Morphological changes of the dorsal contour of the corpus callosum during the first two years of life.

BACKGROUND: In the medicolegal literature, focal concavities or notching of the corpus callosum has been thought to be associated with fetal alcohol spectrum disorders. Recent work suggests corpus callosum notching is a dynamic and normal anatomical feature, although it has not yet been defined in early life or infancy. OBJECTIVE: Our purpose was to characterize the dorsal contour of the corpus callosum during the first 2 years of life by defining the prevalence, onset and trajectory of notching on midsagittal T1-weighted images. MATERIALS AND METHODS: We reviewed retrospectively 1,157 consecutive patients between birth and 2 years of age. Corpus callosum morphology was evaluated and described. A notch was defined as a dorsal concavity of at least 1 mm in depth along the dorsal surface of the corpus callosum. Patient age as well as notch depth, location, number and presence of the pericallosal artery in the notch were noted. RESULTS: Two hundred thirty-three notches were identified in 549 patients: 36 anterior, 194 posterior and 3 patients with undulations. A statistically significant (R2=0.53, Beta=0.021, P=0.002) positive correlation between posterior notch prevalence and age in months was noted. A positive correlation between age and depth of the posterior notch was also statistically significant (r=0.32, n=179, P≤0.001). A trend for increased anterior notch prevalence with age was identified with significant correlation between visualized pericallosal artery indentation and anterior notching (r=0.20, n=138, P=0.016). Sub-analysis of the first month of life showed corpus callosum notching was not present. CONCLUSION: The presence of posterior notching increased significantly with age and was more frequent than that of anterior notching. Corpus callosum notching was absent in the first week of life, building on prior studies suggesting corpus callosum notching is acquired. This study provides baseline data on normative corpus callosum notching trajectories by age group during early life, a helpful correlate when associating corpus callosum morphology with disease.

A phase I/IIa clinical trial in stage IV melanoma of an autologous tumor-dendritic cell fusion (dendritoma) vaccine with low dose interleukin-2.

BACKGROUND: Stage IV melanoma has high mortality, largely unaffected by traditional therapies. Immunotherapy including cytokine therapies and checkpoint inhibitors improves outcomes, but has significant toxicities. In this phase I/IIa trial, we investigated safety and efficacy of a dendritoma vaccine, an active, specific immunotherapy, in stage IV melanoma patients. METHODS: Autologous tumor lysate and dendritic cells were fused creating dendritoma vaccines for each patient. Phase I patients were vaccinated every 3 months with IL-2 given for 5 days after initial inoculation. Phase IIa patients were vaccinated every 6 weeks with IL-2 given on days 1, 3 and 5 after initial inoculation. Toxicity and clinical outcomes were assessed. RESULTS: Twenty-five patients were enrolled and inoculated. All dendritoma and IL-2 toxicities were

Interim analysis of a phase I/IIa trial assessing E39+GM-CSF, a folate binding protein vaccine, to prevent recurrence in ovarian and endometrial cancer patients.

BACKGROUND: Folate binding protein(FBP) is an immunogenic protein over-expressed in endometrial(EC) and ovarian cancer(OC). We are conducting a phase I/IIa trial of E39 (GALE 301)+GM-CSF, an HLA-A2-restricted, FBP-derived peptide vaccine to prevent recurrences in disease-free EC and OC patients. This interim analysis summarizes toxicity, immunologic responses, and clinical outcomes to date. METHODS: HLA-A2+ patients were vaccinated(VG), and HLA-A2- or -A2+ patients were followed as controls(CG). Six monthly intradermal inoculations of E39+250mcg GM-CSF were administered to VG. Demographic, safety, immunologic, and recurrence rate(RR) data were collected and evaluated. RESULTS: This trial enrolled 51 patients; 29 in the VG and 22 in the CG. Fifteen patients received 1000mcg E39, and 14 received <1000mcg. There were no clinicopathologic differences between groups(all p ≥ 0.1). E39 was well-tolerated regardless of dose. DTH increased pre- to post-vaccination (5.7±1.5 mm vs 10.3±3.0 mm, p = 0.06) in the VG, and increased more in the 1000mcg group (3.8±2.0 mm vs 9.5±3.5 mm, p = 0.03). With 12 months median follow-up, the RR was 41% (VG) vs 55% (CG), p = 0.41. Among the 1000mcg patients, the RR was 13.3% vs 55% CG, p = 0.01. Estimated 2-year DFS was 85.7% in the 1000mcg group vs 33.6% in the CG (p = 0.021). CONCLUSIONS: This phase I/IIa trial reveals that E39+GM-CSF is well-tolerated and elicits a strong, dose-dependent in vivo immune response. Early efficacy results are promising in the 1000 mcg dose cohort. This study proves the safety and establishes the dose of E39 for a larger prospective, randomized, controlled trial in HLA-A2+ EC and OC patients to prevent recurrence.

Analysis of Clinical and Pathologic Factors of Pure, Flat Epithelial Atypia on Core Needle Biopsy to Aid in the Decision of Excision or Observation.

BACKGROUND: The optimal treatment of flat epithelial atypia (FEA) found on breast core needle biopsy (CNB) is controversial. We performed a retrospective review of our institutional experience with FEA to determine if excisional biopsy may be deferred. METHODS: Surgical records from 2009 to 2012 were reviewed for FEA diagnosis. After exclusion for concomitant lesions, CNBs of pure FEA were classified using a previously agreed upon descriptor of "focal" versus "prominent". Data was analyzed with the Fisher's Exact and Student-t test as appropriate. RESULTS: Of 71 CNBs evaluated, pure FEA was identified on 27 CNBs. Final excisional biopsy was benign in 24 of 27 cases (88%) with associated ductal carcinoma in-situ (DCIS) in 3 of 27 cases (11%). Eighteen of 27 (67%) CNBs were classified as focal while 9 (33%) were described as prominent. Zero of the 18 focal patients had a malignancy compared to 3 of the 9 in the prominent group (0% vs 33%, p=0.02). Of the 27 pure FEA CNBs, 6 patients had a personal history of breast carcinoma, five DCIS and one invasive ductal carcinoma. No malignancies were found in the 21 patients without a personal history of breast carcinoma versus three in the patients with a positive history (0/21 v 3/6, p=0.007). CONCLUSIONS: Our data suggests those women who have adequate sampling and sectioning of CNBs, with focal, pure FEA on pathology, and are without a personal history of breast cancer may undergo a period of imaging surveillance. Conversely, patients with a history of breast cancer or pure, prominent FEA on CNB disease should proceed to excisional biopsy.

Novel dendritic cell-based vaccination in late stage melanoma.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play an important role in stimulating an immune response of both CD4(+) T helper cells and CD8(+) cytotoxic T lymphocytes (CTLs). As such, DCs have been studied extensively in cancer immunotherapy for their capability to induce a specific anti-tumor response when loaded with tumor antigens. However, when the most relevant antigens of a tumor remain to be identified, alternative approaches are required. Formation of a dentritoma, a fused DC and tumor cells hybrid, is one strategy. Although initial studies of these hybrid cells are promising, several limitations interfere with its clinical and commercial application. Here we present early experience in clinical trials and an alternative approach to manufacturing this DC/tumor cell hybrid for use in the treatment of late stage and metastatic melanoma.

The HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence: correlation of immunologic data with clinical response.

Nelipepimut-S (formerly known as E75) is an immunogenic peptide from the HER2 protein that is highly expressed in breast cancer. The NeuVax™ (Galena, OR, USA) vaccine, nelipepimut-S plus granulocyte-macrophage colony-stimulating factor, is designed for the prevention of clinical recurrences in high risk, disease-free breast cancer patients. Although cancer vaccines such as NeuVax represent promising approaches to cancer immunotherapy, much remains to be elucidated regarding their mechanisms of action: particularly given that multiple cancer vaccine trials have failed to demonstrate a correlation between immunologic data and clinical outcome. Here, we briefly discuss our clinical trial experience with NeuVax focusing on immunologic response data and its implication on how the immune system may be affected by this peptide vaccine. Most importantly, we demonstrate the potential capability of certain immunologic assays to predict clinical benefit in our trials.

Future directions for monitoring treatment responses in breast cancer.

In the prior review, we outlined the current standard of care for monitoring treatment responses in breast cancer and discussed the many challenges associated with these strategies. We described the challenges faced in common clinical settings such as the adjuvant setting, neoadjuvant setting, and the metastatic setting. In this review, we will expand upon future directions meant to overcome several of these current challenges. We will also explore several new and promising methods under investigation to enhance how we monitor treatment responses in breast cancer. Furthermore, we will highlight several new technologies and techniques for monitoring breast cancer treatment in the adjuvant, neoadjuvant and metastatic setting.

Current approaches and challenges in monitoring treatment responses in breast cancer.

Monitoring response to treatment is a key element in the management of breast cancer that involves several different viewpoints from surgery, radiology, and medical oncology. In the adjuvant setting, appropriate surgical and pathological evaluation guides adjuvant treatment and follow up care focuses on detecting recurrent disease with the intention of improving long term survival. In the neoadjuvant setting, assessing response to chemotherapy prior to surgery to include evaluation for pathologic response can provide prognostic information to help guide follow up care. In the metastatic setting, for those undergoing treatment, it is crucial to determine responders versus non-responders in order to help guide treatment decisions. In this review, we present the current guidelines for monitoring treatment response in the adjuvant, neoadjuvant, and metastatic setting. In addition, we also discuss challenges that are faced in each setting.

Current approaches and challenges in early detection of breast cancer recurrence.

Early detection of breast cancer recurrence is a key element of follow-up care and surveillance after completion of primary treatment. The goal is to improve survival by detecting and treating recurrent disease while potentially still curable assuming a more effective salvage surgery and treatment. In this review, we present the current guidelines for early detection of recurrent breast cancer in the adjuvant setting. Emphasis is placed on the multidisciplinary approach from surgery, medical oncology, and radiology with a discussion of the challenges faced within each setting.

Future directions for the early detection of recurrent breast cancer.

The main goal of follow-up care after breast cancer treatment is the early detection of disease recurrence. In this review, we emphasize the multidisciplinary approach to this continuity of care from surgery, medical oncology, and radiology. Challenges within each setting are briefly addressed as a means of discussion for the future directions of an effective and efficient surveillance plan of post-treatment breast cancer care.