An introduction to the Cyrcadia Breast Monitor: A wearable breast health monitoring device.

BACKGROUND: The most common breast cancer detection modalities are generally limited by radiation exposure, discomfort, high costs, inter-observer variabilities in image interpretation, and low sensitivity in detecting cancer in dense breast tissue. Therefore, there is a clear need for an affordable and effective adjunct modality that can address these limitations. The Cyrcadia Breast Monitor (CBM) is a non-invasive, non-compressive, and non-radiogenic wearable device developed as an adjunct to current modalities to assist in the detection of breast tissue abnormalities in any type of breast tissue. METHODS: The CBM records thermodynamic metabolic data from the breast skin surface over a period of time using two wearable biometric patches consisting of eight sensors each and a data recording device. The acquired multi-dimensional temperature time series data are analyzed to determine the presence of breast tissue abnormalities. The objective of this paper is to present the scientific background of CBM and also to describe the history around the design and development of the technology. RESULTS: The results of using the CBM device in the initial clinical studies are also presented. Twenty four-hour long breast skin temperature circadian rhythm data was collected from 93 benign and 108 malignant female study subjects in the initial clinical studies. The predictive model developed using these datasets could differentiate benign and malignant lesions with 78% accuracy, 83.6% sensitivity and 71.5% specificity. A pilot study of 173 female study subjects is underway, in order to validate this predictive model in an independent test population. CONCLUSIONS: The results from the initial studies indicate that the CBM may be valuable for breast health monitoring under physician supervision for confirmation of any abnormal changes, potentially prior to other methods, such as, biopsies. Studies are being conducted and planned to validate the technology and also to evaluate its ability as an adjunct breast health monitoring device for identifying abnormalities in difficult-to-diagnose dense breast tissue.

p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy.

Purpose: To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer.Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses.Results: Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response. TOXICITY: there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients.Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+ T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. Clin Cancer Res; 24(6); 1315-25. ©2018 AACR.

p53MVA therapy in patients with refractory gastrointestinal malignancies elevates p53-specific CD8+ T-cell responses.

PURPOSE: To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers. EXPERIMENTAL DESIGN: Three patients were vaccinated with 1.0×10(8) plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6×10(8) pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro. RESULTS: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T-cell compartment (P=0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1+ T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P=0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent. CONCLUSION: p53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit.

Evaluation of expert criteria for preoperative magnetic resonance imaging of newly diagnosed breast cancer.

Despite 2 randomized trials reporting no reduction in operations or local recurrence at 1 year, preoperative magnetic resonance imaging (MRI) is increasingly used in diagnostic workup of breast cancer. We evaluated 5 utilization criteria recently proposed by experts. Of women (n = 340) newly diagnosed with unilateral breast cancer who underwent bilateral MRI, most (69.4%) met at least 1 criterion before MRI: mammographic density (44.4%), under consideration for partial breast irradiation (PBI) (19.7%), genetic-familial risk (12.9%), invasive lobular carcinoma (11.8%), and multifocal/multicentric disease (10.6%). MRI detected occult malignant lesion or extension of index lesion in 21.2% of index, 3.3% of contralateral, breasts. No expert criterion was associated with MRI-detected malignant lesion, which associated instead with pre-MRI plan of lumpectomy without PBI (48.2% of subjects): Odds Ratio 3.05, 95% CI 1.57-5.91 (p adjusted for multiple hypothesis testing = 0.007, adjusted for index-vs-contralateral breast and covariates). The expert guidelines were not confirmed by clinical evidence.

Adipose stromal vascular fraction isolation: a head-to-head comparison of four commercial cell separation systems.

BACKGROUND: Supplementation of fat grafts with stromal vascular fraction cells is an emerging technique used to improve graft reliability. A variety of systems for isolating stromal vascular fraction cells are commercially available. The lack of performance data obtained operating the systems in a standardized environment prevents objective assessment of performance. This prospective, blinded study compared performance of four commercially available stromal vascular fraction isolation systems when operated in a clinical outpatient surgery environment. METHODS: Four different systems were compared: (1) PNC's Multi Station, (2) CHA Biotech Cha-Station, (3) Cytori Celution 800/CRS System, and (4) Medi-Khan's Lipokit with MaxStem. Identical lipoaspirate samples from five separate volunteer donors were used to evaluate system process time, viable cell yield, composition, residual enzyme, and operating costs. RESULTS: The mean processing time ranged from 88 to 115 minutes. The highest mean number of viable nucleated cells was obtained using the Celution System (2.41 × 10 cells/g) followed by the Multi Station (1.07 × 10 cells/g). Lipokit and Cha-Station systems yielded nearly a log fewer nucleated cells (0.35 × 10 cells/g and 0.05 × 10 cells/g, respectively). The Celution System also yielded significantly more endothelial cells, CD34/CD31 cells, and adipose-derived stem cells (colony-forming unit-fibroblast). Residual enzyme levels observed with the Multi Station, Cha-Station, and Lipokit, respectively, averaged 5.1-, 13.0-, and 57-fold higher than that observed with the Celution System. CONCLUSIONS: Although all systems generated measurable amounts of stromal vascular fraction, significant variability exists in the number, identity, and safety profiles of recovered viable cells. Side-by-side clinical trials will be required to establish the relevance of these differences.

The evolution of surgical technique for total gastrectomy over a 12-year period: a single institution's experience.

Despite the wide acceptance of laparoscopic surgical techniques, its use for gastric cancer has been limited. Laparoscopic total gastrectomy poses many technical challenges when compared with open gastrectomy. Our objective was to evaluate our institutional experience and surgical technique for total gastrectomy. Through a review of patients undergoing total gastrectomy (1999 to 2011), 50 patients were identified. During the first decade, 25 per cent of total gastrectomies were performed laparoscopically compared with 77 per cent since 2009. Compared with open cases, laparoscopic cases yielded a significantly higher number of examined lymph nodes (29 vs 19), lower estimated blood loss (200 vs 450 mL), and shorter length of stay (8 vs 14 days). Median operative time, average tumor size, and number of positive lymph nodes were not different. Morbidity rates were much lower in the laparoscopic series; and 30-day mortality rates were similar in both groups. Laparoscopic total gastrectomy and D2 lymphadenectomy are comparable in safety and have improved efficacy than our open total gastrectomy experience. After initiation of a laparoscopic total gastrectomy program in 2009, the majority of cases in our institution are now performed by laparoscopic techniques.

Magnetic resonance imaging-guided breast biopsy in lesions not visualized by mammogram or ultrasound.

The use of magnetic resonance imaging (MRI) for the diagnosis and evaluation of breast lesions is still in evolution. The aim of this study was to evaluate the outcome of MR-guided biopsy for suspicious lesions seen on MRI but not visualized by mammography or ultrasound. A retrospective review was conducted on all patients undergoing MRI-guided core needle biopsy at a National Cancer Institute-designated comprehensive cancer center. Biopsies were performed using a 1.5-Tesla MR with a seven-channel breast coil taking six cores in a clock face configuration with a 10-gauge vacuum-assisted VACORA biopsy device. One hundred twenty-seven patients underwent 187 biopsies without major complication. The lesion size ranged from 4 to 12 mm. Pathology on MRI-guided core biopsy material revealed 126 (68%) benign lesions. Of these, 12 were intraductal papillomas and two were fibroadenomas. Sixty-one (32%) were deemed clinically significant and included the following pathology: invasive cancer 19 patients (10%), ductal carcinoma in situ (DCIS) in 25 patients (13%), atypical ductal hyperplasia (ADH) 15 patients (8%), and lobular carcinoma in situ in one patient (1%). There were two specimens upgraded from ADH to DCIS and one specimen that was biopsied was called ADH but there was no residual atypia on final pathology. With a median follow-up of 24 months, there were no patients with benign pathology returning with a clinically significant lesion later. MRI-guided biopsy provides an accurate and safe method for sampling suspicious lesions when no other reasonable means of biopsy is available. MRI-guided biopsy yielded clinically significant findings in approximately one-third of the sampled specimens. This technique can provide a good representative sample of clinically significant pathology. MRI-guided biopsy is a relatively new modality, which can provide a nonsurgical diagnostic specimen in the absence of mammographic or ultrasound findings.

Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth.

Generating antitumor responses through the inhibition of tumor-derived immune suppression represents a promising strategy in the development of cancer immunotherapeutics. Here, we present a strategy incorporating delivery of the bacterium Salmonella typhimurium (ST), naturally tropic for the hypoxic tumor environment, transformed with a small hairpin RNA (shRNA) plasmid against the immunosuppressive molecule indoleamine 2,3-dioxygenase 1 (shIDO). When systemically delivered into mice, shIDO silences host IDO expression and leads to massive intratumoral cell death that is associated with significant tumor infiltration by polymorphonuclear neutrophils (PMN). shIDO-ST treatment causes tumor cell death independently of host IDO and adaptive immunity, which may have important implications for use in immunosuppressed patients with cancer. Furthermore, shIDO-ST treatment increases reactive oxygen species (ROS) produced by infiltrating PMNs and, conversely, PMN immunodepletion abrogates tumor control. Silencing of host IDO significantly enhances S. typhimurium colonization, suggesting that IDO expression within the tumor controls the immune response to S. typhimurium. In summary, we present a novel approach to cancer treatment that involves the specific silencing of tumor-derived IDO that allows for the recruitment of ROS-producing PMNs, which may act primarily to clear S. typhimurium infection, but in the process also induces apoptosis of surrounding tumor tissue resulting in a vigorous antitumor effect.

Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma discuss the workup and management of tumors of the exocrine pancreas. These NCCN Guidelines Insights provide a summary and explanation of major changes to the 2012 NCCN Guidelines for Pancreatic Adenocarcinoma. The panel made 3 significant updates to the guidelines: 1) more detail was added regarding multiphase CT techniques for diagnosis and staging of pancreatic cancer, and pancreas protocol MRI was added as an emerging alternative to CT; 2) the use of a fluoropyrimidine plus oxaliplatin (e.g., 5-FU/leucovorin/oxaliplatin or capecitabine/oxaliplatin) was added as an acceptable chemotherapy combination for patients with advanced or metastatic disease and good performance status as a category 2B recommendation; and 3) the panel developed new recommendations concerning surgical technique and pathologic analysis and reporting.

Survivin the battle against immunosuppression.

Improving on the limited success of cancer immunotherapy requires new approaches to inhibit immunosuppressive pathways initiated by tumor cells to "escape" protective immunity. One unique approach utilizes Salmonella for systemic delivery of inhibitory RNA, targeting the immunosuppressive molecule Stat3, and a Survivin vaccine to suppress growth of aggressive murine tumors.

Recombinant modified vaccinia virus ankara (MVA) expressing wild-type human p53 induces specific antitumor CTL expansion.

The p53 gene product is an attractive target for tumor immunotherapy. The present study aims to understand the potential of MVAp53 vaccine to induce expansion of p53-specific cytotoxic T lymphocyte ex vivo in cancer patients. The result indicated that 14 of 23 cancer patients demonstrated p53-specific IFN-γ production, degranulation, cell proliferation, and lysis of p53 overexpressed human tumor cell lines. These experiments show that MVAp53 stimulation has the potential to induce the expansion of p53-specific cytotoxic T lymphocyte from the memory T cell repertoire. The data suggest that MVAp53 vaccine is an ideal candidate for cancer immunotherapy.

Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma.

BACKGROUND: Neoadjuvant therapy has been used to improve survival in operable pancreatic cancer. The authors' objective was to compare long-term outcomes in patients receiving neoadjuvant versus adjuvant therapy for resectable pancreatic adenocarcinoma. METHODS: The California Cancer Surveillance Program for Los Angeles County retrospectively identified 458 patients with nonmetastatic pancreatic adenocarcinoma who underwent definitive pancreatic resection and received systemic chemotherapy between 1987 and 2006. The cohort was grouped by timing of systemic therapy-neoadjuvant or adjuvant. Clinicopathologic characteristics and overall survival were compared. Multivariate Cox regression analysis was used to determine the benefit of neoadjuvant therapy, independent of other significant factors. RESULTS: Of the 458 patients, 39 (8.5%) received neoadjuvant therapy, and 419 (91.5%) received adjuvant therapy. There was a significantly lower rate of lymph node positivity in the neoadjuvant group (45% vs 65%; P = .011) despite a higher rate of extrapancreatic tumor extension. On Kaplan-Meier analysis, the neoadjuvant group had significantly better overall survival compared with the adjuvant group (median survival, 34 vs 19 months; P = .003). Overall survival was also improved in the neoadjuvant therapy patients with extrapancreatic disease (median survival, 31 vs 19 months; P = .018). On multivariate Cox regression analysis, neoadjuvant therapy was an independent predictor of improved survival (hazard ratio, 0.57; 95% confidence interval, 0.37-0.89; P = .013). CONCLUSIONS: This is the first population-based study to compare neoadjuvant versus adjuvant treatment strategies in resectable pancreatic cancer. Neoadjuvant therapy is associated with a lower rate of lymph node positivity and improved overall survival and should be considered an acceptable alternative to the surgery-first paradigm in operable pancreatic cancer.

Enhancement of cancer vaccine therapy by systemic delivery of a tumor-targeting Salmonella-based STAT3 shRNA suppresses the growth of established melanoma tumors.

Cancer vaccine therapies have only achieved limited success when focusing on effector immunity with the goal of eliciting robust tumor-specific T-cell responses. More recently, there is an emerging understanding that effective immunity can only be achieved by coordinate disruption of tumor-derived immunosuppression. Toward that goal, we have developed a potent Salmonella-based vaccine expressing codon-optimized survivin (CO-SVN), referred to as 3342Max. When used alone as a therapeutic vaccine, 3342Max can attenuate growth of aggressive murine melanomas overexpressing SVN. However, under more immunosuppressive conditions, such as those associated with larger tumor volumes, we found that the vaccine was ineffective. Vaccine efficacy could be rescued if tumor-bearing mice were treated initially with Salmonella encoding a short hairpin RNA (shRNA) targeting the tolerogenic molecule STAT3 (YS1646-shSTAT3). In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4(+) and CD8(+) T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets. Interestingly, mice treated with YS1646-shSTAT3 or 3342Max alone were similarly unsuccessful in rejecting established tumors, whereas the combined regimen was highly potent. Our findings establish that a combined strategy of silencing immunosuppressive molecules followed by vaccination can act synergistically to attenuate tumor growth, and they offer a novel translational direction to improve tumor immunotherapy.

Minimally invasive total gastrectomy for gastric cancer: a pilot series.

BACKGROUND: Minimally invasive surgery for select gastrointestinal disease has gained worldwide acceptance. However, laparoscopic total gastrectomy for cancer remains controversial. The purpose of this study was to examine an initial experience with laparoscopic total gastrectomy. METHODS: Medical records of 16 consecutive patients who underwent laparoscopic total gastrectomy between September 2007 and December 2009 were reviewed in a retrospective manner. Esophagojejunostomy was completed using a transorally delivered anvil, with double-stapled esophageal anastomosis. RESULTS: There were no conversions to open procedures. Two patients (12.5%) required extended resections with en bloc distal pancreatectomy and splenectomy, one of whom also underwent transverse colectomy. The median lymph node count for patients who underwent D2 lymphadenectomy (n = 12) for gastric adenocarcinoma was 31. There were no perioperative deaths and the median length of stay was 8 days. There were no anastomotic leaks, but three patients developed anastomotic strictures amenable to dilatation. CONCLUSIONS: Minimally invasive total gastrectomy can be performed safely and with adequate lymphadenectomy. The procedure provides an excellent short-term outcome with potential for improved patient outcome.

Modified vaccinia Ankara expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model.

Survivin is overexpressed by 70-80% of pancreatic cancers, and is associated with resistance to chemotherapy and a poor prognosis. Gemcitabine has been a standard treatment for patients with advanced pancreatic cancer for a decade. Recent reports have demonstrated that gemcitabine treatment attenuates the tumor-suppressive environment by eliminating CD11b(+)/Gr-1(+) myeloid-derived suppressor cells (MDSCs). We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when combined with gemcitabine. In this study, we tested this hypothesis using modified vaccinia Ankara (MVA) expressing full-length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which expresses murine survivin and is syngeneic to C57BL/6, was used for this study. Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy was associated with decreased CD11b(+)/Gr-1(+) MDSCs. To analyze the survivin-specific immune response to MVA-survivin immunization, we utilized a peptide library of 15mers with 11 residues overlapping from full-length murine survivin. Splenocytes from mice immunized with MVA-survivin produced intracellular γ-interferon in response to in vitro stimulation with the overlapping peptide library. Increased survivin-specific CD8(+) T cells that specifically recognized the Pan02 tumor line were seen in mice treated with MVA-survivin and gemcitabine. These data suggest that vaccination with MVA-survivin in combination with gemcitabine represents an attractive strategy to overcome tumor-induced peripheral immune tolerance, and this effect has potential for clinical benefit in pancreatic cancer.

The incidence and outcomes of pancreatectomy in patients with metastatic pancreatic adenocarcinoma.

CONTEXT: Despite current management guidelines, patients with metastatic pancreatic cancer continue to undergo pancreatic resection. OBJECTIVE: Our objective was to determine the incidence and outcomes of pancreatic resection in the setting of known metastatic disease. DESIGN: Using the Los Angeles County Cancer Surveillance Program, patients with pancreatic adenocarcinoma who underwent pancreatic resection with known M1 (AJCC stage IV) metastatic disease between the years 1988-2006 were assessed. SETTING: Large population based database query. PATIENTS: Patients with biopsy proven M1 pancreatic adenocarcinoma. INTERVENTIONS: Pancreatic resection, systemic chemotherapy, radiation therapy. MAIN OUTCOME MEASURE: Overall survival. RESULTS: Of 8,549 patients with pancreatic adenocarcinoma from Cancer Surveillance Program, 54% (n=4,649) initially presented with M1 disease. Within this M1 cohort, 2% (n=92) of patients underwent pancreatic resection and formed our final study cohort; these patients comprised 7% of the overall number of pancreatic resections performed for pancreatic adenocarcinoma during the study period. Only 35% (n=32) of the study cohort received adjuvant chemotherapy; and 13% (n=12) received adjuvant radiotherapy. Median survival for the study cohort was 6.3 months. Surgery provided no survival benefit over chemotherapy in patients with M1 disease and was associated with an 18% 30-day mortality. CONCLUSION: A large number of patients from Los Angeles County have undergone pancreatic resection despite the presence of known metastatic disease. Patient survival remains abysmal in this setting and these results are likely a microcosm of the surgical management of metastatic pancreatic cancer in the USA. These results highlight the necessary efforts to maintain appropriate standards of care in the management of pancreatic cancer.

Heterologous prime/boost immunization with p53-based vaccines combined with toll-like receptor stimulation enhances tumor regression.

The p53 gene product is overexpressed in approximately 50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated that a modified vaccinia Ankara (MVA) vaccine expressing human p53 (MVA-p53) was moderately active when given as a homologous prime/boost in a human p53 knock in (Hupki) mouse model. We needed to improve upon the inefficient homologous boosting approach, because development of neutralizing immunity to the vaccine viral vector backbone suppresses its immunogenicity. To enhance specificity, we examined the combination of 2 different vaccine vectors provided in sequence as a heterologous prime/boost. Hupki mice were evaluated as a human p53 tolerant model to explore the capacity of heterologous p53 immunization to reject human p53-expressing tumors. We employed attenuated recombinant Listeria monocytogenes expressing human p53 (LmddA-LLO-p53) in addition to MVA-p53. Heterologous p53 immunization resulted in a significant increase in p53-specific CD8 and CD4 T cells compared with homologous single vector p53 immunization. Heterologous p53 immunization induced protection against tumor growth but had only a modest effect on established tumors. To enhance the immune response we used synthetic double-strand RNA (polyinsosinic:polycytidylic acid) and unmethylated CpG-containing oligodeoxynucleotide to activate the innate immune system via Toll-like receptors. Treatment of established tumor-bearing Hupki mice with polyinsosinic:polycytidylic acid and CpG-oligodeoxynucleotide in combination with heterologous p53 immunization resulted in enhanced tumor rejection relative to treatment with either agent alone. These results suggest that heterologous prime/boost immunization and Toll-like receptor stimulation increases the efficacy of a cancer vaccine, targeting a tolerized tumor antigen.