Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review).

Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in solid tumors. More than 90% of pancreatic ductal adenocarcinoma (PDAC) are driven by mutations in the KRAS gene, suggesting the importance of targeting this oncogene in PDAC. Initial efforts to target KRAS have been unsuccessful due to its small size, high affinity for guanosine triphosphate/guanosine diphosphate, and lack of distinct drug­binding pockets. Therefore, much of the focus has been directed at inhibiting the activation of major signaling pathways downstream of KRAS, most notably the PI3K/AKT and RAF/MAPK pathways, using tyrosine kinase inhibitors and monoclonal antibodies. While preclinical studies showed promising results, clinical data using the inhibitors alone and in combination with other standard therapies have shown limited practicality, largely due to the lack of efficacy and dose­limiting toxicities. Recent therapeutic approaches for KRAS­driven tumors focus on mutation­specific drugs such as selective KRASG12C inhibitors and son of sevenless 1 pan­KRAS inhibitors. While KRASG12C inhibitors showed great promise against patients with non­small cell lung cancer (NSCLC) harboring KRASG12C mutations, they were not efficacious in PDAC largely because the major KRAS mutant isoforms in PDAC are G12D, G12V, and G12R. As a result, KRASG12D and pan­KRAS inhibitors are currently under investigation as potential therapeutic options for PDAC. The present review summarized the importance of KRAS oncogenic signaling, challenges in its targeting, and preclinical and clinical targeted agents including recent direct KRAS inhibitors for blocking KRAS signaling in PDAC.

Mediastinal Intrathymic Parathyroid Adenoma: A Case Report and Review of the Literature.

The classic clinical vignette of primary hyperparathyroidism is well described as "bones, stones, abdominal moans, and psychiatric overtones" to reflect the effects of excess parathyroid hormone (PTH) and calcium. Most commonly, primary hyperparathyroidism is due to a functional parathyroid adenoma situated by the thyroid gland. Rarely, the primary focus of autonomously produced PTH is located ectopically within the mediastinum. A 19-year-old Caucasian female with no relevant past medical history presented to the emergency department with tachycardia, nausea, vomiting, and a five-day history of vague, mid-abdominal pain. Initial computed tomography (CT) with contrast of the abdomen and pelvis was negative for acute findings, and she subsequently underwent biochemical screening. The patient was found to have elevated serum calcium and PTH, raising suspicion for the diagnosis of primary hyperparathyroidism. Further evaluation for a parathyroid adenoma was negative by a CT scan of the neck and thyroid ultrasound. A nuclear medicine parathyroid single-photon emission computed tomography (SPECT)/CT with technetium (Tc) 99m sestamibi found an abnormal nodular uptake within the left prevascular mediastinum suggestive of an ectopic parathyroid adenoma. A left-sided, video-assisted thoracoscopic surgery (VATS) with successful excision of the ectopic mediastinal parathyroid adenoma was performed. Surgical pathology revealed that the parathyroid adenoma was completely excised and surrounded by thymus and adipose tissue. The patient tolerated the procedure well and was discharged without further complications. The rarity of mediastinal, intrathymic parathyroid adenomas resulted in delayed diagnosis in this patient, understandably so as errant embryogenesis does not occur commonly. Visualization with SPECT/CT and successful specimen excision by minimally invasive VATS resulted in the accurate diagnosis and ultimate cure of this patient's primary hyperparathyroidism.

National Economic Conditions May Impact the Financial Barriers to Travel for Cancer Operations.

Background: Better cancer-related outcomes are associated with physicians and hospitals with higher case volume. This serves as an incentive to refer patients requiring complex cancer operations to large referral centers, which may require increased travel for patients. However, barriers exist for patients to travel for cancer care, some of which may be aggravated or alleviated by factors relating to the health of the national economy. This impact may be reflected in variability of travel distances for cancer operations over time particularly for complex operation such as pancreatectomy and esophagectomy compared with less complex resections such as those for breast cancer or melanoma. Methods: We obtained the estimated travel distance for patients undergoing operations for cancer of the pancreas, esophagus, skin (melanoma), and breast from the National Cancer Database from 2004 to 2017 and correlated them with economic factors obtained from public sources. We then examined the impact of unemployment rates, gas prices, and inflation on travel distances regarding disadvantaged groups. Correlations were measured by the (rank-based, nonparametric) Spearman's correlation coefficient, and the corresponding P value is obtained by the asymptotic distribution of the coefficient. A P value of 0.05 equates to an absolute correlation value of 0.532. To adjust for multiple tests, a more restrictive P value of 0.01 was also assessed, which equates to correlation coefficients of absolute value greater than 0.661. Results: There were 4,222,380 cases in the dataset, of which 1,781,056 remained after exclusion. The economic factors that were associated most strongly with the distance patients traveled for all cancer operation types were the labor force participation rate, personal savings, consumer price index, and changes in gasoline prices. Inflation and rising gasoline prices were often inversely related with travel distance in lower-income and less well-educated regions and African American patients. Conclusions: Several macroeconomic factors correlate with the travel distance for operations, suggesting that the economic health of the nation may aggravate or alleviate the financial barriers to travel for cancer operations. Financially disadvantaged groups may be particularly vulnerable to changes in gasoline prices and inflation. Organizations serving these populations may need to increase patient support services during times of economic hardship to avoid the exacerbation of health care disparities.

Nab-Paclitaxel in the Treatment of Gastrointestinal Cancers-Improvements in Clinical Efficacy and Safety.

Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.

Inhibition of signaling downstream of beta-2 adrenoceptor by propranolol in prostate cancer cells.

BACKGROUND: There is accumulating evidence that propranolol, an antagonist of beta-1 and beta-2 adrenoreceptors, extends survival of patients with prostate cancer; yet it is not known whether propranolol inhibits beta-adrenergic signaling in prostate cancer cells, or systemic effects of propranolol play the leading role in slowing down cancer progression. Recently initiated clinical studies offer a possibility to test whether administration of propranolol inhibits signaling pathways in prostate tumors, however, there is limited information on the dynamics of signaling pathways activated downstream of beta-2 adrenoreceptors in prostate cancer cells and on the inactivation of these pathways upon propranolol administration. METHODS: Western blot analysis was used to test the effects of epinephrine and propranolol on activation of protein kinase (PKA) signaling in mouse prostates and PKA, extracellular signal-regulated kinase (ERK), and protein kinase B/AKT (AKT) signaling in prostate cancer cell lines. RESULTS: In prostate cancer cell lines epinephrine induced robust phosphorylation of PKA substrates pS133CREB and pS157VASP that was evident 2 min after treatments and lasted for 3-6 h. Epinephrine induced phosphorylation of AKT in PTEN-positive 22Rv1 cells, whereas changes of constitutive AKT phosphorylation were minimal in PTEN-negative PC3, C42, and LNCaP cells. A modest short-term increase of pERK in response to epinephrine was observed in all tested cell lines. Incubation of prostate cancer cells with 10-fold molar excess of propranolol for 30 min inhibited all downstream pathways activated by epinephrine. Subjecting mice to immobilization stress induced phosphorylation of S133CREB, whereas injection of propranolol at 1.5 mg/kg prevented the stress-induced phosphorylation. CONCLUSIONS: The analysis of pS133CREB and pS157VASP allows measuring activation of PKA signaling downstream of beta-2 adrenoreceptors. Presented results on the ratio of propranolol/epinephrine and the time needed to inhibit signaling downstream of beta-2 adrenoreceptors will help to design clinical studies that examine the effects of propranolol on prostate tumors.

Efficacy of intraoperative cholangiography versus preoperative magnetic resonance cholangiography in patients with intermediate risk for common bile duct stones.

BACKGROUND: This is the first randomized trial to evaluate the efficacy of intraoperative cholangiography (IOC) and magnetic resonance cholangiopancreatography (MRCP) in patients with suspected CBDS. METHODS: This unblinded, multicenter RCT was conducted at five swiss hospitals. Eligibility criteria were suspected CBDS. Patients were randomized to IOC and laparoscopic cholecystectomy (LC), followed by endoscopic retrograde cholangiopancreatography (ERCP) if needed, or MRCP followed by ERCP if needed, and LC. Primary outcome was length of stay (LOS), secondary outcomes were cost, stone detection, and complication rates. RESULTS: 122 Patients were randomised to the IOC Group (63) or the MRCP group (59). Median LOS for the IOC and the MRCP groups were 4 days IQR [3, 6] and [4, 6], with an estimated increase of LOS of 1.2 days in the MRCP group (p = 0.0799) in the linear model. Median cost in the IOC and MRCP groups were 10 473 Swiss Francs (CHF) and 10 801 CHF, respectively (p = 0.694). CBDS were found in 24 and 12 patients in the IOC and the MRCP groups, respectively (p = 0.0387). The complication rate did not differ between both groups. CONCLUSION: There is equipoise between both pathways. IOC has a significantly higher diagnostic yield than MRCP. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02351492: Radiological Investigation of Bile Duct Obstruction (RIBO).

Melatonin and andrographolide synergize to inhibit the colospheroid phenotype by targeting Wnt/beta-catenin signaling.

ß-catenin signaling, and angiogenesis are associated with colospheroid (CSC), development. CSCs, spheroids derived from colon cancer cells, are responsible for metastasis, drug resistance, and disease recurrence. Whether dysregulating ß-catenin and inhibiting angiogenesis reduce CSC growth is unknown. In this study, the molecular mechanism of CSC growth inhibition was evaluated using a novel combination of melatonin (MLT) and andrographolide (AGP). These drugs have anticarcinogenic, antioxidant, and antimetastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT-15). The viability and stemness were monitored (FDA propidium iodide staining and immunoblot for CD44, CD133, Nanog, Sox2, and Oct4). The drug combination synergistically diminished stemness via increased reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential and ATP level. MLT + AGP induced cell death by inhibiting ß-catenin expression and its downregulatory signals, Cyclin D1, c-Myc. MLT + AGP treated cells exhibited translocation of phospho-ß-catenin to the nucleus and dephosphorylated-ß-catenin. Downregulation of ß-catenin activation and its transcription factors (TCF4 and LEF1) and GTP binding/G-protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF messenger RNA transcripts (VEGF189), phosphorylated VEGF receptor protein expression, matrigel invasion, and capillary tube inhibition. In vivo, the intravenous injection of MLT + AGP slowed HT29 metastatic colon cancer. Histopathology indicated significant reduction in microvascular density and tumor index. Immunohistochemistry for caspase 7, and ß-catenin found increased apoptosis and downregulation of ß-catenin signals. The mechanism(s) of decreased colospheroids growth were the inhibition of the Wnt/ß-catenin pathway. Our results provide a rationale for using MLT in combination with AGP for the inhibition of CRCs.

Cytokine Interaction With Cancer-Associated Fibroblasts in Esophageal Cancer.

Esophageal cancer (EC) is a highly aggressive cancer with poor outcomes under current treatment regimens. More recent findings suggest stroma elements, specifically cancer-associated fibroblasts (CAFs), play a role in disease occurrence and progression. Cancer-associated fibroblasts are largely the product of converted fibroblasts, but a variety of other local cell types including epithelial cells, endothelial cells, and mesenchymal cells have also been shown to transform to CAFs under the correct conditions. Cancer-associated fibroblasts primarily function in the communication between the tumor microenvironment and cancer cells via cytokine and chemokine secretions that accentuate immunosuppression and cancer growth. Cancer-associated fibroblasts also pose issues for EC treatment by contributing to resistance of current chemotherapeutics like cisplatin. Targeting this cell type directly proves difficult given the heterogeneity between CAFs subpopulations, but emerging research provides hope that treatment is on the horizon. This review aims to unravel some of the complexities surrounding CAFs' impact on EC growth and therapy.

Surgical Outcomes After Neoadjuvant Chemoradiation Followed by Curative Surgery in Patients With Esophageal Cancer: An Intergroup Phase III Trial of the Swiss Group for Clinical Cancer Research (SAKK 75/08).

OBJECTIVE: To assess the impact of surgical technique in regard to morbidity and mortality after neoadjuvant treatment for esophageal cancer. BACKGROUND: The SAKK trial 75/08 was a multicenter phase III trial (NCT01107639) comparing induction chemotherapy followed by chemoradiation and surgery in patients with locally advanced esophageal cancer. METHODS: Patients in the control arm received induction chemotherapy with cisplatin and docetaxel, followed by concomitant chemoradiation therapy with cisplatin, docetaxel, and 45Gy. In the experimental arm, the same regimen was used with addition of cetuximab. After completion of neoadjuvant treatment, patients underwent esophagectomy. The experimental arm received adjuvant cetuximab. Surgical outcomes and complications were prospectively recorded and analyzed. RESULTS: Total of 259 patients underwent esophagectomy. Overall complication rate was 56% and reoperation rate was 15% with no difference in complication rates for transthoracic versus transhiatal resections (56% vs 54%, P = 0.77), nor for video assisted thoracic surgeries (VATS) versus open transthoracic resections (67% vs 55%, P = 0.32). There was a trend to higher overall complication rates in squamous cell carcinoma versus adenocarcinoma (65% vs 51%, P = 0.035), and a significant difference in ARDS in squamous cell carcinoma with 14% versus 2% in adenocarcinoma (P = 0.0002). For patients with involved lymph nodes, a lymph node ratio of ≥0.1 was an independent predictor of PFS (HR 2.5, P = 0.01) and OS (HR 2.2, P = 0.03). CONCLUSIONS: This trial showed no difference in surgical complication rates between transthoracic and transhiatal resections. For patients with involved lymph nodes, lymph node ratio was an independent predictor of progression free survival and overall survival.

Targeted FGFR/VEGFR/PDGFR inhibition with dovitinib enhances the effects of nab-paclitaxel in preclinical gastric cancer models.

Standard chemotherapy regimens for gastric adenocarcinoma (GAC) have limited efficacy and considerable toxicity profiles. Nab-paclitaxel has shown promising antitumor benefits in previous GAC preclinical studies. Dovitinib inhibits members of the receptor tyrosine kinase family including FGFR, VEGFR and PDGFR, and has exhibited antitumor effects in many solid tumors including GAC. Based on the antimitotic, antistromal and EPR effects of nab-paclitaxel, we investigated augmentation of nab-paclitaxel response by dovitinib in multiple GAC preclinical models. In MKN-45 subcutaneous xenografts, inhibition in tumor growth by nab-paclitaxel and dovitinib was 75% and 76%, respectively. Dovitinib plus nab-paclitaxel had an additive effect on tumor growth inhibition and resulted in tumor regression (85% of its original value). Dovitinib monotherapy resulted in minimal improvement in animal survival (25 days) compared to control (23 days), while nab-paclitaxel monotherapy or dovitinib plus nab-paclitaxel combination therapy led to a clinically significant lifespan extension of 83% (42 days) and 187% (66 days), respectively. IHC analysis of subcutaneous tumors exhibited reduced tumor cell proliferation and tumor vasculature by dovitinib. In vitro studies demonstrated that dovitinib and nab-paclitaxel individually reduced tumor cell proliferation, with an additive effect from combination therapy. Immunoblot analyses of MKN-45 and KATO-III cells revealed that dovitinib decreased phospho-FGFR, phospho-AKT, phospho-ERK, phospho-p70S6K, phospho-4EBP1, Bcl-2 and increased cleaved PARP-1, cleaved-caspase-3, p27, Bax, Bim, with an additive effect from combination therapy. These results demonstrate that the FGFR/VEGFR/PDGFR inhibitor, dovitinib, has the potential to augment the antitumor effects of nab-paclitaxel, with implications for use in the advancement of clinical GAC therapy.

Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer.

Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.

Management of post-operative subcutaneous emphysema with the application of wound VAC therapy.

Extensive subcutaneous emphysema (SE) complicates between 1 and 6% of elective thoracic procedures. The management of SE is varied, and may include increasing the suction of chest tubes, placement of additional chest tubes, placement of subcutaneous drains and creation of releasing incisions. We present five patients with post-operative SE treated successfully with a subcutaneous infraclavicular incision and wound VAC therapy. A 5-cm incision was made 2 cm below the clavicle down and through the pectoralis major fascia. A VAC dressing was fitted to the wound and suction was applied to -125 mm Hg. Data were retrospectively collected and analyzed. VAC dressing was placed a median of 6 days after initial operation. All patients had improvement in symptoms and resolution of SE by VAC dressing therapy. Subcutaneous infraclavicular incision and VAC dressing placement is a viable treatment for patients with post-operative SE who fail conservative therapy.

Targeted dual inhibition of c-Met/VEGFR2 signalling by foretinib improves antitumour effects of nanoparticle paclitaxel in gastric cancer models.

Elevated expression of multiple growth factors and receptors including c-Met and VEGFR has been reported in gastric adenocarcinoma (GAC) and thus provides a potentially useful therapeutic target. The therapeutic efficacy of foretinib, a c-Met/VEGFR2 inhibitor, was determined in combination with nanoparticle paclitaxel (NPT) in GAC. Animal studies were conducted in NOD/SCID mice in subcutaneous and peritoneal dissemination xenografts. The mechanism of action was assessed by Immunohistochemical and Immunoblot analyses. In c-Met overexpressing MKN-45 cell-derived xenografts, NPT and foretinib demonstrated inhibition in tumour growth, while NPT plus foretinib showed additive effects. In c-Met low-expressing SNU-1 or patient-derived xenografts, the foretinib effect was smaller, while NPT had a similar effect compared with MKN-45, as NPT plus foretinib still exhibited an additive response. Median mice survival was markedly improved by NPT (83%), foretinib (100%) and NPT plus foretinib (230%) in peritoneal dissemination xenografts. Subcutaneous tumour analyses exhibited that foretinib increased cancer cell death and decreased cancer cell proliferation and tumour vasculature. NPT and foretinib suppressed the proliferation of GAC cells in vitro and had additive effects in combination. Further, foretinib caused a dramatic decrease in phosphorylated forms of c-Met, ERK, AKT and p38. Foretinib led to a decrease in Bcl-2, and an increase in p27, Bax, Bim, cleaved PARP-1 and cleaved caspase-3. Thus, these findings highlight the antitumour impact of simultaneous suppression of c-Met and VEGFR2 signalling in GAC and its potential to enhance nanoparticle paclitaxel response. This therapeutic approach might lead to a clinically beneficial combination to increase GAC patients' survival.

A case of squamous cell lung cancer presented as a cystic lesion and recurrent pneumothoraces.

We report a rare case of a 70-year-old male with recurrent pneumothoraces within one year treated with intermittent insertion of chest tube on each occasion. Diagnostic testing was notable for a cystic lesion in the left lung that was initially interpreted as bulla on chest x-ray and chest computed tomographic scan. Due to thickening and nodularity changes of the thin wall of the cystic lesion, the patient underwent left upper lobectomy. Pathology showed poorly differentiated squamous cell carcinoma of the cystic lesion wall. This case emphasizes the importance of monitoring pulmonary cystic lesions especially in patients with a history of smoking and emphysema.

Nestin and CD34 expression in colorectal cancer predicts improved overall survival.

BACKGROUND: Nestin, a class VI intermediate filament protein of the cytoskeleton, and CD34, a transmembrane phosphoglycoprotein, are markers of progenitor cells. This study aimed to evaluate their expression and clinical significance in colorectal cancer. METHODS: A clinically annotated tissue microarray, including 599 patients with colorectal cancer, was analyzed by immunohistochemistry. Furthermore, nestin and CD34 correlations with HIF-1a and a panel of cytokines and chemokines were assessed using quantitative reverse transcription PCR and The Cancer Genome Atlas dataset. RESULTS: Expression of nestin and CD34 was observed only in the tumor stroma. Patients displaying high expression of nestin and CD34 demonstrated higher rates of T1 and T2 tumors (p = .020), lower vascular invasion (p < .001) and improved 5-year overall survival (65%; 95% CI = 55-73 vs 45%; 95% CI = 37-53) after adjusting for clinicopathological characteristics (HR: 0.67; 95% CI = 0.46-0.96). A moderate to strong correlation (r = 0.37-0.78, p < .03) of nestin and CD34 was demonstrated for the following markers; HIF-1α, CD4, CD8, FOXP3, IRF1, GATA3, CCL2, CCL3, CXCL12 and CCL21. CONCLUSIONS: Combined expression of nestin and CD34 expression is associated with better overall survival possibly by modulating a favorable immune response.

ß2-adrenoreceptor Signaling Increases Therapy Resistance in Prostate Cancer by Upregulating MCL1.

There is accumulating evidence that continuous activation of the sympathetic nervous system due to psychosocial stress increases resistance to therapy and accelerates tumor growth via ß2-adrenoreceptor signaling (ADRB2). However, the effector mechanisms appear to be specific to tumor type. Here we show that activation of ADRB2 by epinephrine, increased in response to immobilization stress, delays the loss of MCL1 apoptosis regulator (MCL1) protein expression induced by cytotoxic drugs in prostate cancer cells; and thus, increases resistance of prostate cancer xenografts to cytotoxic therapies. The effect of epinephrine on MCL1 protein depended on protein kinase A (PKA) activity, but was independent from androgen receptor expression. Furthermore, elevated blood epinephrine levels correlated positively with an increased MCL1 protein expression in human prostate biopsies. In summary, we demonstrate that stress triggers an androgen-independent antiapoptotic signaling via the ADRB2/PKA/MCL1 pathway in prostate cancer cells. IMPLICATIONS: Presented results justify clinical studies of ADRB2 blockers as therapeutics and of MCL1 protein expression as potential biomarker predicting efficacy of apoptosis-targeting drugs in prostate cancer.

Low Expression of Programmed Death 1 (PD-1), PD-1 Ligand 1 (PD-L1), and Low CD8+ T Lymphocyte Infiltration Identify a Subgroup of Patients With Gastric and Esophageal Adenocarcinoma With Severe Prognosis.

Prognosis of gastric and esophageal cancer is poor and treatment improvements are needed. Programmed cell death 1 receptor (PD-1) interaction with its ligand PD-L1 in tumor micro-environment promotes immune tolerance and blocking monoclonal antibodies have entered clinical practice. However, clinical significance of PD-1 and PD-L1 expression in gastric and esophageal adenocarcinomas, particularly in non-Asian patients, is still unclear. Three tissue microarrays including 190 clinically annotated esophageal (n = 31) and gastric (n = 159) adenocarcinomas and 58 paired mucosa specimens, were stained with PD-1, PD-L1, and CD8-specific reagents in indirect immunohistochemistry assays. PD-L1 expression was detectable in 23.2% of cancer specimens. High PD-1 expression was detectable in 37.3% of cases and high CD8+ infiltration in 76%. PD-L1 and high PD1 expression significantly correlated with each other (r s = 0.404, P < 0.0001) and both significantly correlated with CD8+ infiltration (r s = 0.435, P = 0.0003, and r s = 0.444; P = 0.0004, respectively). CD8+ lymphocyte infiltration correlated with improved survival in univariate (P = 0.009), but not multivariate analysis. Most interestingly, multivariate analysis and Kaplan-Meier curves indicate that combined low PD-1/PD-L1 expression and low CD8+ lymphocyte infiltration significantly correlate with poor prognosis. Our data document the clinical significance of a microenvironmental signature including PD-1/PD-L1 expression and CD8+ lymphocyte infiltration in gastric and esophageal adenocarcinomas and contribute to identify a patients' subset requiring more aggressive peri-operative treatments.

Effectiveness of hemostatic agents in thyroid surgery for the prevention of postoperative bleeding.

Postoperative bleeding remains one of the most frequent, but rarely life-threatening complications in thyroid surgery. Although arterial bleeding is the main cause of postoperative hemorrhage, most often no actively bleeding vessel can be found during revision. Therefore, the coagulation technique for larger vessels may play a minor role, and hemostatic agents could be of higher importance. In this descriptive, retrospective study, data of 279 patients with thyroid surgery (total of 414 thyroid lobectomies) were collected. We reviewed the electronic medical record by analyzing the histological, operative, laboratory and discharge reports in regards to postoperative bleeding. Of the 414 operated thyroid lobes, 2.4% (n = 10) bled. 1.4% (n = 6) needed reoperation while the other 1.0% (n = 4) could be treated conservatively. Hemostatic patches were applied 286 (69.1%) times. Of the 128 (30.9%) patch-free operated sides, 4.7% (n = 6) suffered postoperative bleeding. Tachosil® alone was used 211 (51.0%) times and bleeding occurred in 1.4% (n = 3). Without statistical significance (p = 0.08) the use of Tachosil® seems to help preventing postoperative bleeding. The combination with other patches doesn't appear to be more efficient.

Combination effect of lapatinib with foretinib in HER2 and MET co-activated experimental esophageal adenocarcinoma.

Recent studies have demonstrated that HER2 and MET receptor tyrosine kinases are co-overexpressed in a subset esophageal adenocarcinoma (EAC). We therefore studied the usefulness of combining HER2 and MET targeting by small-molecule inhibitors lapatinib and foretinib, respectively, both in in-vitro and in-vivo models of experimental EAC. We characterized MET and HER2 activation in a panel of human EAC cell lines, and the differential susceptibility of these EAC cell lines to single agent or combination of foretinib and lapatinib. We then explored the antitumor efficacy with survival advantage following foretinib and lapatinib monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. The OE33 EAC cell line with strong expression of phosphorylated both MET and HER2, demonstrated reduced sensitivity to foretinib and lapatinib when used as a single agent. The co-administration of foretinib and lapatinib effectively inhibited both MET and HER2 phosphorylation, enhanced inhibition of cell proliferation and xenograft tumor growth by inducing apoptosis, and significantly enhanced mouse overall survival, overcoming single agent resistance. In the OE19 EAC cell line with mainly HER2 phosphorylation, and the ESO51 EAC cell line with mainly MET phosphorylation, profound cell growth inhibition with induction of apoptosis was observed in response to single agent with lack of enhanced growth inhibition when the two agents were combined. These data suggest that combination therapy with foretinib and lapatinib should be tested as a treatment option for HER2 positive patients with MET-overexpressing EAC, and could be a novel treatment strategy for specific EAC patients.

The impact of surgical site infections on hospital contribution margin-a European prospective observational cohort study.

BACKGROUND: Surgical site infections (SSIs) are common surgical complications that lead to increased costs. Depending on payer type, however, they do not necessarily translate into deficits for every hospital. OBJECTIVE: We investigated how surgical site infections (SSIs) influence the contribution margin in 2 reimbursement systems based on diagnosis-related groups (DRGs). METHODS: This preplanned observational health cost analysis was nested within a Swiss multicenter randomized controlled trial on the timing of preoperative antibiotic prophylaxis in general surgery between February 2013 and August 2015. A simulation of cost and income in the National Health Service (NHS) England reimbursement system was conducted. RESULTS: Of 5,175 patients initially enrolled, 4,556 had complete cost and income data as well as SSI status available for analysis. SSI occurred in 228 of 4,556 of patients (5%). Patients with SSIs were older, more often male, had higher BMIs, compulsory insurance, longer operations, and more frequent ICU admissions. SSIs led to higher hospital cost and income. The median contribution margin was negative in cases of SSI. In SSI cases, median contribution margin was Swiss francs (CHF) -2045 (IQR, -12,800 to 4,848) versus CHF 895 (IQR, -2,190 to 4,158) in non-SSI cases. Higher ASA class and private insurance were associated with higher contribution margins in SSI cases, and ICU admission led to greater deficits. Private insurance had a strong increasing effect on contribution margin at the 10th, 50th (median), and 90th percentiles of its distribution, leading to overall positive contribution margins for SSIs in Switzerland. The NHS England simulation with 3,893 patients revealed similar but less pronounced effects of SSI on contribution margin. CONCLUSIONS: Depending on payer type, reimbursement systems with DRGs offer only minor financial incentives to the prevention of SSI.