Identifying an early treatment window for predicting breast cancer response to neoadjuvant chemotherapy using immunohistopathology and hemoglobin parameters.

BACKGROUND: Breast cancer pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) varies with tumor subtype. The purpose of this study was to identify an early treatment window for predicting pCR based on tumor subtype, pretreatment total hemoglobin (tHb) level, and early changes in tHb following NAC. METHODS: Twenty-two patients (mean age 56 years, range 34-74 years) were assessed using a near-infrared imager coupled with an Ultrasound system prior to treatment, 7 days after the first treatment, at the end of each of the first three cycles, and before their definitive surgery. Pathologic responses were dichotomized by the Miller-Payne system. Tumor vascularity was assessed from tHb; vascularity changes during NAC were assessed from a percentage tHb normalized to the pretreatment level (%tHb). After training the logistic prediction models using the previous study data, we assessed the early treatment window for predicting pathological response according to their tumor subtype (human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), triple-negative (TN)) based on tHb, and %tHb measured at different cycles and evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: In the new study cohort, maximum pretreatment tHb and %tHb changes after cycles 1, 2, and 3 were significantly higher in responder Miller-Payne 4-5 tumors (n = 13) than non-or partial responder Miller-Payne 1-3 tumors (n = 9). However, no significance was found at day 7. The AUC of the predictive power of pretreatment tHb in the cohort was 0.75, which was similar to the performance of the HER2 subtype as a single predictor (AUC of 0.78). A greater predictive power of pretreatment tHb was found within each subtype, with AUCs of 0.88, 0.69, and 0.72, in the HER2, ER, and TN subtypes, respectively. Using pretreatment tHb and cycle 1 %tHb, AUC reached 0.96, 0.91, and 0.90 in HER2, ER, and TN subtypes, respectively, and 0.95 regardless of subtype. Additional cycle 2 %tHb measurements moderately improved prediction for the HER2 subtype but did not improve prediction for the ER and TN subtypes. CONCLUSIONS: By combining tumor subtypes with tHb, we predicted the pCR of breast cancer to NAC before treatment. Prediction accuracy can be significantly improved by incorporating cycle 1 and 2 %tHb for the HER2 subtype and cycle 1 %tHb for the ER and TN subtypes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02092636 . Registered in March 2014.

Assessment of Functional Differences in Malignant and Benign Breast Lesions and Improvement of Diagnostic Accuracy by Using US-guided Diffuse Optical Tomography in Conjunction with Conventional US.

Purpose To investigate ultrasonography (US)-guided diffuse optical tomography to distinguish the functional differences of hemoglobin concentrations in a wide range of malignant and benign breast lesions and to improve breast cancer diagnosis in conjunction with conventional US. Materials and Methods The study protocol was approved by the institutional review boards and was HIPAA compliant. Written informed consent was obtained from all patients. Patients (288 women; mean age, 50 years; range, 17-94 years) who underwent US-guided biopsy were imaged with a handheld US and optical probe. The US-imaged lesion was used to guide reconstruction of light absorption maps at four wavelengths, and total hemoglobin (tHb), oxygenated hemoglobin (oxyHb), and deoxygenated hemoglobin (deoxyHb) were computed from the absorption maps. A threshold (80 µmol/L) was chosen on the basis of this study population. Two radiologists retrospectively evaluated US images on the basis of the US Breast Imaging Reporting and Data System lexicon, and a lesion was considered malignant when a score of 4C or 5 was given or a lesion had tHb greater than 80 µmol/L. A two-sample t test was used to calculate significance between groups, and Spearman ρ was computed between hemoglobin parameters and tumor pathologic grades. Results Three tumors were Tis, 37 were T1, 19 were T2-T4 carcinomas, and 233 were benign lesions. The mean maximum tHb, oxyHb, and deoxyHb of Tis-T1 and T2-T4 groups were 89.3 µmol/L ± 20.2 (standard deviation), 65.0 µmol/L ± 20.8, and 33.5 µmol/L ± 11.3, respectively, and 84.7 µmol/L ± 32.8, 57.1 µmol/L ± 19.8, and 34.7 µmol/L ± 18.9, respectively. The corresponding values of benign lesions were 54.1 µmol/L ± 23.5, 38.0 µmol/L ± 17.4, and 25.2 µmol/L ± 13.8, respectively. The mean maximum tHb, oxyHb, and deoxyHb were significantly higher in the malignant groups than the benign group (P <.001, <.001, and .041, respectively). For malignant lesions, the mean maximum tHb moderately correlated with tumor histologic grade and nuclear grade (ρ = 0.283 and 0.315, respectively). The mean maximum oxyHb moderately correlated with tumor nuclear grade (ρ = 0.267). When radiologists' US diagnosis and the tHb were used together, the sensitivity, specificity, positive predictive value, and negative predictive value were 96.6%-100%, 77.3%-83.3%, 52.7%-59.4%, and 99.0%-100%, respectively, for the combined malignant group. Conclusion The tHb and oxyHb correlate with breast cancer pathologic grade and can be used as an adjunct to US to improve sensitivity and negative predictive value in breast cancer diagnosis. (©) RSNA, 2016 Online supplemental material is available for this article.

Ultrasound-Guided Diffuse Optical Tomography for Predicting and Monitoring Neoadjuvant Chemotherapy of Breast Cancers: Recent Progress.

In this manuscript, we review the current progress of utilizing ultrasound-guided diffuse optical tomography (US-guided DOT) for predicting and monitoring neoadjuvant chemotherapy (NAC) outcomes of breast cancer patients. We also report the recent advance on optical tomography systems toward portable and robust clinical use at multiple clinical sites. The first patient who has been closely monitored before NAC, at day 2, day 8, end of first three cycles of NAC, and before surgery is given as an example to demonstrate the potential of US-guided DOT technique.

Delayed hypersensitivity reaction related to the use of pegfilgrastim.

Filgrastim and pegfilgrastim are granulocyte colony-stimulating factor products, which have been part of the supportive treatment of cancer patients for years to increase the white blood cell count and absolute neutrophil count with the objective of preventing neutropenic fever in patients at risk because of chemotherapy. Pegfilgrastim is a glycosylated form of filgrastim with a prolonged duration of effect, a reduced renal clearance, and relatively fewer side effects. We present a patient with early breast cancer who developed a rash more than a week after the use of pegfilgrastim. Clinicians must be aware of the possibility of a delayed hypersensitivity reaction as the application of this drug is increasing and an adverse event can result in delay of chemotherapy treatment.

Pathologic response prediction to neoadjuvant chemotherapy utilizing pretreatment near-infrared imaging parameters and tumor pathologic criteria.

INTRODUCTION: The purpose of this study is to develop a prediction model utilizing tumor hemoglobin parameters measured by ultrasound-guided near-infrared optical tomography (US-NIR) in conjunction with standard pathologic tumor characteristics to predict pathologic response before neoadjuvant chemotherapy (NAC) is given. METHODS: Thirty-four patients' data were retrospectively analyzed using a multiple logistic regression model to predict response. These patients were split into 30 groups of training (24 tumors) and testing (12 tumors) for cross validation. Tumor vascularity was assessed using US-NIR measurements of total hemoglobin (tHb), oxygenated (oxyHb) and deoxygenated hemoglobin (deoxyHb) concentrations acquired before treatment. Tumor pathologic variables of tumor type, Nottingham score, mitotic index, the estrogen and progesterone receptors and human epidermal growth factor receptor 2 acquired before NAC in biopsy specimens were also used in the prediction model. The patients' pathologic response was graded based on the Miller-Payne system. The overall performance of the prediction models was evaluated using receiver operating characteristic (ROC) curves. The quantitative measures were sensitivity, specificity, positive and negative predictive values (PPV and NPV) and the area under the ROC curve (AUC). RESULTS: Utilizing tumor pathologic variables alone, average sensitivity of 56.8%, average specificity of 88.9%, average PPV of 84.8%, average NPV of 70.9% and average AUC of 84.0% were obtained from the testing data. Among the hemoglobin predictors with and without tumor pathological variables, the best predictor was tHb combined with tumor pathological variables, followed by oxyHb with pathological variables. When tHb was included with tumor pathological variables as an additional predictor, the corresponding measures improved to 79%, 94%, 90%, 86% and 92.4%, respectively. When oxyHb was included with tumor variables as an additional predictor, these measures improved to 77%, 85%, 83%, 83% and 90.6%, respectively. The addition of tHb or oxyHb significantly improved the prediction sensitivity, NPV and AUC compared with using tumor pathological variables alone. CONCLUSIONS: These initial findings indicate that combining widely used tumor pathologic variables with hemoglobin parameters determined by US-NIR may provide a powerful tool for predicting patient pathologic response to NAC before the start of treatment. TRIAL REGISTRATION: ClincalTrials.gov ID: NCT00908609 (registered 22 May 2009).

High-dose eicosapentaenoic acid and docosahexaenoic acid supplementation reduces bone resorption in postmenopausal breast cancer survivors on aromatase inhibitors: a pilot study.

Postmenopausal breast cancer survivors are living longer; however, a common class of drugs, aromatase inhibitors (AI), depletes estrogen levels, promotes bone loss, and heightens fracture risk. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may offset AI effects to bone because of the known effects on cellular processes of bone turnover. Therefore, we hypothesized that 4 g of EPA and DHA daily for 3 mo would decrease bone turnover in postmenopausal breast cancer survivors on AI therapy in a randomized, double-blind, placebo controlled pilot study that included 38 women. At baseline and 3 mo, serum fatty acids, bone turnover, and inflammatory markers were analyzed. Serum EPA and DHA, total and long-chain (LC) omega (n)-3 polyunsaturated fatty acids (PUFA) increased, whereas arachidonic acid, total and LC n-6 PUFA, and the LC n-6:n-3 PUFA ratio decreased compared to placebo (all P < .05). Bone resorption was inhibited in the fish oil responders compared to placebo (P < .05). Inflammatory markers were not altered. This short-term, high-dose fish oil supplementation study's findings demonstrate that fish oil can reduce bone resorption; however, longer-term studies are needed to assess bone density preservation and to explore mechanistic pathways in this population at high risk for bone loss.

The perfect storm: hemophagocytic lymphohistiocytosis complicating disseminated yersiniosis.

Hemophagocytic lymphohistio-cytosis (HLH) is a rare but serious medical condition with variable clinical outcome. HLH presents real diagnostic and therapeutic challenges to the treating physician despite the major advances in molecular laboratory testing and the immune-chemotherapeutic interventions. Here we present a unique case ofHLH in the setting of hemoglobin H disease provoked by disseminated Yersinia enterocolitica infection. The hemoglobinopathy led to an iron overload state, which provided an optimal milieu for the siderophilic bacterium, Y. enterocolitica, to disseminate. This over whelming infection triggered an uncontrolled and dysregulated inflammatory cytokine cascade with resulting clinical sequelae. The patient was treated conservatively without immunosuppressive therapy and recovered quickly. The long-term outcome of such cases needs further definition.

Breast cancer: assessing response to neoadjuvant chemotherapy by using US-guided near-infrared tomography.

PURPOSE: To assess initial breast tumor hemoglobin (Hb) content before the initiation of neoadjuvant chemotherapy, monitor the Hb changes at the end of each treatment cycle, and correlate these findings with tumor pathologic response. MATERIALS AND METHODS: The HIPAA-compliant study protocol was approved by the institutional review boards of both institutions. Written informed consent was obtained from all patients. Patients who were eligible for neoadjuvant chemotherapy were recruited between December 2007 and May 2011, and their tumor Hb content was assessed by using a near-infrared imager coupled with an ultrasonography (US) system. Thirty-two women (mean age, 48 years; range, 32-82 years) were imaged before treatment, at the end of every treatment cycle, and before definitive surgery. The patients were graded in terms of their final pathologic response on the basis of the Miller-Payne system as nonresponders and partial responders (grades 1-3) and near-complete and complete responders (grades 4 and 5). Tumor vascularity was assessed from total Hb (tHb), oxygenated Hb (oxyHb), and deoxygenated Hb (deoxyHb) concentrations. Tumor vascularity changes during treatment were assessed from percentage tHb normalized to the pretreatment level. A two-sample two-sided t test was used to calculate the P value and to evaluate statistical significance between groups. Bonferroni-Holm correction was applied to obtain the corrected P value for multiple comparisons. RESULTS: There were 20 Miller-Payne grade 1-3 tumors and 14 grade 4 or 5 tumors. Mean maximum pretreatment tHb, oxyHb, and deoxyHb levels were significantly higher in grade 4 and 5 tumors than in grade 1-3 tumors (P = .005, P = .008, and P = .017, respectively). The mean percentage tHb changes were significantly higher in grade 4 or 5 tumors than in grade 1-3 tumors at the end of treatment cycles 1-3 (P = .009 and corrected P = .009, P = .002 and corrected P = .004, and P < .001 and corrected P < .001, respectively). DISCUSSION: These findings indicate that initial tumor Hb content is a strong predictor of final pathologic response. Additionally, the tHb changes during early treatment cycles can further predict final pathologic response.

Cardiac and noncardiac biomarkers in patients undergoing anthracycline chemotherapy - a prospective analysis.

BACKGROUND: Biomarkers represent a potential tool to identify individuals at risk for anthracycline-induced cardiotoxicity (AICT) prior to symptom onset or left ventricular dysfunction. METHODS: This study examined the levels of cardiac and noncardiac biomarkers before, after the last dose of, and 3-6 months after completion of doxorubicin chemotherapy. Cardiac biomarkers included 5th generation high-sensitivity cardiac troponin T (cTnT), N-terminal pro-brain natriuretic peptide, growth/differentiation factor-15 (GDF-15), and soluble suppression of tumorigenesis-2 (sST2). Noncardiac biomarkers included activated caspase-1 (CASP-1), activated caspase-3, C-reactive protein, tumor necrosis factor-α, myeloperoxidase (MPO), galectin-3, and 8-hydroxy-2'-deoxyguanosine. Echocardiographic data (LVEF and LVGLS) were obtained at pre- and post-chemotherapy. Subanalysis examined interval changes in biomarkers among high (cumulative doxorubicin dose ≥ 250 mg/m2) and low exposure groups. RESULTS: The cardiac biomarkers cTnT, GDF-15, and sST2 and the noncardiac biomarkers CASP-1 and MPO demonstrated significant changes over time. cTnT and GDF-15 levels increased after anthracycline exposure, while CASP-1 and MPO decreased significantly. Subanalysis by cumulative dose did not demonstrate a larger increase in any biomarker in the high-dose group. CONCLUSIONS: The results identify biomarkers with significant interval changes in response to anthracycline therapy. Further research is needed to understand the clinical utility of these novel biomarkers.

Qualitative Assessment of Perceived Organizational Support for Employed Breast Cancer Survivors.

OBJECTIVE: A more detailed understanding of unmet organizational support needs and workplace-based best practices for supporting cancer survivors is needed. METHODS: Ninety-four working breast cancer survivors responded to an open-ended survey question regarding the desired types of organizational support that were and were not received during early survivorship. We performed content-analysis of qualitative data. RESULTS: Major themes included instrumental support, emotional support, and time-based support. The need for flexible arrangements and reduced workloads was mostly met. Unmet needs included navigation/coordination, understanding/empathy, and time off for treatment and recovery. CONCLUSIONS: Organizational support can help cancer survivors manage their health and work roles, diminishing work-health conflict and turnover intent. Study findings can be used to design targeted interventions to fulfill cancer survivors' unmet organizational support needs, which may also apply to workers with other chronic health conditions.

Perceptions of clinical support for employed breast cancer survivors managing work and health challenges.

PURPOSE: A substantial portion of breast cancer survivors are active in the workforce, yet factors that allow survivors to balance work with cancer management and to return to work are poorly understood. We examined breast cancer survivors' most valued/desired types of support in early survivorship. METHODS: Seventy-six employed breast cancer survivors answered an open-ended survey question assessing the most valued/desired support to receive from healthcare providers during early survivorship to manage work and health. Cutrona's (Journal of Social and Clinical Psychology 9:3-14, 1990) optimal matching theory and House's (1981) conceptualization of social support types informed our analyses. Data were content-analyzed to identify themes related to support, whether needed support was received or not, and the types of healthcare providers who provided support. RESULTS: We identified six themes related to types of support. Informational support was valued and mostly received by survivors, but they expected more guidance related to work. Emotional support was valued but lacking, attributed mainly to providers' lack of personal connection and mental health support. Instrumental (practical) support was valued but received by a small number of participants. Quality of life support to promote well-being and functionality was valued and often received. Other themes included non-specific support and non-support. CONCLUSIONS: This study expands our understanding of how breast cancer survivors perceive work-related support from healthcare professionals. Findings will inform targeted interventions designed to improve the support provided by healthcare professionals. IMPLICATIONS FOR CANCER SURVIVORS: Breast cancer survivors managing work and health challenges may benefit by having their unmet support needs fulfilled.

Early-stage invasive breast cancers: potential role of optical tomography with US localization in assisting diagnosis.

PURPOSE: To investigate the potential role of optical tomography in the near-infrared (NIR) spectrum with ultrasonographic (US) localization as a means of differentiating early-stage cancers from benign lesions of the breast. MATERIALS AND METHODS: The protocol was approved by the institutional review boards and was HIPAA compliant; all participants signed an informed consent. One hundred seventy-eight consecutive women (mean age, 52 years; range, 21-89 years) who underwent US-guided biopsy were imaged with a hand-held probe consisting of a coregistered US transducer and an NIR imager. The lesion location provided by coregistered US was used to guide optical imaging. Light absorption was measured at two optical wavelengths. From this measurement, tumor angiogenesis was assessed on the basis of calculated total hemoglobin concentration (tHb) and was correlated with core biopsy results. For patients diagnosed with carcinomas and followed up with subsequent excision, the tHb was correlated with pathologic parameters. RESULTS: There were two in situ carcinomas (Tis), 35 T1 carcinomas, 24 T2-T4 carcinomas, and 114 benign lesions. The mean maximum and mean average tHb of the Tis-T1 group were 102.0 micromol/L +/- 28.5 (standard deviation) and 71.9 micromol/L +/- 18.8, and those of the T2-T4 group were 100.3 micromol/L +/- 26.4 and 67.0 micromol/L +/- 18.3, respectively. The mean maximum and mean average tHb of the benign group were 55.1 micromol/L +/- 22.7 and 39.1 micromol/L +/- 14.9, respectively. Both mean maximum and mean average tHb levels were significantly higher in the malignant groups than they were in the benign group (P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value for Tis-T1 cancers were 92%, 93%, 81%, and 97%. The corresponding values for T2-T4 tumors were 75%, 93%, 69%, and 95%. CONCLUSION: The angiogenesis (tHb) contrast imaged by using the NIR technique with US holds promise as an adjunct to mammography and US for distinguishing early-stage invasive breast cancers from benign lesions.

A Predictor of Pathological Complete Response to Neoadjuvant Chemotherapy Stratifies Triple Negative Breast Cancer Patients with High Risk of Recurrence.

We developed a test to predict which patients will achieve pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) and which will have residual disease (RD). Gene expression data from pretreatment biopsies of patients with all breast cancer subtypes were combined into a 519-patient cohort containing 177 TNBC patients. Two RNA classifiers of 16 genes each were sequentially applied to the total cohort, classifying patients into 3 distinct classes. The test performance was further validated in an independent 304-patient cohort. The test accurately identified 70.5% (79/112) of pCR and 83.5% (340/407) of RD patients in the total population, and 75.0% (45/60) of pCR and 75.2% (88/117) of RD patients in the TNBC subset. For the independent cohort, the test identified 91.5% RD patients in the total population and 86.2% RD patients in the TNBC subset. However, the identification of pCR in both total and TNBC population are as low as 21.1% and 30%, respectively. The TNBC RD patients were subdivided by our classifiers, with one class showing significantly higher levels of Ki67 expression and having significantly poorer survival rates than the other classes. This stratification of patients may allow predicted residual disease classes to be assigned an alternative therapy.

Optical tomography with ultrasound localization for breast cancer diagnosis and treatment monitoring.

Optical tomography with ultrasound (US) localization uses coregistered ultrasound images to guide optical imaging reconstruction. To simultaneously acquire US images and optical measurements, the authors used a hand-held probe consisting of a commercial US transducer and near-infrared optical imaging sensors of multiple wavelengths. A novel image scheme was used to map the ultrasound-visible lesions for optical imaging reconstruction. As a result, the problem of intense light scattering caused by breast tissue was overcome and reliable tumor hemoglobin concentration and blood oxygen saturation distributions from a group of patients were obtained. These functional parameters are valuable for aiding US diagnosis and for assessing chemotherapy response.

Treatment of Male Breast Cancer by Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade and Response Prediction Using Novel Optical Tomography Imaging: A Case Report.

Male breast cancer, although rare, is on the rise. Prospective clinical trials are unlikely and current management mirrors that of post-menopausal women. Neoadjuvant chemotherapy is widely used and pathologic complete response (pCR) predicts long-term survival. The addition of dual HER2 (human epidermal growth factor receptor 2) blockade has shown the highest pCR rates; however, there is no published data of this approach in men. Also, newer monitoring tools are necessary during a neoadjuvant therapy to help personalize treatment.  Here, we describe the case of a 64-year-old man with Stage IIB (tumor size 2 to 5 cm with involvement of axillary lymph nodes), high-grade estrogen receptor, progesterone receptor, and HER2-positive invasive ductal carcinoma with a germline breast cancer susceptibility gene 1 (BRCA1) mutation who was treated in a neoadjuvant fashion with dual HER2 blockade and platinum-based chemotherapy regimen. A novel predictive tool, ultrasound-localized diffuse optical tomography, was used to monitor his progress during treatment.

Effect of Adjuvant Chemotherapy on Left Ventricular Remodeling in Women with Newly Diagnosed Primary Breast Cancer: A Pilot Prospective Longitudinal Cardiac Magnetic Resonance Imaging Study.

PURPOSE: The aim of this study was to assess the left ventricular (LV) remodeling response to chemotherapy in low-cardiac-risk women with newly diagnosed nonmetastatic breast cancer. Cardiotoxic effects of chemotherapy are an increasing concern. To effectively interpret cardiac imaging studies performed for screening purposes in patients undergoing cancer therapy it is necessary to understand the normal changes in structure and function that may occur. METHODS: Twenty women without preexisting cardiovascular disease, of a mean age of 50 years, newly diagnosed with nonmetastatic breast cancer and treated with anthracycline or trastuzumab, were prospectively enrolled and evaluated at four time points (at baseline, during chemotherapy, 2 weeks after chemotherapy, and 6 months after chemotherapy) using cardiac magnetic resonance imaging, blood samples, and a clinical questionnaire. RESULTS: Over a 6-month period, the left ventricular ejection fraction (%) decreased (64.15±5.30 to 60.41±5.77, P<0.002) and the LV end-diastolic (mm) and end-systolic (mm) volumes increased (124.73±20.25 to 132.21±19.33, P<0.04 and 45.16±11.88 to 52.57±11.65, P<0.00, respectively). The LV mass (g) did not change (73.06±11.51 to 69.21±15.3, P=0.08), but the LV mass to LVEDV ratio (g/mm) decreased (0.594±0.098 to 0.530±0.124, P<0.04). CONCLUSIONS: In low-cardiac-risk women with nonmetastatic breast cancer, the increased LV volume and a mildly decreased left ventricular ejection fraction during and after chemotherapy do not seem to be associated with laboratory or clinical evidence of increased risk for heart failure.

Optimal probing of optical contrast of breast lesions of different size located at different depths by US localization.

We report a frequency domain optical tomography system utilizing three RF modulation frequencies, which are optimized for probing breast lesions of different size located at different depths. A real-time co-registered ultrasound scanner is used to provide on-site estimation of lesion size and location. Based on the lesion information, an optimal light modulation frequency can be selected, which may yield more accurate estimates of lesion angiogenesis and hypoxia. Phantom experiments have demonstrated that a high modulation frequency, such as 350Mhz, is preferable for probing small lesions closer to the surface while a low modulation frequency, such as 50Mhz, is desirable for imaging deeper and larger lesions. A clinical example of a large invasive carcinoma is presented to demonstrate the application of this novel technique.

Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein and chronic myelogenous leukemia.

PURPOSE: To test the feasibility, safety, immunogenicity, and clinical efficacy of an autologous vaccine of leukocyte-derived heat shock protein 70-peptide complexes (Hsp70PC), in conjunction with imatinib mesylate, in patients with chronic myeloid leukemia (CML) in chronic phase. EXPERIMENTAL DESIGN: Patients had cytogenetic or molecular evidence of disease, despite treatment with imatinib mesylate for all except one patient, at the beginning of study. Hsp70PCs were purified from the leukopheresed peripheral blood mononuclear cells and were administered in eight weekly intradermal injections at 50 microg/dose without adjuvant. Clinical responses were assessed by bone marrow analysis before and after vaccinations. An IFN-gamma enzyme-linked immunospot assay was used to estimate the effect of treatment on natural killer cells and T cells against CML. RESULTS: Twenty patients were treated. The manufacturing of Hsp70PCs was successful and the administration was safe for all patients. Minimal or no side effects were reported. Clinical responses were seen in 13 of 20 patients as measured by cytogenetic analysis of bone marrow Philadelphia chromosome-positive cells in metaphases and/or, when possible, the level of Bcr/Abl transcript by PCR. Immunologic responses were observed in 9 of 16 patients analyzed, characterized by an increase in the frequency of CML-specific IFN-gamma-producing cells and IFN-gamma-secreting natural killer cells in the blood. A significant correlation between clinical responses and immunologic responses was observed. CONCLUSIONS: Autologous Hsp70PC vaccination is feasible and safe. When combined with imatinib mesylate, it is associated with immunologic and possible clinical responses against CML in chronic phase.

Late recurrence of gastric cancer with isolated brain metastasis.

A 70-year-old woman presented to our clinic in 2007 after an evaluation for dysphagia revealed a poorly differentiated adenocarcinoma of the gastroesophogeal junction. Workup for metastatic disease was negative at presentation. She had a complete response to treatment, which was completed in November 2007. She continued to follow up regularly until 2011 when she presented again with neurologic symptoms and was found to have an isolated brain metastasis. She underwent resection of the lesion, and pathology was consistent with her originally diagnosed gastric cancer. The patient received adjuvant radiation therapy, however, unfortunately had rapid progression of disease 1 month later and was transitioned to hospice. Here, we report a rare case of late recurrence of gastric cancer with isolated brain metastasis with a review of literature.