the metformin group vs 22.6% (5 complete responses, 16 partial responses) in the non-metformin group. Median OS was 45.9 months in the non-metformin group vs 10.8 months in metformin group (HR 1.99, 95% CI 0.95-4.21, p = 0.064). Median PFS of 6.6 months vs 2.5 months (HR 1.75, 95% CI 0.93-3.29, p = 0.077). Moreover, metformin usage was associated with shorter median OS of 10.8 months (HR 1.96, 95% CI 0.75-5.09, p = 0.16) vs 20.9 months among patients with T2DM. OS was significantly worse in patients with poor ECOG performance status 2-3, MELD score 10-23, higher grade tumor histology, AFP &gt; = 400, and use of IO in later lines of therapy. Conclusions: In this retrospective study metformin use was associated with worse clinical outcomes in advanced HCC patients treated with ICIs. </jats:p