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Breast cancers are heterogeneous with variable clinical courses and treatment responses.We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents.Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOncoThirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029).Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy.ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers.We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab.Eligible patients had advanced or metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic analyses of varlitinib and paclitaxel were performed.Thirty-seven patients were enrolled into eight cohorts with median 4 (0-14) prior lines of palliative systemic therapies. Carboplatin area under the curve 1.5 and paclitaxel 80 mg/mThe recommended phase II dose of varlitinib with paclitaxel is 300 mg twice daily intermittently dosed. This is active in HER2+ metastatic breast cancer. Subcutaneous trastuzumab can be added safely to varlitinib and paclitaxel. This combination is currently being evaluated as neoadjuvant therapy in HER2+ breast cancer (NCT02396108).NCT02396108, date of registration: 25 March, 2015.

Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM.Forty-four patients with GCPM received IP PTX (40 mg/mThe median OS for the IP and SC groups was 14.6 and 10.6 months (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.26-0.74; p = 0.002). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI 0.25-0.66; p 0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p = 0.021) and had better performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p = 0.007) compared with the IP cohort. In IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95% CI 13.1-35.3) months and 1-year OS of 84.6%.IP PTX with XELOX is a promising treatment option for GCPM patients. In patients with good response, conversion surgery was feasible with favourable outcomes.

Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in

Preclinical studies have demonstrated synergy between poly(ADP-ribose) polymerase (PARP) and phosphatidylinositol-3-kinase (PI3K)/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose-escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2-wildtype cancers harboring somatic DNA damage response (DDR) or PI3K/AKT pathway alterations. The combination was well-tolerated. Recommended phase 2 doses for the two schedules were: olaparib 300mg BID with either capivasertib 400mg BID 4- days-on, 3-days-off, or capivasertib 640mg BID 2-days-on, 5-days-off. Pharmacokinetics were dose-proportional. Pharmacodynamic studies confirmed pGSK3β suppression, increased pERK and decreased BRCA1 expression. 25 (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST CR/PR or stable disease ≥4 months), including patients with tumors harboring germline BRCA1/2- mutations and BRCA1/2-wildtype cancers with or without DDR and PI3K/AKT pathway alterations.

The incidence of atypical femoral fractures (AFFs) was 2.95% among 6644 hip and femoral fractures. Independent risk factors included the use of bisphosphonates (BPs), osteopenia or osteoporosis, rheumatoid arthritis, increased femoral curvatures, and thicker femoral cortices. Patients with AFFs and BP treatment were more likely to have problematic healing than those with typical femoral fractures (TFFs) and no BP treatment.To determine the incidence and risk factors of atypical femoral fractures (AFFs), we performed a multicenter case-control study. We also investigated the effects of bisphosphonates (BPs) on AFF healing.We retrospectively reviewed the medical records and radiographs of 6644 hip and femoral fractures of patients from eight tertiary referral hospitals. All the radiographs were reviewed to distinguish AFFs from TFFs. Univariate and multivariate logistic regression analyses were performed to identify risk factors, and interaction analyses were used to investigate the effects of BPs on fracture healing.The incidence of AFFs among 6644 hip and femoral fractures was 2.95% (90 subtrochanter and 106 femoral shaft fractures). All patients were females with a mean age of 72 years, and 75.5% were exposed to BPs for an average duration of 5.2 years (range, 1-17 years). The use of BPs was significantly associated with AFFs (p 0.001, odds ratio = 25.65; 95% confidence interval = 10.74-61.28). Other independent risk factors for AFFs included osteopenia or osteoporosis, rheumatoid arthritis, increased anterior and lateral femoral curvatures, and thicker lateral femoral cortex at the shaft level. Interaction analyses showed that patients with AFFs using BPs had a significantly higher risk of problematic fracture healing than those with TFFs and no BP treatment.The incidence of AFFs among 6644 hip and femoral fractures was 2.95%. Osteopenia or osteoporosis, use of BPs, rheumatoid arthritis, increased anterior and lateral femoral curvatures, and thicker lateral femoral cortex were independent risk factors for the development of AFFs. Patients with AFFs and BP treatment were more likely to have problematic fracture healing than those with TFFs and no BP treatment.

While revision of total hip arthroplasty (THA) is being performed with increasing frequency, outcomes of repeated revisions have been rarely reported in the literature. The purpose of this study was to report mid-term outcomes of re-revision of failed revision THA acetabular components. We performed at least two revisions of the failed acetabular component in 57 patients (57 hips) between August 1996 and April 2008. Of these, 15 patients with infection were excluded and one died before 4-year evaluation. The final study cohort consisted of 41 patients (41 hips) with a mean age of 55.5 years (range, 37 to 82). Preoperative acetabular bone defects was classified as Paprosky Type IIA in 4 hips, Type IIB in 6, Type IIC in 9, Type IIIA in 16, and Type IIIB in 6. The mean duration of follow-up was 7.2 years (range, 4 to 15). Mean Harris hip score improved 45 points preoperatively to 83 points postoperatively. Six hips (14.6%) required additional revision procedure: 3 for aseptic loosening, 2 for deep infection, and 1 for recurrent instability. Complications included 2 dislocations and 1 peroneal nerve palsy. Kaplan-Meier survivorship with an end point of reoperation for any reason was 88.5% (95% CI, 78.0% to 100%) at 7.2 years. For aseptic loosening of the acetabular component, the survival was 91.8% (95% CI, 80.8% to 100%) at 7.2 years. Rerevision with contemporary uncemented cup or antiprotrusio cage for failed revision THA acetabular components showed encouraging mid-term outcomes for this technically challenging condition.

Loss of coxsackievirus and adenovirus receptor (CAR) is frequently observed in malignant cancer, hampering adenoviral gene therapy approaches. Complexing adenovirus with cationic liposomes can increase adenoviral transgene expression, particularly in cells with CAR-deficiency. We investigated whether other factors such as lipid composition might be involved in determining the efficiency of liposome-complexed adenoviral gene transfer in cancer cells.Human cancer cell lines with different expression levels of CAR were infected with a GFP transgene. The efficiency of transgene expression was assessed by determining GFP expression using FACS analysis.The efficiency of liposome-complexed adenoviral gene transfer was dependent on the lipid composition constituting liposomes. Polyethylene glycol (PEG)-containing liposomes were most effective in increasing liposome-complexed adenoviral gene transfer. In CAR-deficient cells, use of PEG-containing liposomes enhanced adenoviral gene transfer, whereas in CAR-expressing cells enhancement varied depending on cell type. In some CAR-expressing cells, the effect of liposome complexing was even comparable to that in CAR-deficient cells. Increased adenoviral transgene expression following complexing with PEG-containing liposomes correlated with liposome uptake in cancer cells.Liposome-complexed adenoviral gene transfer appears to depend on lipid composition and the level of liposome uptake by cancer cells, in addition to CAR levels. Our study suggest that these multiple factors should be considered in designing liposome-complexed adenoviral vectors to improve outcomes of current adenoviral cancer gene therapies.

To determine the prophylactic effect of 0.2% brimonidine in reducing the elevated intraocular pressure (IOP) in patients undergoing Nd:YAG laser posterior capsulotomy.The 81 patients (81 eyes), who underwent Nd:YAG laser posterior capsulotomy, were allocated to two treatment groups. One drop of 0.2% brimonidine or vehicle was instilled 1 hour preoperatively and one drop immediately after capsulotomy. IOPs were measured preoperatively and 1, 2, 3, and 24 hours postoperatively.Intraocular pressure decreased from the baseline in the brimonidine group by the third postoperative hour (P0.05), while the vehicle group exhibited an increase. Intraocular pressure elevations of 5 mm Hg or greater occurred in 7.3% (3/41) in the brimonidine group compared to 20.0% (8/40) in the vehicle group. IOP elevations of 10 mm Hg or greater occurred in 2.4% (1/41) in the brimonidine group compared to 7.5% (3/40) in the vehicle group.One drop of 0.2% brimonidine instilled 1 hour preoperatively and immediately after capsulotomy was found to be efficacious and safe in preventing IOP elevations that frequently follow Nd:YAG laser posterior capsulotomy.

Autosomal dominantly transmitted hereditary multiple exostoses is an uncommon disorder consisting of multiple projections of bone capped by cartilage. The lesions are most numerous in the metaphyses of long bones but may appear on flat bones. Sarcomatous transformation occurs in 1-25% of patients. We report a 33-year-old man with sciatica, previously diagnosed as hereditary multiple exostoses, presenting with multiple peripheral nerve compressions. Electrodiagnostic studies showed profound axon-loss multiple neuropathies involving the sciatic, superior gluteal, and inferior gluteal nerves. Magnetic resonance imaging of the left pelvis showed a large mass in the sacral area that was suggestive of a chondrosarcoma. An open intralesional excision biopsy confirmed chondrosarcoma transformed from chondromatosis. Excision of the lesion was effective in eliminating the impingement of nerves and retarding progressive osseous growth. We suggest that malignant transformation be suspected in cases with focal compression neuropathy of patients known to have multiple exostoses. Osteochondroma as a possible cause for compression neuropathy is discussed.

It is important to determine the anterior capsular zonular free zone (ZFZ) in order to minimize the risk of zonular disinsertion. From this point of view the size of the ZFZ of normal suspended lenses was directly measured in 199 human eyes obtained postmortem. The cornea was completely excised and the iris removed to allow clear visualization of the anterior surface of the lens to the equator. After measuring lens diameter with a caliper, a 4 mm continuous curvilinear capsulorhexis was performed, and lens substrate was completely removed by phacoemulsification. Care was taken to minimize trauma to the zonules during surgery. The anterior insertion of the zonules was identified at high power magnification; the size of the ZFZ was measured with a caliper. The mean age was 75.5 +/- 10.3 (+/-SD) years (age range, 50 approximately 100 years). The mean diameter of the lenses was 9.72 +/- 0.31 mm. The mean diameter of the ZFZ was 6.83 +/- 0.35 mm. Statistical analysis revealed no significant correlation between the size of the ZFZ and age, or between the size of the ZFZ and lens diameter. The present study indicates that the size of the ZFZ was constant regardless of age or lens diameter.

Protein kinase C (PKC) plays an important role in activation of human immunodeficiency virus type 1 (HIV-1). Because of a molecular and biochemical heterogeneity of PKC, we have studied the effects of PKC isozymes in HIV-1 activation in a latently infected promonocytic cell line, U1, using various PKC isozyme agonists. 12-Deoxyphorbol 13-phenylacetate (dPP), an agonist of both Ca(++)-dependent and Ca(++)-independent isozymes, and thymeleatoxin (TT), an agonist of Ca(++)-dependent PKC isozymes, induced HIV-1 production at 10 nM with increase in a concentration dependent manner, whereas 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA), an PKC beta I isozyme agonist, did not induce viral production at 100 nM. We verified that dPPA induced translocation of PKC beta isozyme with the isozyme-specific monoclonal antibody using flow cytometry. This study demonstrates that activation of PKC isozymes leads to an induction of latent HIV-1 in U1 cells whereas PKC beta I isozyme may not be important.

The construction of dams across the mouths of major tidal rivers in the development of the Kranji Reservoir, Western Catchments Scheme and the Sungei Seletar Reservoir in Singapore created suitable environmental conditions for the propagation of anopheline brackish-water breeders. The employment of foreign contract workers from malarious areas for the projects further increased the potential risk of malaria transmission. However, constant vigilance and environmental management aimed at the permanent elimination of vector breeding habitats, supplemented with chemical control and anti-parasite measures successfully prevented the reintroduction of malaria in these highly receptive and vulnerable areas.

A nation-wide outbreak of 260 cases of DF/DHF with 1 death occurred in Singapore from Apr-Sept 1986. The outbreak originated from 3 separate foci of transmission at the western, south-eastern and north-eastern parts of the island and then spread to other dengue receptive urban and suburban areas. The morbidity rate was highest in young male Chinese adults between 15 and 24 years of age. The outbreak was rapidly brought under control through destruction of adult Aedes mosquitoes, surveys and source reduction of larval breeding habitats, health education and to a certain extent law enforcement. The Aedes population was high in the main foci of transmission although the overall house index was only 1.1. Other factors which could have precipitated the outbreak included waning herd immunity of the human population and continuous introduction of dengue virus into the country.