Michael Giacomantonio

Neurenteric cysts—A spectrum

This review encompasses seven patients with clinically important cystic lesions of the gastrointestinal (GI) tract, exhibiting a wide range of vertebral anomalies and connections to the neural canal. Three patients had mediastinal masses connected to lower cervical and upper thoracic anomalous vertebrae with intraspinal extensions. In addition, one of these patients had a separate, juxtapancreatic intestinal duplication cyst. One infant with colonic duplication had a lumbar vertebral anomaly and an epithelial-lined tract between the two. Another patient had a presacral cystic mass which was the site of recurrent infections and meningitis until a connection with the rectum was divided. A newborn baby had a completely split notochord syndrome with a large dorsal enteric fistula. Finally, one patient had a dorsal enteric cyst with a direct intraspinal connection. Four of the seven patients had associated significant congenital anomalies, two of whom died early in the neonatal period. The rest of the patients did well. This broad range of enteric lesions with associated vertebral and intraspinal abnormalities suggests that the clinical spectrum of neurenteric cystic lesions is much wider than is generally appreciated.

Paraesophageal hernia after Nissen fundoplication: A real complication in pediatric patients*

Eighty-nine pediatric patients aged 6 weeks to 20 years (mean, 3.8 years) who underwent Nissen fundoplication were reviewed. Follow-up, including upper gastrointestinal (GI) series, was obtained in 55 patients (61.8%). Fifteen patients developed paraesophageal hernia (PEH) (16.8%). PEH was diagnosed between 4 and 36 months following fundoplication (mean, 17 months). Patients were divided into three groups: A, those with significant mental dysfunction (45); B, those with previous tracheoesophageal fistula (12); and C, others (32). Incidence of PEH is 20% for group A, 16.8% group B, and 12.5% group C. Combining groups B and C, 5 of 25 patients (20%) who underwent fundoplication at less than 1 year of age developed PEH, whereas one of 19 older patients (5.3%) developed PEH. One of 25 patients (4%) who had crural repair at fundoplication developed PEH, whereas 14 of 64 patients without crural repair (21.9%) developed PEH. At surgery, PEH occurred at the left posterolateral aspect of esophagus. We conclude that (1) follow-up after fundoplication should continue for 36 months and include upper GI series; (2) patients under one year of age undergoing fundoplication may be at a higher risk for PEH; and (3) technical refinement including crural repair may be required to prevent PEH.

Neonatal Ovarian Torsion: Report of Three Cases and Review of the Literature

Ovarian cysts are common incidental findings in term infants and, if unusually large, may result in dystocia, torsion, or rupture. Torsion and infarction of a normal ovary tend to occur in older childhood. During a 4-month period, 3 cases of neonatal ovarian torsion were observed after antenatal ultrasonography had detected fetal pelvico-abdominal cystic lesions. The three infants were explored between 4 and 16 days of age. Ovarian torsion was right-sided in all 3, and 1 ovary had been autoamputated. The resected specimens were nontense, thin-walled cysts, filled with hemorrhagic fluid, that measured between 4.5 and 8 cm in diameter. Microscopically, focal calcification and widespread necrosis precluded recognition of underlying histologic landmarks. Neonatal ovarian cysts or cystic ovaries greater than 4 cm in diameter should be excised, even if asymptomatic, because they are prone to, or have undergone, torsion.

Core needle biopsy of breast cancer tumors increases distant metastases in a mouse model.

INTRODUCTION: Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely performed before surgical excision of breast cancer tumors are hypothesized to increase the risk of metastatic disease. In this study, we experimentally determined whether CNB of breast cancer tumors results in increased distant metastases and examine important resultant changes in the primary tumor and tumor microenvironment associated with this outcome. METHOD: To evaluate the effect of CNB on metastasis development, we implanted murine mammary 4T1 tumor cells in BALB/c mice and performed CNB on palpable tumors in half the mice. Subsequently, emulating the human scenario, all mice underwent complete tumor excision and were allowed to recover, with attendant metastasis development. Tumor growth, lung metastasis, circulating tumor cell (CTC) levels, variation in gene expression, composition of the tumor microenvironment, and changes in immunologic markers were compared in biopsied and non-biopsied mice. RESULTS: Mice with biopsied tumors developed significantly more lung metastases compared to non-biopsied mice. Tumors from biopsied mice contained a higher frequency of myeloid-derived suppressor cells (MDSCs) accompanied by reduced CD4 + T cells, CD8 + T cells, and macrophages, suggesting biopsy-mediated development of an increasingly immunosuppressive tumor microenvironment. We also observed a CNB-dependent up-regulation in the expression of SOX4, Ezh2, and other key epithelial-mesenchymal transition (EMT) genes, as well as increased CTC levels among the biopsy group. CONCLUSION: CNB creates an immunosuppressive tumor microenvironment, increases EMT, and facilitates release of CTCs, all of which likely contribute to the observed increase in development of distant metastases.

Nipple Discharge and Breast Lump Related to Montgomery's Tubercles in Adolescent Females

Four adolescent girls, aged 12 to 14 years, were seen for evaluation of spontaneous nipple discharge, two of whom had associated breast lumps in the ipsilateral breast. Clinical examination showed the discharge to be arising from one or several of Montgomerys areolar tubercles, with the breast lumps localized to the subareolar region immediately beneath the discharging tubercle. The secretions were episodic, thin, varied in color from clear to brown, but were not milky. All discharges resolved within 3 to 5 weeks, and the associated breast lumps resolved within 4 months without treatment. There were no associated clinical complaints or physical findings and detailed endocrinologic assessments including serum prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid function tests, and 17 beta estradiol; they were all normal. None of these patients was pregnant, and follow-up from 4 to 18 months did not reveal evidence of recurrence or other pathology. Experience gained from these four cases suggests that cysts and spontaneous, non-milky discharge related to Montgomerys tubercles in otherwise healthy, nonpregnant adolescent females, represents a benign, self-limiting problem. Unless other indications are present, endocrinologic investigation is unnecessary and spontaneous resolution can be expected.

Survival in neonatal congenital hernia without extracorporeal membrane oxygenation support

The experience with high-risk congenital diaphragmatic hernia (CDH) at an institution that does not offer extracorporeal membrane oxygenation (ECMO) was reviewed. Between January 1, 1983 and December 31, 1993, 38 children presented with Bochdalek-type CDH. Excluded were two infants with lethal cardiac anomalies and four presenting after 4 hours of age. Thus, the authors identified 32 high-risk patients. All had early respiratory distress and were intubated within 5 hours of birth. Sixteen were inborn; 16 were referred to the Izaak Walton Killam Childrens Hospital (IWK) within 24 hours of birth. There were 19 males and 13 females. Three died before surgery could be attempted. Twenty-two survived, giving an overall survival rate of 69% (22 of 32). For 28 of the 32, the best preoperative postductal Pao2 (BPDPao2) was recorded. Fifteen of the 28 children had a BPDPao2 of greater than 100 mm Hg. Survival in this group was 14 of 15 (93%). Thirteen of the 28 patients had a BPDPao2 of less than 100 mm Hg. Survival in this group was 5 of 13 (38%). These survival rates are comparable to those of centers offering ECMO. BPDPao2 appears to be a useful discriminating variable.

Perianal Ependymoma Presenting in the Neonatal Period

Extraspinal ependymomas are a rare type of glioma that may arise in the sacrococcygeal region, presenting as a pelvic mass in an infant or child. Ependymoma presenting in the newborn period has not been described previously. Herein we describe a case of a newborn boy who presented with a perianal ependymoma, which was subsequently found to have presacral extension. The major diagnostic challenge this case presented was to rule out the alternative diagnosis of sacrococcygeal teratoma or a developmental malformation/heterotopia.

Undifferentiated Mesenchymal Neoplasm of the Esophagus in a Child: Case Report and Comparison with Gastrointestinal Stromal Tumor

Mesenchymal neoplasms of the esophagus are relatively uncommon in adults and exceedingly rare in children. Childhood tumors consist almost exclusively of smooth muscle tumors (leiomyomas). We report a case of an undifferentiated mesenchymal neoplasm occurring in the distal esophagus of a 15-year-old boy which is not a gastrointestinal stromal tumor. To our knowledge, this is the first reported case of such a neoplasm occurring in the esophagus of either an adult or child.

Dying to Be Noticed: Epigenetic Regulation of Immunogenic Cell Death for Cancer Immunotherapy

Immunogenic cell death (ICD) activates both innate and adaptive arms of the immune system during apoptotic cancer cell death. With respect to cancer immunotherapy, the process of ICD elicits enhanced adjuvanticity and antigenicity from dying cancer cells and consequently, promotes the development of clinically desired antitumor immunity. Cancer ICD requires the presentation of various “hallmarks” of immunomodulation, which include the cell-surface translocation of calreticulin, production of type I interferons, and release of high-mobility group box-1 and ATP, which through their compatible actions induce an immune response against cancer cells. Interestingly, recent reports investigating the use of epigenetic modifying drugs as anticancer therapeutics have identified several connections to ICD hallmarks. Epigenetic modifiers have a direct effect on cell viability and appear to fundamentally change the immunogenic properties of cancer cells, by actively subverting tumor microenvironment-associated immunoevasion and aiding in the development of an antitumor immune response. In this review, we critically discuss the current evidence that identifies direct links between epigenetic modifications and ICD hallmarks, and put forward an otherwise poorly understood role for epigenetic drugs as ICD inducers. We further discuss potential therapeutic innovations that aim to induce ICD during epigenetic drug therapy, generating highly efficacious cancer immunotherapies.

Abstract B23: Citral reduces ALDH1A3 activity in breast cancer: Potential applications in targeting breast cancer stem cells

Breast tumors contain a subpopulation of cells known as cancer stem cells (CSCs) which are highly tumorigenic, resistant to typical chemo- and radiotherapy, and express high levels of aldehyde dehydrogenase (ALDH) isoforms ALDH1A3 and ALDH1A1. These enzymes initiate retinoic acid (RA) signaling and potentially contribute to detoxification of chemotherapy. A compound that inhibits these enzymes could be used as an adjuvant therapy to target breast CSCs and/or re-sensitize this population to chemotherapy. In particular, there are no currently characterized inhibitors of the ALDH1A3 isoform, so twelve general ALDH inhibitors were tested for their effectiveness in targeting ALDH1A3 activity. Ability to directly inhibit ALDH activity was quantified with the Aldefluor assay on a patient tumor xenograft and on breast cancer cell lines MDA-MB-231, MDA-MB-468, and SKBR3. Inhibition of RA signaling was quantified by measuring RA-inducible gene expression after 24 hours treatment with ALDH inhibitor. To investigate the anti-cancer properties of these compounds, apoptosis was quantified with the annexin V assay after 24 hours treatment. To determine if increased ALDH1A3 expression is involved in chemoresistance, MDA-MB-231 cells overexpressing ALDH1A3 and MDA-MB-468 cells with ALDH1A3 shRNA knockdown were treated for 72 hours with doxorubicin, 4-hydroperoxycyclophosphamide, or paclitaxel. Increased ALDH1A3 expression did not affect the amount of chemotherapy-induced apoptosis or cell proliferation rates. Citral significantly reduced ALDH1A3-mediated expression of RA-inducible genes and significantly reduced the ALDH activity of the patient-derived xenograft as well as ALDH1A3-overexpression MDA-MB-231 cells. Citral induced apoptosis in an ALDH1A3-dependant manner in breast cancer cell lines, and its ability to reduce MDA-MB-231 in vivo growth was investigated by implanting MDA-MB-231 cells in female NOD/SCID mice and injecting with 0.1mg/kg citral. Tumor size was not affected by citral injections, however recent data suggests that micelle-encapsulated citral has the potential to reduce tumor bulk. Should citral prove to be an effective breast cancer and ALDH1A3 inhibitor in future tumor xenograft experiments, this compound could potentially be used as adjuvant therapy for breast cancer patients. Citation Format: Margaret L. Thomas, Krysta M. Coyle, Brianne Cruickshank, Michael Giacomantonio, Melissa Wallace, Carman Giacomantonio, Paola Marcato. Citral reduces ALDH1A3 activity in breast cancer: Potential applications in targeting breast cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B23.