Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with liver involvement.

BACKGROUND: We examined outcomes of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) combined with liver resection. METHODS: All patients undergoing CRS/HIPEC between 2007 and 2014 were retrospectively reviewed: patients who underwent synchronous liver resection (group 1) were compared with those who did not (group 2) in terms of perioperative and long-term results. RESULTS: Group 1 included 103 patients with colorectal cancer (CRC, n = 28), appendiceal cancer (n = 34), and other malignancies. Compared with group 2 (n = 166), group 1 had higher number of organs resected, increased intraoperative blood loss, and longer hospital stay (all P ≤ 0.004) but similar major morbidity (24.3% vs. 18.1%, P = 0.22) and perioperative mortality rates. Two patients from group 1 developed liver resection-related complications. A comparison between patients who underwent parenchymal liver resection (n = 42) and matched pairs from group 2 with similar extent of cytoreduction did not yield significant differences in morbidity/mortality. CRC patients from group 1 had poorer median overall survival (45.1 vs. 73.5 months from stage IV diagnosis, P = 0.009). CONCLUSIONS: Liver involvement denotes high peritoneal carcinomatosis burden, which often requires resection of multiple organs in order to achieve optimal cytoreduction. However, liver resection-related morbidity is low and overall morbidity/mortality rates are comparable to other extensive CRS/HIPEC procedures. J. Surg. Oncol. 2016;113:432-437. © 2016 Wiley Periodicals, Inc.

Early Childhood Adversity and its Associations With Anxiety, Depression, and Distress in Women With Breast Cancer.

BACKGROUND: Certain vulnerability factors have been found to place patients at risk for depression and anxiety, especially within the context of medical illness. OBJECTIVES: We sought to describe the relationships among early childhood adversity (ECA) and anxiety, depression and distress in patients with breast cancer. METHODS: Patients with breast cancer (stages 0-IV) were assessed for ECA (i.e., the Risky Families Questionnaire subscales include Abuse/Neglect/Chaotic Home Environment), distress (i.e., Distress Thermometer and Problem List), anxiety (Hospital Anxiety and Depression Scale-Anxiety), depression (Hospital Anxiety and Depression Scale-Depression), meeting standardized cut-off thresholds for distress (Distress Thermometer and Problem List ≥4 or ≥7)/anxiety (Hospital Anxiety and Depression Scale-Anxiety ≥8)/depression (Hospital Anxiety and Depression Scale-Depression ≥8) and demographic factors. RESULTS: A total of 125 participants completed the study (78% response rate). ECA was associated with depression (p <0.001), anxiety (p = 0.001), and distress (p = 0.006), meeting cut-off threshold criteria for distress (p = 0.024), anxiety (p = 0.048), and depression (p = 0.001). On multivariate analysis, only depression (p = 0.04) and emotional issues (i.e., component of Distress Thermometer and Problem List) (p = 0.001) were associated with ECA. Neglect, but not Abuse and Chaotic Home Environment, was associated with depression (ß = 0.442, p < 0.001), anxiety (ß = 0.342, p = 0.002), and self-identified problems with family (ß = 0.288, p = 0.022), emotion (ß = 0.345, p = 0.004), and physical issues (ß = 0.408, p < 0.001). CONCLUSION: ECA and neglect are associated with multiple psychologic symptoms, but most specifically depression in the setting of breast cancer. ECA contributes to psychologic burden as a vulnerability factor. ECA may help to explain individual patient trajectories and influence the provision of patient-centered care for psychologic symptoms in patients with breast cancer.

Downstaging cancer in rural Africa.

Cancer is usually diagnosed late in rural Africa leading to incurability and abbreviated survival. Many curable cancers present on the body surface, often recognizable early by laymen as suspicious, justifying professional referral. Cancer diagnoses in two randomly chosen Tanzanian villages were compared after conventional dispensary self-referral vs. proactive visits in the home. Village navigators organized trips for professional consultation. In the control village 21% were self-referred, 20% of them were sent on as suspicious, 78% had cancer (8% in men) 0.9% of the village population. In the intervention village 99% were screened, 14% were referred for professional opinion, 93% had cancer (32% in men) 1.6% (p < 0.01 compared with control village). In the second and third years similar activity yielded 0.5% cancer annually in the control village for a 3 year total of 1.86% whereas interventional villagers had 1.4% and 0.6% cancer for a 3 year total of 3.56% (p < 0.001). Downstaging was recognized in the second and third years of intervention from 23 to 51 to 74% Stages I and II (p < 0.001) but in the control village Stages I and II changed from 11% to 22% to 37% (p = NS). The greatest downstaging occurred in breast and cervix cancers.

Assessing prognostic significance of preoperative alpha-fetoprotein in hepatitis B-associated hepatocellular carcinoma: normal is not the new normal.

BACKGROUND: Hepatitis B (HBV)-associated hepatocellular carcinoma (HCC) is often associated with alpha-fetoprotein (AFP) production. Although serum AFP has been demonstrated to be a prognostic factor for patient survival, optimal cutoff levels remain unclear. METHODS: Patients with HBV-associated HCC treated by primary liver resection were prospectively followed at a single institution between 1995 and 2008. AFP level was categorized into quintiles for Kaplan­Meier analysis and multivariable Cox proportional hazards regression models. RESULTS: Best 5-year survival after surgery was observed for patients with AFP in the first quintile (1.4-4.1 ng/mL), with progressively worse outcomes for patients in each increasing quintile. AFP was associated with overall survival (HR = 1.61; 95 % CI 1.30-1.98), disease-free survival (HR = 1.26; 95 % CI 1.10-1.44), and 2-year recurrence (HR = 1.30; 95 % CI 1.07-1.57) in multivariate analysis. Noncirrhotic patients (Ishak 1-5) with AFP in quintile 1 had 94 % 5-year survival, compared with 0 % survival for patients with AFP in quintile 5 (2,332.7-327,560.0 ng/mL) and Ishak stage 6 cirrhosis. CONCLUSIONS: Preoperative serum AFP is an independent predictor of prognosis among HBV-HCC patients following surgical resection. Categorizing AFP into quintiles creates the opportunity to observe differences in outcomes even at low serum levels within the normal range. Additionally, combining AFP quintiles and fibrosis staging provides a predictive model of prognosis for HCC. Thus, even small differences in AFP within the normal range may impact prognosis and disease progression for HBV-HCC.

Survival analysis of robotic versus traditional laparoscopic surgical staging for endometrial cancer.

OBJECTIVE: The purpose of this study was to compare the survival of women with endometrial cancer managed by robotic- and laparoscopic-assisted surgery. STUDY DESIGN: This was a retrospective study conducted at 2 academic centers. Primary outcomes were overall survival, disease-free survival (DFS), and disease recurrence. RESULTS: From 2003 through 2010, 415 women met the study criteria. A total of 183 women had robotic and 232 women had laparoscopic-assisted surgery. Both groups were comparable in age, body mass index, comorbid conditions, histology, surgical stage, tumor grade, total nodes retrieved, and adjuvant therapy. With a median follow-up of 38 months (range, 4-61 months) for the robotic and 58 months (range, 4-118 months) for the traditional laparoscopic group, there were no significant differences in survival (3-year survival 93.3% and 93.6%), DFS (3-year DFS 83.3% and 88.4%), and tumor recurrence (14.8% and 12.1%) for robotic and laparoscopic groups, respectively. Univariate and multivariate analysis showed that surgery is not an independent prognostic factor of survival. CONCLUSION: Robotic-assisted surgery yields equivalent oncologic outcomes when compared to traditional laparoscopic surgery for endometrial adenocarcinoma.

KLF6 loss of function in human prostate cancer progression is implicated in resistance to androgen deprivation.

Inactivation of the transcription factor/tumor suppressor Krüppel-like factor 6 (KLF6) has been described in prostate cancer (PC). This study investigated the prevalence and significance of KLF6 exon 2 mutations and splice variants (SVs) in different stages of human PC progression. By using laser-capture microdissection and recombinant clone isolation of DNA sequences to enhance sensitivity, base changes were found in 20 (24.7%) of 81 PC tissues versus 1 (4%) of 25 normal prostate tissues (P = 0.02). Of 26 base changes, 54% produced nonsynonymous mutations. Only three mutations had driver characteristics (PCs, 4%; NPs, 0%). By using microdissection of fresh-frozen tissues and recombinant isolation of RNA sequences, SVs were found in 39 (75%) of 52 PCs and in 10 (45%) of 22 NPs (P = 0.01). Sixteen different SVs, including 13 unique SVs, were identified that used cryptic splicing sites and encoded nonfunctional KLF6 proteins. PCs that had survived hormone (androgen)-deprivation therapy (n = 21) had a significantly higher (P < 0.05) incidence, number, and expression level of nonfunctional SVs than either NPs (n = 22) or hormone-naïve PCs (n = 25). Forced expression of nonfunctional SVs conferred a survival advantage of androgen-dependent LNCaP cells under castration-simulated culture conditions. Together, these data suggest that decreased availability of functional KLF6 contributes to clinical PC progression. This decrease arises infrequently by somatic mutation and more commonly by the acquisition of SVs that provide a survival advantage under castrate conditions, enabling resistance to hormone therapy.

Outcomes after adjuvant platinum-based chemotherapy in elderly NSCLC patients with T4 disease.

BACKGROUND: The postoperative management of elderly patients with T4, N0-1, M0 non-small cell lung cancer (NSCLC) remains controversial. The objective of this study was to evaluate the association of adjuvant chemotherapy with survival and toxicity among these patients. METHODS: Using surveillance, epidemiology and end results registry data linked to Medicare claims, we identified 389 elderly patients with resected T4, N0-1, M0 NSCLC diagnosed between 1992 and 2007. We compared survival of patients treated with and without platinum-based chemotherapy using a Cox regression adjusting for propensity scores for chemotherapy use and use of radiotherapy. We used logistic regression to assess the risk of adverse events in patients receiving chemotherapy. RESULTS: No benefit was noted in overall survival with adjuvant chemotherapy after PS adjustment for both N0 (hazard ratio 0.78, 95% confidence interval 0.50-1.23) and N1 (hazard ratio 1.01, 95% confidence interval 0.67-1.53) cancers. Patients receiving adjuvant chemotherapy experienced severe adverse events more frequently than patients who did not receive chemotherapy. CONCLUSIONS: Use of adjuvant chemotherapy in elderly patients with T4, N0-1, M0 NSCLC was not associated with a survival advantage and was associated with higher rates of severe toxicity.

A Phase I Trial of VEGF-A Inhibition Combined with PD-L1 Blockade for Recurrent Glioblastoma.

Purpose: The treatment of glioblastoma (GBM) poses challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by low mutational burden and low T-cell infiltration. The combination of ICI with other treatment modalities may improve efficacy. Patient and Methods: Patients with recurrent GBM were treated with avelumab, a human IgG1 antibody directed against PD-L1 (part A), or avelumab within a week after laser interstitial thermal therapy (LITT) and continuation of avelumab (part B). Bevacizumab was allowed to be combined with ICI to spare steroid use. The primary objective was to characterize the tolerability and safety of the regimens. The secondary objectives included overall survival, progression-free survival (PFS), signatures of plasma analytes, and immune cells. Results: A total of 12 patients (median age 64; range, 37-73) enrolled, five in part A and seven in part B. Two serious adverse events occurred in the same patient, LITT treated, not leading to death. The median survival from enrollment was 13 months [95% confidence interval (CI), 4-16 months] with no differences for part A or B. The median PFS was 3 months (95% CI, 1.5-4.5 months). The decrease in MICA/MICB, γδT cells, and CD4+ T cell EMRA correlated with prolonged survival. Conclusions: Avelumab was generally well tolerated. Adding bevacizumab to ICI may be beneficial by lowering cytokine and immune cell expression. The development of this combinatorial treatment warrants further investigation. Exploring the modulation of adaptive and innate immune cells and plasma analytes as biomarker signatures may instruct future studies in this dismal refractory disease. Significance: Our phase I of PD-L1 inhibition combined with LITT and using bevacizumab to spare steroids had a good safety profile for recurrent GBM. Developing combinatory treatment may help outcomes. In addition, we found significant immune modulation of cytokines and immune cells by bevacizumab, which may enhance the effect of ICI.

Gene-expression signature of vascular invasion in hepatocellular carcinoma.

BACKGROUND & AIMS: Vascular invasion is a major predictor of tumor recurrence after surgical treatments for hepatocellular carcinoma (HCC). While macroscopic vascular invasion can be detected by radiological techniques, pre-operative detection of microscopic vascular invasion, which complicates 30-40% of patients with early tumors, remains elusive. METHODS: A total of 214 patients with hepatocellular carcinoma who underwent resection were included in the study. By using genome-wide gene-expression profiling of 79 hepatitis C-related hepatocellular carcinoma samples (training set), a gene-expression signature associated with vascular invasion was defined. The signature was validated in formalin-fixed paraffin-embedded tissues obtained from an independent set of 135 patients with various etiologies. RESULTS: A 35-gene signature of vascular invasion was defined in the training set, predicting vascular invasion with an accuracy of 69%. The signature was independently associated with the presence of vascular invasion (OR 3.38, 95% CI 1.48-7.71, p=0.003) along with tumor size (diameter greater than 3 cm, OR 2.66, 95% CI 1.17-6.05, p=0.02). In the validation set, the signature discarded the presence of vascular invasion with a negative predictive value of 0.77, and significantly improved the diagnostic power of tumor size alone (p=0.045). CONCLUSIONS: The assessment of a gene-expression signature obtained from resected biopsied tumor specimens improved the diagnosis of vascular invasion beyond clinical variable-based prediction. The signature may aid in candidate selection for liver transplantation, and guide the design of clinical trials with experimental adjuvant therapies.

Lymph node ratio as a prognostic factor in elderly patients with pathological N1 non-small cell lung cancer.

BACKGROUND: Lymph node (LN) metastasis is an important predictor of survival for patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of the extent of LN involvement among patients with N1 disease remains unknown. A study was undertaken to evaluate whether involvement of a higher number of N1 LNs is associated with worse survival independent of known prognostic factors. METHODS: Using the Surveillance, Epidemiology and End Results-Medicare database, 1682 resected patients with N1 NSCLC diagnosed between 1992 and 2005 were identified. As the number of positive LNs is confounded by the total number of LNs sampled, the cases were classified into three groups according to the ratio of positive to total number of LNs removed (LN ratio (LNR)): ≤0.15, 0.16-0.5 and >0.5. Lung cancer-specific and overall survival was compared between these groups using Kaplan-Meier curves. Stratified and Cox regression analyses were used to evaluate the relationship between the LNR and survival after adjusting for potential confounders. RESULTS: Lung cancer-specific and overall survival was lower among patients with a high LNR (p<0.0001 for both comparisons). Median lung cancer-specific survival was 47 months, 37 months and 21 months for patients in the ≤0.15, 0.16-0.5 and >0.5 LNR groups, respectively. In stratified and adjusted analyses, a higher LNR was also associated with worse lung cancer-specific and overall survival. CONCLUSIONS: The extent of LN involvement provides independent prognostic information in patients with N1 NSCLC. This information may be used to identify patients at high risk of recurrence who may benefit from aggressive postoperative therapy.

Quality Care in Survivorship: Lessons Learned From the ASCO Quality Oncology Practice Initiative.

PURPOSE: The ASCO Quality Oncology Practice Initiative (QOPI) project was established to evaluate the influence of guideline recommendations on routine clinical practice. METHODS: QOPI provided summary data from 839 unique practices in which data were collected every six months from the Fall of 2015 to the Spring of 2019. From these data, six items were chosen based on their relationship to domains of survivorship. A zero-inflated negative binomial regression model was used to test for trends in QOPI measures adherence rates over time. The models were adjusted for the time period, region, practice-ownership, multispecialty site, fellowship program, and hospital type. RESULTS: Smoking cessation counseling recommended and smoking cessation counseling administered or referred both increased over time, 50%-61% (adjusted incidence rate ratios (IRR), 1.028; 95% CI, 1.016 to 1.040; P < .001) and 34%-49% (adjusted IRR, 1.052; 95% CI, 1.035 to 1.070; P < .001), respectively. Infertility risks discussed before chemotherapy increased from 36% to 53% (adjusted IRR, 1.056; 95% CI, 1.035 to 1.078; P < .001) and fertility options discussed or referred to specialists increased from 23% to 38% (adjusted IRR, 1.074; 95% CI, 1.046 to 1.102; P < .001). Twenty-nine percent documented a positron emission tomography, computed tomography, or bone scan within the first 12 months for women diagnosed with early breast cancer treated for curative intent (adjusted IRR, 1.000; 95% CI, 0.977 to 1.024; P = .971). Tumor marker surveillance within 12 months increased from 78% to 87% (adjusted IRR, 1.018; 95% CI, 1.002 to 1.033; P = .023). CONCLUSION: As scientific evidence to guide cancer survivorship care grows, the role of guideline recommendations permeating clinical practice using quality metrics will become increasingly important.

Non-myeloablative conditioning and allogeneic transplantation for multiple myeloma.

In multiple myeloma (MM), allogeneic stem cell transplantation (alloHCT) carries a lower relapse risk than autologous transplantation but a greater transplant-related mortality. Nonmyeloablative conditioning for allogeneic transplantation (NST) reduces transplant-related toxicity. Results are encouraging when used during first remission in low-risk patients, but less-so in relapsed or refractory disease. This is a single-center retrospective analysis of 20 previously treated MM patients who underwent NST from matched-related or matched-unrelated donors from 2000-2006. Median age was 52.7 years (37.2-68.0). Twenty-five percent had advanced or high-risk disease. Eleven still had active disease prior to NST. Conditioning was total body irradiation 200 cGy on a single fraction on day -5, followed by antithymocyte globulin (ATG) 1.5 mg/kg/day and fludarabine 30 mg/m(2)/day on days -4 to -2. All received immunosuppression, most commonly with oral mycofenylate mofetil and cyclosporine beginning on day -5. At day 100, 50% had achieved complete remission. Transplant-related mortality was 25%. Median overall survival (OS) was 21.2 months (0.6-90+) and progression-free survival (PFS) 6.6 months (0.6-90+). Both OS and PFS were 24% at 3 years. OS was significantly greater for patients with age <52 years (median 27 months vs. 7.9 months, P = 0.031), and there was a trend toward greater OS for those with beta2 microglobulin <2.5 mg/l (median 27 months vs. 7.7 months, P = 0.08). Donor characteristics and Ig type had no significant effect on survival. These data suggest a benefit of NST in relapsed/refractory MM. Randomized trials must be performed to confirm and further qualify this benefit.

Combined Vaccination with NY-ESO-1 Protein, Poly-ICLC, and Montanide Improves Humoral and Cellular Immune Responses in Patients with High-Risk Melanoma.

Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1-specific CD4+ T-cell and humoral responses. CD8+ T-cell responses were mainly detected in patients receiving montanide. T-cell avidity toward NY-ESO-1 peptides was higher in patients vaccinated with montanide. In conclusion, NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4+ T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8+ T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8+ T-cell responses to NY-ESO-1.

Combined bone marrow and peripheral blood progenitor cell autografts for patients with poor mobilization.

BACKGROUND AIMS: Peripheral blood progenitor cell (PBPC) autografts with low CD34(+) cell content provide inadequate platelet (Plt) and red blood cell (RBC) reconstitution. Repeat collection and bone marrow (BM) harvesting are used in this situation. Minimum cell contents for BM-PBPC combined grafts are undefined. METHODS: A retrospective analysis of 19 autologous stem cell transplants (ASCT) with combined BM-PBPC for poor initial PBPC collection was carried out. Mobilization was with filgrastim (10 microg/kg/day) alone for 5 days or after chemotherapy. BM was harvested if PBPC collections were CD34+<2.5 x 10(6)/kg. RESULTS: The median age was 55 years (range 19-74). The diagnoses were multiple myeloma (7), non-Hodgkin's lymphoma (7), Hodgkin's disease (4) and acute myeloid leukemia (1). The median cell content (CD34+/kg x 10(6)) was 1.1 (0.3-2.7) for BM, 1.2 (0.04-2.8) for PBPC and 2.2 (1.4-4.9) combined. Eight grafts contained <2.0 x 10(6) CD34+/kg (1.4-1.8). The median engraftment in days (range) was: absolute neutrophil count (ANC) > 500, 12 (9-39); Plt > 20 000, 25 (15-70); RBC transfusion independence, 17 (6-93). Six patients died of progressive disease (58-293 days post-ASCT), one of infection on day 141 and one of AML on day 11. All patients except one maintained ANC > 1000 without filgrastim support beyond day 19. One patient had cholecystitis and delayed graft failure on day 90. PBPC CD34+ content did not predict CD34+ BM content but correlated with ANC > 500 (r= - 0.64, P=0.003). BM and combined CD34+ and BM TNC/kg did not correlate with engraftment or outcomes. Combined CD34+/kg < or > = 2.0 x 10(6) produced similar engraftment and mortality. CONCLUSIONS: After a failed PBPC collection, BM harvest is a reliable option for obtaining an adequate combined autograft. Combined BM-PBPC autografts with <2.0x10(6) CD34+/kg can produce satisfactory engraftment.

Laparoscopic Assessment to Determine the Likelihood of Achieving Optimal Cytoreduction in Patients Undergoing Primary Debulking Surgery for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of laparoscopic assessment to determine the likelihood of achieving optimal cytoreduction (OC) in patients undergoing primary debulking surgery (PDS) for ovarian cancer. METHODS: All patients who underwent diagnostic laparoscopy and PDS at our institution from January 2008 to December 2013 were identified. We determined the likelihood of achieving optimal cytoreduction by laparoscopic assessment based on tumor site, pattern of spread, and disease burden. Sensitivity was defined as the number of patients who achieved optimal cytoreduction after laparoscopic assessment divided by the number of patients with disease deemed resectable by laparoscopy. RESULTS: We identified 55 patients during study period. Twenty-one of the 55 patients (38%) were early stage disease. Six (10.9%) patients had disease deemed unresectable and 49 (89.1%) had disease deemed resectable at the time of laparoscopy. OC was achieved in 48 of 49 (97.9%) patients. The sensitivity of laparoscopy in predicting OC was 98% (95% confidence interval, 89.3%-99.9%). The operation was completed laparoscopically in 23 of 49 patients (47%); in 26 of 49 (53%), PDS was performed by laparotomy. There were no port site metastases reported. The rate of postoperative complications was 16%. With a median follow-up of 30 months, the median overall survival was not reached and the 75th percentile for overall survival was 37 months. CONCLUSIONS: Laparoscopy was shown to have a high sensitivity in predicting OC and is a feasible tool in triaging patients with ovarian cancer. Laparoscopy is not associated with adverse surgical outcomes.

Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial.

Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells.Patients and Methods: In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood.Results: Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (

Expression of Wnt5A and Wnt10B in non-immortalized breast cancer cells.

Wnt signaling is usually divided into two pathways: the 'canonical', acting through beta-catenin, and the 'non-canonical' acting through the Ca2+ and planar cell polarity pathway. Both pathways have been implicated in different types of cancer. Most results obtained with established cell lines have been contradictory. Here, we have investigated the expression of Wnt10B (canonical) and Wnt5A (non-canonical) in a panel of finite life-span and established normal and breast cancer cells using quantitative RT-PCR. It was found that there were both significant overexpression of Wnt5A and underexpression of Wnt10B in the metastasis-derived finite life-span breast cancer cells when they were compared to the finite life-span normal and established normal and breast tumor cells. Since expression profiles of primary breast cancer cultures are closer to the original tumor than the established cell lines, future research in this area should take into consideration these differences.

Patient-derived Interstitial Fluids and Predisposition to Aggressive Sporadic Breast Cancer through Collagen Remodeling and Inactivation of p53.

Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiologic examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors.Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells.Results: We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also downregulates RYBP, leading to degradation of p53. Furthermore, in mammary glands of heterozygous p53-mutant knock-in mice, IFHigh promotes spontaneous tumor formation.Conclusions: Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers. Clin Cancer Res; 23(18); 5446-59. ©2017 AACR.

Decision-Making in Breast Cancer Surgery: Where Do Patients Go for Information?

Patient decision-making regarding breast cancer surgery is multifactorial, and patients derive information on surgical treatment options from a variety of sources which may have an impact on choice of surgery. We investigated the role of different information sources in patient decision-making regarding breast cancer surgery. Two hundred and sixty-eight patients with breast cancer, eligible for breast-conserving therapy were surveyed in the immediate preoperative period, and clinical data were also collected. This survey evaluated the scope and features of patient-driven research regarding their ultimate choice of surgical treatment. The two most common sources of information used by patients were written material from surgeons (199/268-74%) and the Internet (184/268-69%). There was a trend for women who chose bilateral mastectomy to use the Internet more frequently than those choosing unilateral mastectomy (P = 0.056). Number of surgeons consulted, genetic testing, and MRI were significant predictors of patient choice of mastectomy over breast-conserving therapy. Multivariate analysis showed that the number of surgeons consulted (P < 0.001) and genetic testing (P < 0.001) were independent predictors of choosing mastectomy, whereas MRI was not. In conclusions, understanding factors driving patient decision-making may promote more effective education for patients requiring breast cancer surgery.

Changes in Pathological Complete Response Rates after Neoadjuvant Chemotherapy for Breast Carcinoma over Five Years.

Historically, neoadjuvant chemotherapy (NACT) was extrapolated from adjuvant regimens. Dual HER2 blockade and the introduction of carboplatin for triple negative breast cancers (TNBC) emerged by December 2013 and have improved pathological complete response (pCR) rates. The objective of this study was to assess the pCR rates before and after the introduction of these new neoadjuvant regimens. Materials and Methods. Stage I-III breast cancer patients who received NACT were analyzed for rates of pCR by clinical characteristics (i.e., age, BMI, axillary lymphadenopathy, and histologic subtype), by time period (1 = 3/2010-11/2013, 2 = 12/2013-3/2015), and by type of chemotherapy (e.g., anthracycline/taxane only, carboplatin-containing, and HER2 blockade). Results. 113 patients received NACT. Overall pCR rate was 26.5 percent (n = 30). The pCR rate increased from 14% to 43.1% (p = 0.001) from time period 1 to time period 2 and were associated with HER2 positivity (p = 0.003), receiving treatment during time period 2 (p = 0.001) and using an anthracycline/taxane plus additional agent type of regimen (p = 0.004). Conclusions. Our study revealed a significant difference in rates of pCR over five years. Window of opportunity trials and other trials that utilize pCR analysis should be encouraged.