Multispectral Endoscopy with Light Gating for Early Cancer Detection.

This paper reports the application of endoscopic light scattering spectroscopy (LSS) with light gating to detect malignancies in the biliary and pancreatic ducts, and also reviews the application of endoscopic LSS for differentiating cystic neoplasms in the pancreas and detecting invisible dysplasia in Barrett's esophagus. Information about tissue structure within the superficial epithelium where malignancy starts is present within the spectra of reflected light. Fortunately, this component of the reflected light is not yet randomized. However multiple scattering randomizes the signal from the underlying connective tissue which obscures the desired signal. In order to extract diagnostic information from the reflected signal the multiple scattering component related to connective tissue scattering and absorption must be removed. This is accomplished using described here spatial or polarization gating implemented with endoscopically compatible fiber optic probes.

Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases.

Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examined the role of normal ABL1 in leukemias induced by oncogenic ABL1 kinases. BCR-ABL1-Abl1(-/-) cells generated highly aggressive chronic myeloid leukemia (CML)-blast phase-like disease in mice compared with less malignant CML-chronic phase-like disease from BCR-ABL1-Abl1(+/+) cells. Additionally, loss of ABL1 stimulated proliferation and expansion of BCR-ABL1 murine leukemia stem cells, arrested myeloid differentiation, inhibited genotoxic stress-induced apoptosis, and facilitated accumulation of chromosomal aberrations. Conversely, allosteric stimulation of ABL1 kinase activity enhanced the antileukemia effect of ABL1 tyrosine kinase inhibitors (imatinib and ponatinib) in human and murine leukemias expressing BCR-ABL1, TEL-ABL1, and NUP214-ABL1. Therefore, we postulate that normal ABL1 kinase behaves like a tumor suppressor and therapeutic target in leukemias expressing oncogenic forms of the kinase.

Management of chronic intractable constipation in children.

BACKGROUND: Chronic intractable constipation (CIC) is a debilitating disease that is challenging to manage. Treatment options in children include medications, enemas, and surgical management in selected cases. METHOD: We reviewed medical records of pediatric patients diagnosed as having CIC at Tufts Medical Center from 2005 to 2012. Demographic variables, diagnostic procedures, and medical and surgical outcomes were collected. Clinical outcome was defined using the Rome III criteria. RESULTS: A total of 14 patients were included in the study (10 boys). The age range was 10 to 21 years. All of the patients had the diagnosis of CIC. Eleven patients had cecostomy placement. During the follow-up period, 10 patients underwent total abdominal colectomy with ileorectal anastomosis, 1 had total colectomy with ileostomy, and 1 had partial colectomy with colorectal anastomosis. Successful clinical outcome was reported in 7 patients with 3 patients reporting persistent fecal incontinence. Colonic motility studies were performed on 12 patients (colonic neuropathy in 11 patients and normal study in 1 patient). Defecography was consistent with isolated pelvic floor dysfunction in 1 patient, abnormal motility and anatomy in 1 patient, pelvic floor dysfunction and abnormal motility in 2 patients, and found abnormal motility only in 5. Defecography study was normal in 5 patients. All of the patients with abnormal colonic manometry underwent a surgical procedure. CONCLUSIONS: Anorectal manometry, colonic manometry, and defecography help in understanding the pathophysiology of defecation disorders in children. The majority of patients with abnormal colonic manometry underwent TAC-IRA. There was no statistical correlation between individual investigations (anorectal manometry, colonic manometry, and defecography) with surgical intervention (P > 0.35). TAC-IRA may be safe and useful intervention in a subset of patients when other treatment options have failed.

IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK.

Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4(+) T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4(+) T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.

Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS.

Here we report that T-cell lymphoma cells carrying the NPM-ALK fusion protein (ALK(+) TCL) frequently express the cell-stimulatory receptor ICOS. ICOS expression in ALK(+) TCL is moderate and strictly dependent on the expression and enzymatic activity of NPM-ALK. NPM-ALK induces ICOS expression via STAT3, which triggers the transcriptional activity of the ICOS gene promoter. In addition, STAT3 suppresses the expression of miR-219 that, in turn, selectively inhibits ICOS expression. ALK(+) TCL cell lines display extensive DNA methylation of the CpG island located within intron 1, the putative enhancer region, of the ICOS gene, whereas cutaneous T-cell lymphoma cell lines, which strongly express ICOS, show no methylation of the island. Treatment of the ALK(+) TCL cell lines with DNA methyltransferase inhibitor reversed the CpG island methylation and augmented the expression of ICOS mRNA and protein. Stimulation of the ICOS receptor with anti-ICOS antibody or ICOS ligand-expressing B cells markedly enhanced proliferation of the ALK(+) TCL cells. These results demonstrate that NPM-ALK, acting through STAT3 as the gene transcriptional activator, induces the expression of ICOS, a cell growth promoting receptor. These data also show that the DNA methylation status of the intronic CpG island affects transcriptional activity of the ICOS gene and, consequently, modulates the concentration of the expressed ICOS protein.

Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma.

The application of kinase inhibitors in cancer treatment is growing rapidly. However, methods for monitoring the effectiveness of the inhibitors are still poorly developed and currently rely mainly on the tracking of changes in the tumor volume, a rather late and relatively insensitive marker of the therapeutic response. In contrast, MRS can detect changes in cell metabolism and has the potential to provide early and patient-specific markers of drug activity. Using human B-cell lymphoma models and MRS, we have demonstrated that the inhibition of the mTOR signaling pathway can be detected in malignant cells in vitro and noninvasively in vivo by the measurement of lactate levels. An mTOR inhibitor, rapamycin, suppressed lactic acid production in lymphoma cell line cultures and also diminished steady-state lactate levels in xenotransplants. The inhibition was time dependent and was first detectable 8 h after drug administration in cell cultures. In xenotransplants, 2 days of rapamycin treatment produced significant changes in lactic acid concentration in the tumor measured in vivo, which were followed by tumor growth arrest and tumor volume regression. The rapamycin-induced changes in lactate production were strongly correlated with the inhibition of expression of hexokinase II, the key enzyme in the glycolytic pathway. These studies suggest that MRS or (18) F-fluorodeoxyglucose positron emission tomography (FDG PET) detection of changes in glucose metabolism may represent effective noninvasive methods for the monitoring of mTOR targeting therapy in lymphomas and other malignancies. Furthermore, the measurement of glucose metabolic inhibition by MRS or FDG PET imaging may also prove to be effective in monitoring the efficacy of other kinase inhibitors given that the rapamycin-sensitive mTOR lies downstream of many oncogenic signaling pathways.

Medullary carcinoma of the colon: a case series and review of the literature.

BACKGROUND: Most colon cancers are adenocarcinoma of the colon, which present with a typical histological type. However, a relatively newly-recognized subtype, called medullary carcinoma of the colon, has been characterized. This type is generally divided into subtypes of poorly-differentiated and undifferentiated medullary carcinoma. Only a handful of studies have been conducted thus far, mostly focusing on immunohistochemical and clinical characteristics of the disease. PATIENTS AND METHODS: Herein we present two cases seen at our hospital within one academic year. The first is the case of a 79-year-old African-American woman, who presented with generalized weakness and gait unsteadiness ultimately diagnosed with a Stage IIIB medullary carcinoma of the proximal colon at the time of surgery, but later found to have metastases to a single paraesophageal lymph node. The second is a case of a 79-year-old Caucasian woman, who presented with several weeks of malaise, nausea, and diarrhea leading to diagnosis of a stage IIB medullary colon carcinoma now receiving chemotherapy. CONCLUSION: Although these tumors tend to be right-sided and therefore present at an advanced stage, distant metastasis is rare at presentation and is primarily to the liver or regional lymph nodes. Only one study has been performed regarding short-term outcomes, which failed to reach statistical significance, but trended towards better prognosis compared to poorly-differentiated and undifferentiated colonic adenocarcinomas.

A unique case of relapsed B-acute lymphoblastic leukemia/lymphoma as an isolated omental mass.

B-acute lymphoblastic leukemia/lymphoma (B-ALL) is a neoplasm of precursor cells committed to the B-cell lineage. Extramedullary involvement is frequent, with particular predilection for the central nervous system, lymph nodes, spleen, liver, and testis. We report an unusual case of B-ALL relapsing as an isolated omental mass along with bone marrow involvement.