Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma.

PURPOSE: Glioblastoma (GBM) carries a dismal prognosis despite standard multimodal treatment with surgery, chemotherapy and radiation. Immune checkpoint inhibitors, such as PD1 blockade, for treatment of GBM failed to show clinical benefit. Rational combination strategies to overcome resistance of GBM to checkpoint monotherapy are needed to extend the promise of immunotherapy to GBM management. Emerging evidence suggests that protein phosphatase 2A (PP2A) plays a critical role in the signal transduction pathways of both adaptive and innate immune cells and that inhibition of PP2A could enhance cancer immunity. We investigated the use of a PP2A inhibitor, LB-100, to enhance antitumor efficacy of PD1 blockade in a syngeneic glioma model. METHODS: C57BL/6 mice were implanted with murine glioma cell line GL261-luc or GL261-WT and randomized into 4 treatment arms: (i) control, (ii) LB-100, (iii) PD1 blockade and (iv) combination. Survival was assessed and detailed profiling of tumor infiltrating leukocytes was performed. RESULTS: Dual PP2A and PD1 blockade significantly improved survival compared with monotherapy alone. Combination therapy resulted in complete regression of tumors in about 25% of mice. This effect was dependent on CD4 and CD8 T cells and cured mice established antigen-specific secondary protective immunity. Analysis of tumor lymphocytes demonstrated enhanced CD8 infiltration and effector function. CONCLUSION: This is the first preclinical investigation of the effect of combining PP2A inhibition with PD1 blockade for GBM. This novel combination provided effective tumor immunotherapy and long-term survival in our animal GBM model.

Case Report of Histiocytoid Invasive Lobular Carcinoma.

The histiocytoid variant of invasive lobular carcinoma (ILC) is a rare subtype of breast cancer that can be challenging to diagnose and aggressive in nature. It is often diagnosed after the disease has metastasized. This report describes a case of a six-centimeter ILC of the histiocytoid subtype. The patient is a 66-year-old female who was initially told that she had dense breast tissue. At the time of diagnosis, she had a large mass and was found to have metastases to the axillary lymph nodes and vertebra. She was started on chemotherapy and immunotherapy, but has since developed multiple new lesions to her spine, rib, and femur. This case highlights the aggressive nature of this variant, which progressed while during treatment.

Case Report of Renal Cell Carcinoma Metastasis to the Breast.

Metastases from other primary malignancies to the breast are extremely rare, with an incidence of up to 2%. Renal cell carcinoma (RCC) is known to form micrometastases in unusual organs. This report describes a case of a RCC metastasis to the breast that was identified 20 years after nephrectomy. The patient, a 68-year-old female, presented after a new abnormality was found on a screening mammogram. The biopsy, which was reviewed by several pathologists, revealed a renal cell carcinoma metastasis. Imaging confirmed no other metastases, and she was treated with a partial mastectomy. This case highlights how RCC metastases can be found many years after a nephrectomy, and staining for RCC should be considered in patients with this history and a newly identified breast mass.

Tall Cell Variant of Invasive Papillary Breast Carcinoma.

Tall cell variant of invasive papillary breast carcinoma is exceedingly rare, with only 30 cases reported in the literature. This report describes a case of a 47-year-old woman who presented to the clinic with bilateral breast masses on a screening mammogram. The patient was lost to follow-up, but she presented again after 4 years when the right breast mass significantly grew in size over several months. Mammography showed a 1.9 cm right breast mass and a 2.3 cm left breast mass. Ultrasound-guided core biopsy revealed right breast triple negative invasive carcinoma of the tall cell papillary variant and left breast fibroadenomatoid nodules. She underwent bilateral lumpectomies with a right sentinel lymph node biopsy and was started on chemotherapy after surgical excision.

Breast Cancer Metastasis to Colon.

Breast cancer metastasis to the colon is exceedingly rare, with only 17 reported cases in the literature thus far. This report describes a 67-year-old female who presented to the Emergency Department for large volume melena in the setting of bilateral metastatic ductal breast carcinoma, left triple negative and right HER2+, and T4N0M0 non-small cell lung cancer. On routine CT abdomen/pelvis imaging, the patient had a 7 cm mass arising from the transverse colon. Colonoscopy revealed a non-obstructing necrotic mass in the proximal descending colon. The patient underwent a partial colectomy, small bowel resection, and gastric wedge resection. The patient recovered from surgery and was discharged home with palliative services. The patient passed away four months after discharge due to numerous metastases.

Thirteen-Centimeter Breast Lymphoma.

Lymphoma of the breast is a rare diagnosis, accounting for less than 0.5% of all breast malignancies. Presentation is usually similar to that of breast cancer, with a painless palpable mass. This report describes a unique case of a 13 cm breast lymphoma. The patient is a 74 year old female who presented to clinic with a right breast mass that has been present since the 1970s. She had previously undergone multiple excisions of lesions on both breasts, always with benign pathology. In 2017, screening mammogram revealed a suspicious lesion in the right upper outer breast with associated axillary lymphadenopathy. She was lost to follow up but presented again after the mass significantly grew in size over several months. Mammography showed a large 13 x 8.7 cm lobulated mass. Biopsy of the lesion revealed diffuse large B-cell lymphoma. Treatment for this patient will begin with chemotherapy.

Tactile Skill-Based Neurosurgical Simulators Are Effective and Inexpensive.

BACKGROUND: Regulations limit residency work hours and operating time, limiting the amount of hands-on surgical training. To develop alternative hands-on training, many programs teach surgical skills in laboratories and workshops with the use of simulators. The expense of computer simulators and lack of replication of the manual skills and tactile feedback of surgery limit their usefulness. We have developed 2 replicable simulators constructed from low-cost materials, which allow residents to practice the manual skills required in key portions of minimally invasive lumbar decompression and Chiari decompression surgeries. The objective was to review the efficacy of our lumbar and Chiari decompression simulators in improving resident and medical student surgical skills. METHODS: Resident and medical student participants completed one or both simulators 10 times. The lumbar decompression simulations were evaluated by the length of time participants blocked the field of view and by the number of times they lost control of the drill. Chiari decompression simulations were evaluated by the length of time to complete the simulation and by the regularity of their sutures. RESULTS: After 10 attempts, participants of the lumbar decompression simulator decreased the amount of time blocking the field of view by 52% and decreased the number of times they lost control of the drill by 69%. Participants of the Chiari decompression simulator decreased their suturing time by 56% and improved the regularity of their sutures. CONCLUSIONS: The simple and inexpensive simulators evaluated in this study were shown to improve the speed, quality of work, and comfort level of the participants.

CAR T Cell Therapy for Pediatric Brain Tumors.

Chimeric Antigen Receptor (CAR) T cell therapy has recently begun to be used for solid tumors such as glioblastoma multiforme. Many children with pediatric malignant brain tumors develop extensive long-term morbidity of intensive multimodal curative treatment. Others with certain diagnoses and relapsed disease continue to have limited therapies and a dismal prognosis. Novel treatments such as CAR T cells could potentially improve outcomes and ameliorate the toxicity of current treatment. In this review, we discuss the potential of using CAR therapy for pediatric brain tumors. The emerging insights on the molecular subtypes and tumor microenvironment of these tumors provide avenues to devise strategies for CAR T cell therapy. Unique characteristics of these brain tumors, such as location and associated morbid treatment induced neuro-inflammation, are novel challenges not commonly encountered in adult brain tumors. Despite these considerations, CAR T cell therapy has the potential to be integrated into treatment schema for aggressive pediatric malignant brain tumors in the future.

A comparison of midline and tracheal gene regulation during Drosophila development.

Within the Drosophila embryo, two related bHLH-PAS proteins, Single-minded and Trachealess, control development of the central nervous system midline and the trachea, respectively. These two proteins are bHLH-PAS transcription factors and independently form heterodimers with another bHLH-PAS protein, Tango. During early embryogenesis, expression of Single-minded is restricted to the midline and Trachealess to the trachea and salivary glands, whereas Tango is ubiquitously expressed. Both Single-minded/Tango and Trachealess/Tango heterodimers bind to the same DNA sequence, called the CNS midline element (CME) within cis-regulatory sequences of downstream target genes. While Single-minded/Tango and Trachealess/Tango activate some of the same genes in their respective tissues during embryogenesis, they also activate a number of different genes restricted to only certain tissues. The goal of this research is to understand how these two related heterodimers bind different enhancers to activate different genes, thereby regulating the development of functionally diverse tissues. Existing data indicates that Single-minded and Trachealess may bind to different co-factors restricted to various tissues, causing them to interact with the CME only within certain sequence contexts. This would lead to the activation of different target genes in different cell types. To understand how the context surrounding the CME is recognized by different bHLH-PAS heterodimers and their co-factors, we identified and analyzed novel enhancers that drive midline and/or tracheal expression and compared them to previously characterized enhancers. In addition, we tested expression of synthetic reporter genes containing the CME flanked by different sequences. Taken together, these experiments identify elements overrepresented within midline and tracheal enhancers and suggest that sequences immediately surrounding a CME help dictate whether a gene is expressed in the midline or trachea.