Long-term benefit of sotorasib in patients with KRAS G12C-mutated non-small-cell lung cancer: plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).

Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.

Leukemic stem cells as a target for eliminating acute myeloid leukemia: Gaps in translational research.

Relapse is common in acute myeloid leukemia (AML) and thought to be due to resistance of underlying leukemic stem cells (LSCs) to current standard therapies, although a lack of tools to measure the quantity and quality of these cells in patients precludes the clinical testing of this concept. This review discusses the current knowledge of LSC properties and appraises strategies aimed to bring the therapeutic targeting of LSCs to the bedside to improve patient outcomes. We highlight pathways and targets of interest and summarize available information on drugs that might eradicate LSCs. Future research is needed to close identified gaps in knowledge and provide evidence for the clinical efficacy of LSC-directed therapies to support the development of treatments that eliminate residual disease and prevent relapse, thereby increasing the cure rates of patients with AML.

Impact of relaxation training on patient-perceived measures of anxiety, pain, and outcomes after interventional electrophysiology procedures.

BACKGROUND: Electrophysiology procedures vary in invasiveness, duration, and anesthesia utilized. While complications are low and efficacy high, cases are elective and patient experiences related to anxiety, pain, and perceived outcomes are not well studied. We sought to determine if a 30-minute audio compact disc (CD) that teaches relaxation techniques and wellness perception prior to an elective procedure impacts validated measures of anxiety, pain, and procedural outcomes. METHODS: Sixty-one patients were randomly assigned to a control group (CG) (N(CG) = 31) or interventional group (IG) (N(IG) = 30). Both groups answered a baseline Hospital Anxiety and Depression Scale (HADS-A) survey consisting only of anxiety assessment questions. The IG listened to the CD the night prior to their procedure. Heart rate and blood pressure were monitored on admission and prior to the procedure. Postprocedure, both groups completed two HADS-A surveys as well as two Patient Experience Surveys (PES). There was no statistical difference in the demographics and the rate of procedural complications between the groups. The statistical significance of our data was determined using a Student's t-test and χ(2) test. RESULTS: At baseline, both groups had equal amounts of anxiety prior to their procedures (P = 0.2). The patients in the IG had lower systolic blood pressures during admission and prior the administration of analgesics in comparison to the CG. Postprocedure, results from administering the HADS-A demonstrated that the IG had 33% lower anxiety (P = 0.02) than CG patients. CONCLUSION: The implementation of basic relaxation teaching techniques prior to planned electrophysiology procedures lowers systolic blood pressure and postprocedural anxiety.

Escherichia coli HU protein has a role in the repair of abasic sites in DNA.

HU is one of the most abundant DNA binding proteins in Escherichia coli. We find that it binds strongly to DNA containing an abasic (AP) site or tetrahydrofuran (THF) (apparent K(d) approximately 50 nM). It also possesses an AP lyase activity that cleaves at a deoxyribose but not at a THF residue. The binding and cleavage of an AP site was observed only with the HUalphabeta heterodimer. Site-specific mutations at K3 and R61 residues led to a change in substrate binding and cleavage. Both K3A(alpha)K3A(beta) and R61A(alpha)R61A(beta) mutant HU showed significant reduction in binding to DNA containing AP site; however, only R61A(alpha)R61A(beta) mutant protein exhibited significant loss in AP lyase activity. Both K3A(alpha)K3A(beta) and R61K(alpha)R61K(beta) showed slight reduction in AP lyase activities. The function of HU protein as an AP lyase was confirmed by the ability of hupA or hupB mutations to further reduce the viability of an E. coli dut(Ts) xth mutant, which generates lethal AP sites at 37 degrees C; the hupA and hupB derivatives, respectively, had a 6-fold and a 150-fold lower survival at 37 degrees C than did the parental strain. These data suggest, therefore, that HU protein plays a significant role in the repair of AP sites in E. coli.

Peridomestic small Indian mongoose: An invasive species posing as potential zoonotic risk for leptospirosis in the Caribbean.

In this study, we investigated Leptospira infection and exposure in small Indian mongoose (Herpestes auropunctatus), an invasive animal species, in two different sites in the Caribbean island of Saint Kitts. Overall a low seroprevalence (12/148; 8.1%: 95%CI: 3.7-12.5) was observed. Agglutinating antibodies to serovars Mankarso (3.4%), Copenhageni (2.7%), Icterohemorrhagiae (1.4%), Bratislava (1.4%), Canicola (1.4%), Autumnalis (0.7%), Alexi (0.7%), Pomona (0.7%) and Grippotyphosa (0.7%) was observed on the microscopic agglutination test. The seroprevalence observed in mongooses trapped from peridomestic sites was significantly higher compared to the arid and less inhabited site (p = 0.0268). The real time PCR targeting lipL32 gene was positive for 9 out of 146 mongooses. Bacterial culture of kidneys resulted in two Leptospira isolates. Whole genome sequencing and analysis suggested that these isolates are closely related to L. interrogans serovar Copenhageni. We observed mild to severe chronic renal lesions in 20.2% of mongooses in the absence of an antibody response or active infection. Our findings emphasize the need to investigate other infectious etiologies or atypical outcomes and potential chronic long-term impact of Leptospira infection in animals and people living in an endemic area. In addition, our data reinforces the need for including locally prevalent Leptospira isolates rather than representative members of a serogroup in the microscopic agglutination test panel in epidemiologic and diagnostic investigations. In conclusion, mongoose inhabiting the island are exposed to and harbor pathogenic Leptospira and hence may play a role in the transmission. The invasive nature of the species highlights their presence as a potential risk factor for this widespread zoonotic disease.

In-Hospital Outcomes of Rotational Atherectomy in High-Risk Patients With Severely Calcified Left Main Coronary Artery Disease: A Single-Center Experience.

BACKGROUND: Severe coronary artery calcification is a challenge for percutaneous coronary intervention (PCI), particularly in left main coronary artery disease (LM-CAD). Rotational atherectomy (RA) is a useful tool for modification of calcified plaque prior to PCI. We report our experience with RA for severely calcified LM-CAD. METHODS: From January 2008 to January 2017, all patients who underwent RA-assisted LM-PCI were evaluated. The study population included both protected and unprotected LM-CAD patients. Clinical characteristics and in-hospital outcomes were collected retrospectively. In-hospital outcomes included post-PCI myocardial infarction, stroke, death, emergency coronary artery bypass graft surgery, and urgent repeat PCI. Angiographic success was defined by residual stenosis <20% and presence of TIMI 3 flow. RESULTS: Fifty-five consecutive patients who underwent RA-assisted PCI of LM-CAD were identified (mean age, 73.0 ± 10 years; 64% male). Mean left ventricular ejection fraction was 37.5 ± 15.7%. Fifty-one patients (93%) had multivessel disease and 39 patients (71%) underwent RA-assisted LM-PCI with use of a mechanical support device. The median largest burr size used was 1.5 mm. The mean number of LM stents implanted was 0.95 ± 0.3. The mean LM stent diameter and length were 3.7 ± 0.3 mm and 15.8 ± 7.5 mm, respectively. Intravascular ultrasound was used to assess vessel size and stent apposition in 20 patients (36.0%). Angiographic success was obtained in all patients (100%). CONCLUSION: Despite technical challenges, RA of the LM coronary artery can be performed safely and is associated with a high rate of angiographic success.

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma.

The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is dismal. Although gemcitabine (GEM) is the standard chemotherapeutic agent for adjuvant therapy of resectable PDAC, recurrent disease is observed in an alarming number of GEM-treated patients. Regardless of the adjuvant therapy, the vast majority of patients treated with chemotherapy after surgical resection show tumor recurrence. A better understanding of the molecular mechanisms that contribute to chemoresistance would aid the development of more effective treatment strategies. GRP78 is an endoplasmic reticulum (ER) chaperone protein that primarily resides in the lumen of the ER and is the master regulator of the unfolded protein response (UPR). Here, we report that expression of GRP78 is significantly higher in GEM-resistant PDAC compared to GEM-sensitive PDAC patient samples. We show that GRP78 induces chemoresistance in PDAC cells. Our results also show that knockdown of GRP78 reduces chemoresistance in PDAC. Finally, we found that IT-139, a ruthenium-based anticancer drug, can overcome GRP78-mediated chemoresistance. In vitro, IT-139 restores sensitivity to cytotoxic drugs in drug-resistant PDAC cells and induces twice as much cell death in combination treatment compared with GEM alone. In vivo, a single weekly IT-139 treatment in combination with GEM caused a 35% increase in median survival and a 25% increase in overall survival compared to GEM alone. Collectively, our data show that GRP78 expression promotes chemoresistance in PDAC and therapeutic strategies, blocking the activity of GRP78 increases the efficacy of currently available therapies. Mol Cancer Ther; 15(5); 1043-52. ©2016 AACR.

Anomalous coronary arteries: cardiovascular computed tomographic angiography for surgical decisions and planning.

Cardiovascular computed tomographic angiography (CCTA) provides an understanding of the three-dimensional (3D) coronary artery anatomy in relation to cardiovascular thoracic structures important to the surgical management of anomalous coronary arteries (ACAs). Although some ACA variants are not clinically significant, others can lead to ischemia/infarction, related acute ventricular dysfunction, ventricular arrhythmias, and sudden cardiac death. The CCTA is important to surgical decision making, as it provides noninvasive visualization of the coronary arteries with (1) assessment of origin, course, and termination of coronary artery anomalies in the context of 3D thoracic anatomy, (2) characterization of anatomy helpful for differentiation of benign versus hemodynamically significant variants, (3) identification of other cardiothoracic anomalies, and (4) detection of coronary artery disease. High-risk ACA anatomy in the appropriate clinical setting can require surgical intervention with decisions including minimally invasive versus open sternotomy approach, correction via reimplantation of a coronary artery, alteration of the ACA course without reimplantation, or bypass of an ACA. Given the rarity of ACA, there is limited data in the literature, and significant controversy related to the management issues. The management of ACA requires comprehensive clinical history, thorough assessment of cardiac function, and detailed anatomic imaging. Future studies will need to address the long-term outcome based on detailed assessment of original anatomy and surgical approach.

Integrative survival-based molecular profiling of human pancreatic cancer.

PURPOSE: To carry out an integrative profile of human pancreatic ductal adenocarcinoma (PDAC) to identify prognosis-significant genes and their related pathways. EXPERIMENTAL DESIGN: A concordant survival-based whole genome in silico array analysis of DNA copy number, and mRNA and miRNA expression in 25 early-stage PDAC was carried out. A novel composite score simultaneously integrated gene expression with regulatory mechanisms to identify the signature genes with the most levels of prognosis-significant evidence. The predominant signaling pathways were determined via a pathway-based approach. Independent patient cohorts (n = 148 and 42) were then used as in vitro validation of the array findings. RESULTS: The composite score identified 171 genes in which expressions were able to define two prognosis subgroups (P = 3.8e-5). Eighty-eight percent (151 of 171) of the genes were regulated by prognosis-significant miRNAs. The phosphoinositide 3-kinase/AKT pathway and SRC signaling were densely populated by prognosis-significant genes and driven by genomic amplification of SRC and miRNA regulation of p85α and CBL. On tissue microarray validation (n = 148), p85α protein expression was associated with improved survival for all patients (P = 0.02), and activated P-SRC (Y418) was associated shorter survival for patients with low-grade histology tumors (P = 0.04). Interacting P-SRC and p85α revealed that they define two distinct PDAC patient subgroups (P = 0.0066). Furthering the importance of these pathways, CBL protein expression was associated with improved survival (P = 0.03) on a separate cohort (n = 42). CONCLUSIONS: These pathways and related genes may represent putative clinical biomarkers and possible targets of individualized therapy in the distinct patient subgroups they define.

Identification of CD166 as a surface marker for enriching prostate stem/progenitor and cancer initiating cells.

New therapies for late stage and castration resistant prostate cancer (CRPC) depend on defining unique properties and pathways of cell sub-populations capable of sustaining the net growth of the cancer. One of the best enrichment schemes for isolating the putative stem/progenitor cell from the murine prostate gland is Lin(-);Sca1(+);CD49f(hi) (LSC(hi)), which results in a more than 10-fold enrichment for in vitro sphere-forming activity. We have shown previously that the LSC(hi) subpopulation is both necessary and sufficient for cancer initiation in the Pten-null prostate cancer model. To further improve this enrichment scheme, we searched for cell surface molecules upregulated upon castration of murine prostate and identified CD166 as a candidate gene. CD166 encodes a cell surface molecule that can further enrich sphere-forming activity of WT LSC(hi) and Pten null LSC(hi). Importantly, CD166 could enrich sphere-forming ability of benign primary human prostate cells in vitro and induce the formation of tubule-like structures in vivo. CD166 expression is upregulated in human prostate cancers, especially CRPC samples. Although genetic deletion of murine CD166 in the Pten null prostate cancer model does not interfere with sphere formation or block prostate cancer progression and CRPC development, the presence of CD166 on prostate stem/progenitors and castration resistant sub-populations suggest that it is a cell surface molecule with the potential for targeted delivery of human prostate cancer therapeutics.

An optimized small molecule inhibitor cocktail supports long-term maintenance of human embryonic stem cells.

A major challenge in stem cell-mediated regenerative medicine is the development of defined culture systems for the maintenance of clinical-grade human embryonic stem (hES) cells. Here, we identify, using a feedback system control scheme, a unique combination of three small molecule inhibitors that enables the maintenance of hES cells on a fibronectin-coated surface through single cell passaging. After 20 passages, the undifferentiated state of the hES cells was confirmed by OCT4, SSEA4 and NANOG expressions, whereas their pluripotent potential and genetic integrity were demonstrated by teratoma formation and normal karyotype, respectively. Our study attests to the power of the feedback system control scheme to quickly pinpoint optimal conditions for desired biological activities, and provides a chemically defined, scalable and single cell passaging culture system for hES cells.