RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients

Purpose

The miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC).

Methods

An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODER^TM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death.

Results

Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%.

Conclusions

The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. {"type":"clinical-trial","attrs":{"text":"NCT01188785","term_id":"NCT01188785"}}NCT01188785     

Breast Cancer Cell Colonization of the Human Bone Marrow Adipose Tissue Niche

BACKGROUND/OBJECTIVES: Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche. METHODS: Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry. RESULTS: Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment. CONCLUSIONS: Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche.     

miR-17 regulates melanoma cell motility by inhibiting the translation of ETV1

Melanoma is an aggressive malignancy with a high metastatic potential. microRNA-17 (miR-17) is a member of the oncogenic miR-17/92 cluster. Here we study the effect of miR-17 on melanoma cell motility. Over expression of the mature or pri-microRNA form of miR-17 in WM-266-4 and 624mel melanoma lines enhances cell motility, evident in both wound healing and transwell migration assays. TargetScan algorithm predicts the PEA3-subfamily member ETV1 as a direct target of miR-17. Indeed, a 3–4-fold decrease of ETV1 protein levels are observed following miR-17 transfection into the various melanoma lines, with no significant change in ETV1 mRNA expression. Dual luciferase experiments demonstrate direct binding of miR-17 to the 3′-untranslated region of ETV1, confirmed by abolishing point mutations in the putative binding site. These combined results suggest regulation of ETV1 by miR-17 by a direct translational repression. Further, in both melanoma cell lines ETV1 knockdown by selective siRNA successfully pheno-copies the facilitated cell migration, while overexpression of ETV1 inhibits cell motility and migration. Altered ETV1 expression does not affect melanoma net-proliferation. In conclusion, we show a new role for miR-17 in melanoma, facilitating cell motility, by targeting the translation of ETV1 protein, which may support the development of metastasis.     

Patient experiences after hospitalizations for elective surgery

Background

Little is known from patients' perspective about the quality of postdischarge care and the causes of rehospitalization after elective surgery.

Methods

A prospective observational cohort study was conducted.

Results

Of 400 patient participants, 374 completed the 30-day follow-up questionnaire (completion rate, 94%). Half of all unplanned rehospitalizations (experienced by 13% of patients) and nonrehospitalization emergency department visits (experienced by 6%) occurred within 10 days of discharge. Patients used emergency departments and were rehospitalized at facilities near their homes (mean distance traveled, 12.1 mi). The most common primary reason for rehospitalization was postoperative complications, according to patient report, clinical records, and administrative data. Poor perceived care coordination was associated with higher readmission risk.

Conclusions

Patients perceive surgical complications as dominating the reasons for rehospitalizations after elective surgery. Strategies to improve care quality around elective surgery at referral centers should target the discharge process and the coordinated management of postoperative complications through care received at regional hospitals.     

Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome

Background

22q11.2 deletion syndrome (22q11.2DS) is a common neurogenetic syndrome associated with high rates of psychosis. The aims of the present study were to identify the unique temperament traits that characterize children with 22q11.2DS compared to children with Williams syndrome (WS) and typically developing (TD) controls, and to examine temperamental predictors of the emergence of psychosis in 22q11.2DS.

Methods

The temperament of 55 children with 22q11.2DS, 36 with WS, and 280 TD children was assessed using the Emotionality, Activity, Sociability (EAS) Temperament Survey, Parental Ratings. The presence of a psychotic disorder was evaluated in 49 children and adolescents with 22q11.2DS at baseline and again 5.43 ± 2.23 years after baseline temperament assessment.

Results

Children with 22q11.2DS scored higher on Shyness compared to WS and TD controls. Children with 22q11.2DS and WS scored higher on Emotionality and lower on Activity compared to TD controls. Shyness was more severe in older compared to younger children with 22q11.2DS. Baseline Shyness scores significantly predicted the later emergence of a psychotic disorder at follow-up, in children with 22q11.2DS.

Conclusions

Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS.     

Prognostic significance of indeterminate lung nodules in renal cell carcinoma

ObjectivesMany patients with renal cell carcinoma (RCC) are found to have lung nodules at the time of diagnosis. The significance of these nodules is unclear. This study sought to determine whether the presence of indeterminate lung nodules affects survival for patients with early-stage RCC.Methods and materialsA retrospective review was performed of patients with stages I to III RCC at an academic hospital who underwent nephrectomy between 2001 and 2006 and had baseline imaging available for review. Presence of lung nodule(s) was determined, along with patient and disease characteristics. The time from diagnosis to last known follow-up, metastasis, and death were determined. The study follow-up period extended to July 2012. Univariate and multivariate Cox proportional hazards models assessed disease-free and overall survival.ResultsOf 548 patients, 240 met the inclusion criteria. Lung nodules were absent in 148 and present in 92 cases. Disease-free survival was associated with the presence of nodules (hazard ratio [HR] = 1.90; 95% CI: 1.04–3.46; P = 0.0362), tumor stage (stage II—HR = 5.61; 95% CI: 2.69–11.72; P<0.001 and stage III—HR = 2.49; 95% CI: 1.21–5.10; P = 0.0129) and tumor grade (HR = 2.43 for grades 3 or 4; 95% CI: 1.31–4.53; P = 0.005). The number and size of nodules were not associated with survival. Overall survival was associated with Charlson comorbidity score (HR = 1.30; 95% CI: 1.15–1.47; P<0.0001) and primary tumor size (HR = 1.29; 95% CI: 1.14–1.46; P<0.0001) but not the presence of lung nodules (HR = 1.73; 95% CI: 0.83–3.60; P = 0.1454).ConclusionsThe presence of indeterminate lung nodules had a negative effect on disease-free survival. Stage and grade were also significant. These findings underscore the importance of baseline imaging and vigilant surveillance of patients in whom nodules are identified.     

Resurgence of Cutaneous Leishmaniasis in Israel, 2001–2012

Cutaneous leishmaniasis has long been endemic in Israel. After a 15-year period of moderate illness rates, reported incidence increased from 0.4 cases per 100,000 population in 2001 to 4.4 cases per 100,000 population in 2012, and the disease emerged in areas where its presence had previously been minimal. We analyzed all cases reported to the national surveillance system and found that outbreak patterns revealed an expansion of Leishmania major infections over large areas in the southern part of the country and the occurrence of spatially focused L. tropica outbreaks in the northern part of the country. Outbreaks often followed new construction in populated areas. Further study of factors affecting the transmission of cutaneous leishmaniasis is needed in Israel, as well as the development of effective methods to control the disease, an increase in awareness among health care professionals, and intensive public education regarding control measures in areas of known leishmaniasis foci.