Targeted therapy in esophageal cancer

Esophageal cancer consists of two distinct histological types, esophageal squamous cell-carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Esophageal carcinoma is a grave malignancy with regards to prognosis and mortality. ESCC remains the dominant histological type of esophageal cancer worldwide, with about 90 percent of all cases worldwide. However, EAC is now much more common in the United States and the Western World, and represents one of the fastest growing cancers there. Despite significant progress in multimodality treatment options, the overall prognosis remains poor, and 5-year survival rates for all-comers are still below 20 percent. Although esophageal cancer initially responds well to systemic therapy, most patients recur and eventually die from their disease. Therefore, new treatment options are urgently needed. The combination of traditional systemic therapy with new biologicals and/or targeted agents is one of these new treatment options. Some of these agents are already approved, while others are currently undergoing clinical trials. These targeted therapies have emerged as an important tool for the treatment of many different cancer types, including esophageal cancer. Herein, we review the recent literature and ongoing clinical trials in esophageal cancer targeted therapies, and discuss the different targeted pathways. Currently, most esophageal cancer patients are still treated with a combination of chemotherapies like taxanes (paclitaxel, docetaxel), platinums (carboplatin, cisplatin), anthracyclines (doxorubicin, epirubicin) or pyrimidine analogs (5-fluorouracil). Future treatment strategies should be based on the molecular features of each patient’s individual tumor, and should include biologicals/targeted agents tailored to these specific findings

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

A novel intraperitoneal metastatic xenograft mouse model for survival outcome assessment of esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) has become the dominant type of esophageal cancer in United States. The 5-year survival rate of EAC is below 20% and most patients present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Improvement of EAC patient outcome requires well-characterized animal models in which to evaluate novel therapeutics. In this study we aimed to establish a peritoneal dissemination xenograft mouse model of EAC that would support survival outcome analyses. To find the best candidate cell line from 7 human EAC cell lines of different origin named ESO26, OE33, ESO51, SK-GT-2, OE19, OACM5.1C and Flo-1 were injected intraperitoneally/subcutaneously into SCID mice. The peritoneal/xenograft tumor formation and mouse survival were compared among different groups. All cell lines injected subcutaneously formed tumors within 3 months at variable rates. All cell lines except OACM5.1C formed intraperitoneal tumors within 3 months at variable rates. Median animal survival with peritoneal dissemination was 108 days for ESO26 cells (5X106), 65 days for OE33 cells (5X106), 88 days for ESO51 cells (5X106), 76 days for SK-GT-2 cells (5X106), 55 days for OE19 cells (5X106), 45 days for OE19 cells (10X106) and 82 days for Flo-1 cells (5X106). Interestingly, only in the OE19 model all mice (7/7 for 5X106 and 5/5 for10X106) developed bloody ascites with liver metastasis after intraperitoneal injection. The median survival time of these animals was the shortest (45 days for 10X106 cells). In addition, median survival was significantly increased after paclitaxel treatment compared with the control group (57 days versus 45 days, p = 0.0034) along with a significant decrease of the relative subcutaneous tumor volume (p = 0.00011). Thus peritoneal dissemination mouse xenograft model for survival outcome assessment after intraperitoneal injection of OE19 cells will be very useful for the evaluation of cancer therapeutics

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

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 (rs = 0.404, P < 0.0001) and both significantly correlated with CD8+ infiltration (rs = 0.435, P = 0.0003, and rs = 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

β2-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 β2-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

Swelling of the right thigh for over 30 years—The rare finding of a De Garengeot hernia

INTRODUCTION: Femoral hernias may – in some rare cases – contain the appendix, a phenomenon called de Garengeot hernia. It is usually an incidental finding in hernia repair. We found our case to be of interest because of the long standing femoral swelling before peracute appendicitis led to its removal. PRESENTATION OF CASE: We present the case of a 71-year-old woman with a swelling of the right medial thigh for over more than 30 years. When the swelling suddenly grew in size and became tender, she was referred to our emergency department. Sonographically as well as clinically a femoral hernia was diagnosed. Intraoperatively, the appendix was found and open appendectomy as well as a hernioplasty was performed. DISCUSSION: Open appendectomy is an elegant and safe procedure to repair a long standing de Garengeot hernia. Most case reports call for extensive diagnostics such as CT scan etc. We found a sonography of the femoral region to be conclusive. CONCLUSION: Apart from the inherent risk of sudden incarceration in hernias, De Garengeot hernias can also develop peracute appendicitis years after their formation. This differential diagnosis needs to be taken into consideration in patients presenting with the clinical signs of a femoral hernia

Obstructing adenocarcinoma of the descending colon in a 31-year-old pregnant woman

INTRODUCTION: Colon cancer in pregnant women is rare and tends to produce unspecific symptoms until advanced stage. Therefore common manifestations during pregnancy must be properly evaluated to avoid delayed diagnosis. PRESENTATION OF CASE: A 31-year-old pregnant woman presented with nausea, vomiting and obstipation. An obtained magnetic resonance imaging (MRI) showed distended colon and the consecutive colonoscopy with biopsies confirmed the diagnosis of stenosing carcinoma of the descending colon. Left sided hemicolectomy was performed 10 days after initial presentation. Tumor histology confirmed the diagnosis of adenocarcinoma of the descendo-sigmoidal junction. Adjuvant chemotherapy with 5-fluorouracil was started in the 29th gestational week. The patient had an uneventful delivery of a healthy baby in her 39th gestational week. DISCUSSION: Colorectal carcinoma during pregnancy is a rare event and its diagnosis is often delayed because symptoms are unspecific until the disease is advanced. Although constipation in pregnancy is a common symptom differential diagnosis of a mechanical stenosis should always be contemplated, especially when conservative treatment of constipation fails. MRI is the imaging tool of choice as abdominal computed tomography (CT) is contraindicated in pregnancy. Endoscopic confirmation should be obtained to gain pathological diagnosis of colorectal carcinoma. Surgery is the gold standard of treatment. In relation to the stage of the disease chemotherapy is of great importance. CONCLUSION: Obstructing colorectal cancer can be a rare reason for the common problem of constipation in pregnancy. Beside clinical examination, MRI scan and colonoscopy will reveal the tumor in most cases and should be followed by surgical treatment and chemotherapy according to the stage of disease

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

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