HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery.

In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.

Association of primary tumor lymph node ratio with burden of liver metastases and survival in stage IV colorectal cancer.

BACKGROUND: The primary objective of our study was to assess the association of primary tumor lymph node ratio (LNR) in stage IV colorectal adenocarcinomas (CRC) with overall survival (OS) and the extent of metastatic disease in the liver. METHODS: We analyzed data on 53 stage IV CRC patients who underwent surgical resection of the primary tumor. The median LNR of 0.25 was used to stratify patients into high LNR (H-LNR) and low LNR (L-LNR) groups. Statistical comparison was performed using chi square test and multiple regression models. OS was calculated using the Kaplan-Meier (KM) method while cox regression was used for multivariate analysis. RESULTS: H-LNR status was associated with the presence of >3 liver metastases (LM) [odds ratio (OR): 2.43, P=0.047] and bilobar LM (OR: 3.94, P=0.039). The OS in H-LNR patients was significantly worse in the entire cohort compared to L-LNR (9% vs. 34% at 3 years, P=0.027). The 5-year OS in patients undergoing liver resection for LM was also significantly worse in the H-LNR group (0% vs. 37%, P=0.013). LNR was independently associated with survival on multivariate analysis [HR: 2.63; 95% confidence intervals (CI), 1.13-6.14; P=0.025]. CONCLUSIONS: In stage IV CRC, LNR is associated with the extent of hepatic tumor burden and was an independent predictor of survival in patients undergoing liver resection.

Chemotherapy does not adversely impact outcome following post-incisional hernia repair with biomaterial mesh.

BACKGROUND: Patients receiving chemotherapy are at increased risk for developing recurrent or post-incisional hernias (PIH). Biological materials are an alternative to synthetic mesh in contaminated fields. The impact of chemotherapy on biomaterial tissue ingrowth and integration has not been well studied. METHODS: From 2008 to 2011 patients who underwent PIH repair with biomaterial mesh (Biodesign®) were selected. Patients were divided into two groups: those receiving chemotherapy (CT) and those not receiving chemotherapy (NCT). RESULTS: Forty-five patients were identified, 28 (62%) in the NCT group and 17 (38%) in the CT group. Median follow up for NCT and CT groups were 27 and 17 months, respectively. A total of 9/45 (20%) surgical site infections (SSI) were diagnosed, with 6/28 (21%) in the NCT and 3/17 (18%) in the CT group (P = 0.53). Seroma formation was seen in 5/28 (18%) of NCT patients and 4/17 (23%) in CT group (P = 0.46). Overall hernia recurrence rate was 22%, and the rates of recurrence were similar among the CT 3/17 (18%) and NCT 7/28 (25%) groups (P = 0.42). CONCLUSION: The use of perioperative chemotherapy did not increase the rate of wound complications following PIH repair with biologic mesh in this group of patients.

Age-related trends in utilization of the internet and electronic communication devices for coordination of cancer care in elderly patients.

OBJECTIVES: In this rapidly changing electronic era, we implemented a study to define age dependent variations in access and use of internet and electronic devices in the exchange of healthcare related information (HRI) and coordination of clinical care (CCC) among elderly patients with cancer. MATERIALS AND METHODS: Data was collected through independently completed surveys after obtaining IRB approval in a single institution cancer center over a 4-month period. Questions regarding internet access and use of electronic media to obtain health information and coordinate care were distributed. The sample was divided in two groups based upon the World Health Organization (WHO) definition of geriatric patients: <65 y/o (group A) and ≥65 y/o (group B). RESULTS: One hundred and twenty-six surveys were analyzed with 70 patients in group A and 56 patients in group B. Access to the internet and use of email was higher in the group A (77% and 71%) vs. group B (36% and 33%, p < 0.001). The younger group felt more comfortable using the internet when compared to the older group (70% vs. 40%, p = 0.01). Patients in group B demonstrated a strong preference for paper copy based HRI and phone calls to CCC than text messages or emails (73% and 95%, p < 0.001). A transition zone between the ages of 65 and 70 years was defined to identify patients with increased reluctance to use internet and electronic devices to exchange HRI and CCC. CONCLUSION: The data supports that there is an age-defined underutilization of internet and electronic devices to exchange HRI and CCC. Characterization of this age-dependent transition zone will enable clinicians to identify patients who may not interface well with electronic communication strategies, and to improve delivery of HRI and CCC for the elderly.

Immunotherapy for solid tumors--a review for surgeons.

Immunotherapy has evolved considerably in the last decade and is becoming an integral component of the armamentarium for the treatment of patients with advanced solid tumors. It is important for clinicians, especially surgeons, to understand the basic principles of novel immunotherapies and the immune system. This review summarizes the evolution of the most relevant immunotherapies, their mechanisms of action, the data supporting their clinical use, and integration of immunotherapy into multidisciplinary management of solid tumors. This review should serve as a primer for clinicians and surgeons to understand the rapidly evolving field of immunotherapy.

Regional hepatic therapies: an important component in the management of colorectal cancer liver metastases.

The treatment of colorectal cancer liver metastases (CRLM) has evolved significantly in the last 15 years. Currently, complete surgical resection remains the only potentially curative option; unfortunately, approximately 80% of patients with CRLM are not candidates for complete tumor resection. For patients with unresectable CRLM the available treatment options were historically limited; however, the development of regional hepatic therapies (RHT) and improvement of systemic chemotherapeutic regimens have emerged as viable options to improve overall survival and quality of life for this group of patients. The selection, sequence and integration of interventions into a multi-modal approach is a complex and evolving discipline. In this article, the currently available RHT modalities for CRLM are presented as a guide to the options for clinical treatment decisions.

Small bowel obstruction from breast cancer metastasis: a case report and review of the literature.

Small bowel obstruction from luminal gastrointestinal metastasis is a rare, but recognized, presentation of metastatic breast cancer. Herein, we report a case of a small bowel obstruction from lobular breast cancer metastasis to the terminal ileum, occurring over a decade after diagnosis and treatment of the initial primary cancer. Our review highlights the presentation and management of this unusual disease manifestation, including diagnosis of the gastrointestinal process, identification of the primary cancer, surgical treatment of the abdominal pathology, systemic therapy for metastatic disease, and survival data for patients with this disease process.

Radiofrequency ablation of primary and metastatic liver tumors: a critical review of the literature.

BACKGROUND: Surgical resection is the treatment of choice for hepatic tumors; however, for various reasons, the vast majority of patients are not operative candidates. As a result, several local ablative therapies have emerged as alternatives to resection or as adjuncts in total oncologic care. Presently, the most widely employed liver-directed treatment is radiofrequency thermal ablation. METHODS: To define the current status of radiofrequency ablation (RFA), the authors reviewed available safety and efficacy data from select studies on RFA. A MEDLINE search was performed using the keywords "tumor type" + "radiofrequency ablation" + "survival." Only those studies containing long-term survival data on greater than 50 patients were included in this analysis. CONCLUSIONS: Although RFA has been readily adopted into treatment paradigms, more rigorous trials are needed to solidify its place in the armamentarium of therapeutic strategies for hepatic malignancy.

Gastric adenocarcinoma arising from fundic gland polyps in a patient with familial adenomatous polyposis syndrome.

Familial adenomatous polyposis (FAP) is a rare hereditary syndrome characterized by multiple colorectal polyps and early development of colorectal cancer. Although FAP uniformly involves the large bowel, it may also produce lesions in the stomach and upper intestinal tract. Fundic gland polyps are the most common gastric lesion in FAP. In the general population, these polyps are considered benign and have no malignant potential. However, in FAP patients, fundic gland polyps have been occasionally recognized as precursor lesions from which invasive cancer may develop. Herein, we present a case of gastric adenocarcinoma arising from fundic gland polyps in an FAP patient. We also review reported cases of gastric cancer in FAP and FAP variant patients in an effort to better understand the pathology, clinical course, and optimal screening and treatment strategies for this disease manifestation.

Attenuation of iNOS in an LPS-stimulated macrophage model by omega-3 fatty acids is independent of COX-2 derived PGE2.

BACKGROUND: Omega-3 fatty acids (n-3 FA) demonstrate significant anti-inflammatory properties thought to occur through three principal mechanisms; (1) displacement of arachidonic acid from the cellular membrane, (2) differential prostaglandin E2 (PGE2) and LTB4 production, and (3) molecular level alterations such as diminished nuclear factor kappa B and AP-1 activation. Recently, n-3 FA have been demonstrated to significantly decrease nitric oxide (NO) production in a lipopolysaccharide (LPS)-stimulated M Phi model. We hypothesized that decreased NO production by n-3 FA occurs through inhibition of cyclooxygenase-2 (COX-2) derived PGE2 and that repletion of the system with PGE2 would obliterate these effects. Selective COX-2 inhibitor (L-748,731) experiments and separate PGE2 repletion studies were used to test this hypothesis. METHODS: NO production was assessed following 24 h with or without LPS/PGE2 in the presence of n-3 FA, L-748,731 (a selective COX-2 inhibitor), or combination (n-3 FA + L-748,731) treatment. Western blots were used to assess inducible NO synthase protein expression. RESULTS: Independently or in the presence of LPS, treatment with a COX-2 inhibitor significantly increased NO production compared with control, n-3 FA, and combination treatment. NO production in combination treatment is slightly increased compared to n-3 FA treatment. In control cells treated with LPS, PGE2 repletion resulted in a significant decrease in NO. All other treatment groups repleted with PGE2 demonstrated no significant alterations in NO production. Inducible NO synthase protein expression levels were similar to NO production across all treatments. CONCLUSION: These experiments disproved our original hypothesis that the decrease in NO production associated with n-3 FA treatment occurs through a COX-2 derived PGE2 dependent mechanism. Eliminating COX-2 derived PGE2 by a selective inhibitor actually increased NO production. Exogenous PGE2 repletion did not restore the system. Therefore, mechanisms other than n-3 FA associated alterations in COX-2 derived PGE2 are likely involved in decreasing NO production in LPS stimulated M Phi.

Inhibition of proliferation by omega-3 fatty acids in chemoresistant pancreatic cancer cells.

BACKGROUND: Pancreatic cancer-gemcitabine (GEM) chemoresistance has been demonstrated to be associated with enhanced NF-kB activation and antiapoptotic protein synthesis. The well-known capacity of omega-3 fatty acids (n-3 FAs) to inhibit NF-kB activation and promote cellular apoptosis has the potential to restore or facilitate gemcitabine chemosensitivity. METHODS: Four pancreatic cancer cell lines (MIA PaCa-2, BxPC-3, PANC-1, and L3.6), each with distinct basal NF-kB and differing GEM sensitivity profiles, were administered: 100 uM of (1) n-3FA, (2) n-6FA, (3) GEM, (4) n-3FA + GEM, or (5) n-6FA + GEM for 24 and 48 hours. Proliferation was assessed using the WST-1 assay. To define the mechanism(s) of altered proliferation, electron mobility shift assay for NF-kB activity, western blots of phoshoStat3, phosphoIkappaB, and poly(ADP-ribose) polymerase (PARP) cleavage were performed in the MIA PaCa-2 cell line. RESULTS: All cell lines demonstrated a time/dose-dependent inhibition of proliferation in response to n-3FA. For MIA PaCa-2 cells, n-3FA and n-3FA + GEM treatment resulted in reduction of I-kB phosphorylation and NF-kB activation when compared with n-6FA control. n-3FA and combination treatment also significantly decreased Stat3 phosphorylation, whereas GEM alone had no effect. n-3FAs and n-3FA + GEM groups demonstrated increased PARP cleavage, mirroring NF-kB activity and Stat3 phosphorylation. CONCLUSIONS: n-3 FA treatment is specifically associated with inhibition of proliferation in these four pancreatic cell lines irrespective of varied gemcitabine resistance. An experimental paradigm to screen for potential contributory mechanism(s) in altered pancreatic cancer cellular proliferation was defined, and using this approach the co-administration of n-3 FA with GEM inhibited GEM-induced NF-kB activation and restored apoptosis in the MIA PaCa-2 cell-line.