Undifferentiated large cell/rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non-small cell lung cancer (NSCLC): clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases.

Undifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications.

Primary gastrointestinal liposarcoma-a clinicopathological study of 8 cases of a rare entity.

Primary gastrointestinal liposarcoma is rare, and information regarding this entity is largely based on single case studies. We report on 8 patients with primary liposarcoma of the gastrointestinal tract and review the pertinent literature. The cohort includes 6 men and 2 women who ranged in age from 51 to 81 years (median 68.5). Two tumors arose in the stomach, 4 in the small intestine, and 2 in the large intestine. Tumors ranged in size from 2.5 to 14.5 cm (median 7 cm), originated in the submucosa or muscularis propria of the intestinal wall, and frequently protruded into the bowel lumen, resulting in mucosal ulceration and luminal obstruction. Six tumors were dedifferentiated liposarcomas, and 2 were well-differentiated liposarcoma. Surgical excision was performed on all tumors except for 1 case of dedifferentiated liposarcoma. On follow-up, 1 patient with dedifferentiated liposarcoma developed a lytic sacral lesion suspicious for metastasis 4 months after resection of the primary, and another underwent marginal resection and presented with recurrence 4 years later, had tumor re-resection, and was considered disease-free at 6 weeks postsurgery. A third patient with dedifferentiated liposarcoma was alive with unknown disease status at 17 months following surgery, and another patient with dedifferentiated liposarcoma was alive without evidence of disease at 30 months following surgery. No follow-up information on the remaining patients is available. Overall, liposarcomas of the intestinal tract are most frequently high-grade dedifferentiated tumors that are biologically aggressive and require surgical excision with widely negative margins to help reduce the risk of local recurrence and dissemination. Important in the differential diagnosis is malignant gastrointestinal stromal tumor. Care must be taken not to misdiagnose one entity for the other because the correct diagnosis carries important therapeutic implications.

Establishment and Characterization of Small Bowel Neuroendocrine Tumor Spheroids.

Small bowel neuroendocrine tumors (SBNETs) are rare cancers originating from enterochromaffin cells of the gut. Research in this field has been limited because very few patient derived SBNET cell lines have been generated. Well-differentiated SBNET cells are slow growing and are hard to propagate. The few cell lines that have been established are not readily available, and after time in culture may not continue to express characteristics of NET cells. Generating new cell lines could take many years since SBNET cells have a long doubling time and many enrichment steps are needed in order to eliminate the rapidly dividing cancer-associated fibroblasts. To overcome these limitations, we have developed a protocol to culture SBNET cells from surgically removed tumors as spheroids in extracellular matrix (ECM). The ECM forms a 3-dimensional matrix that encapsulates SBNET cells and mimics the tumor micro-environment for allowing SBNET cells to grow. Here, we characterized the growth rate of SBNET spheroids and described methods to identify SBNET markers using immunofluorescence microscopy and immunohistochemistry to confirm that the spheroids are neuroendocrine tumor cells. In addition, we used SBNET spheroids for testing the cytotoxicity of rapamycin.

Loss of PTEN and Increased pAKT Expression Distinguishes Aggressive Low-grade Neuroendocrine Tumors.

A major problem in neuroendocrine pathology is the identification and separation of aggressive low-grade neuroendocrine tumors (LGNETs) from those with a benign or more indolent behavior. Presently there are no known morphologic or molecular parameters which can predict how localized LGNETs will behave. The phosphatase and tensin homolog (PTEN) gene negatively regulates the PI3K-AKT-mTOR pathway and inhibits neoplastic cell survival and proliferation and has recently been identified as a neuroendocrine tumor differentiation marker. We hypothesized loss of PTEN may also identify LGNETs that demonstrate aggressive behavior. We studied PTEN and pAKT expression in 18 LGNETs using specific monoclonal antibodies. Follow up was obtained for a minimum of five years on all patients. 8/18 cases had strong PTEN expression and showed no evidence of disease on >5 years follow-up. 10 cases demonstrated loss of PTEN expression; 9/10 had positive pAKT expression, and 7/9 had recurrence and/or metastases. Lung and appendiceal LGNETs uniformly had high PTEN expression and a markedly better prognosis than their gastroenteropancreatic (GEP) counterparts. Loss of PTEN correlated significantly with the positive expression of pAKT (P=0.0027) and aggressive behavior of LGNETs (p=0.0002). Loss of PTEN and increased pAKT correlated with the metastatic potential of LGNETs (p=0.0011 and 0.0248 respectively). Loss of PTEN and increased pAKT expression distinguishes aggressive LGNETs from those with more indolent behavior.

Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from enterochromaffin cells scattered in the intestinal mucosa of the ileum and jejunum. Loss of one copy of chromosome 18 is the most frequent observed aberration in primary tumors and metastases. The aim of this study was to investigate possible involvement of 5-hydroxymethylcytosine (5hmC), TET1 and TET2 in SI-NETs. METHODS: The analysis was conducted using 40 primary tumors and corresponding 47 metastases. The level of 5hmC, TET1 and TET2 was analyzed by DNA immune-dot blot assay and immunohistochemistry. Other methods included a colony forming assay, western blotting analysis, and quantitative bisulfite pyrosequencing analysis. The effect of the exportin-1 nuclear transport machinery inhibitors on cell proliferation and apoptosis was also explored using two SI-NET cell lines. RESULTS: Variable levels of 5hmC and a mosaic staining appearance with a mixture of positive and negative cell nuclei, regardless of cell number and staining strength, was observed overall both in primary tumors and metastases. Similarly aberrant staining pattern was observed for TET1 and TET2. In a number of tumors (15/32) mosaic pattern together with areas of negative staining was also observed for TET1. Abolished expression of TET1 in the tumors did not seem to involve hypermethylation of the TET1 promoter region. Overexpression of TET1 in a colony forming assay supported a function as cell growth regulator. In contrast to 5hmC and TET1, TET2 was also observed in the cytoplasm of all the analyzed SI-NETs regardless of nuclear localization. Treatment of CNDT2.5 and KRJ-I cells with the exportin-1 (XPO1/CRM1) inhibitor, leptomycin B, induced reduction in the cytoplasm and nuclear retention of TET2. Aberrant partitioning of TET2 from the nucleus to the cytoplasm seemed therefore to involve the exportin-1 nuclear transport machinery. Reduced cell proliferation and induction of apoptosis were observed after treatment of CNDT2.5 and KRJ-I cells with leptomycin B or KPT-330 (selinexor). CONCLUSIONS: SI-NETs are epigenetically dysregulated at the level of 5-hydroxymethylcytosine/ TET1/TET2. We suggest that KPT-330/selinexor or future developments should be considered and evaluated for single treatment of patients with SI-NET disease and also in combinations with somatostatin analogues, peptide receptor radiotherapy, or everolimus.

Loss of expression and prognosis value of alpha-internexin in gastroenteropancreatic neuroendocrine neoplasm.

BACKGROUND: The neuronal intermediate filament alpha-internexin (α-internexin) is a cytoskeleton protein which is involved in the tumor initiation and progression. In this study, we examined the expression and prognosis value of α-internexin in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). METHODS: α-internexin was detected with immunohistochemical staining in 286 tumor specimens from patients with GEP-NENs. Methylation status of α-internexin was evaluated by bisulfite genomic sequencing. We assessed the prognostic value of α-internexin and its correlation with relevant clinicalpathological characteristics. RESULTS: The reduced/loss of expression rate of α-internexin in GEP-NEN was 73.4% (210/286), while the positive expression rate was 26.6% (76/286). The difference of α-internexin deficiency was not statistically significant between gastrointestinal NENs (GI-NENs) and pancreatic NENs (pNENs). However, we found significant difference of reduced/loss of α-internexin expression among different sites of GI-NENs (χ2 = 43.470, P < 0.001). The reduced/loss of expression of α-internexin was significantly associated with poorly differentiation (P < 0.001) and advanced tumor stage (P < 0.001). Univariate analyses showed that reduced/loss of expression of α-internexin predicted worse overall survival (OS) in GEP-NEN patients (P < 0.001), especially in subtype of GI-NENs (P < 0.001). However, in multivariable regression analysis, α-internexin expression was not an independent prognostic factor. The hypermethylation of α-internexin gene was significantly correlated with protein deficiency in GI-NENs, but not in pNENs. Hypermethylation of several CpG sites was significantly associated with poorly differentiated and advanced stage (P values range from 0.018 to 0.044). However, the methylation status of α-internexin was not associated with patient OS. CONCLUSIONS: The expression of α-internexin was highly heterougeneous in different sites of GEP-NENs. The reduced/loss of expression of α-internexin was closely related to tumors with aggressiveness and patient's adverse prognosis. The hypermethylation of the regulatory region examined may be an important epigenetic regulation mechanism of α-internexin deficiency in subtype of GI-NENs.

Neural and neurogenic tumours of the gastroenteropancreaticobiliary tract.

Neural lesions occur uncommonly in the gastroenteropancreaticobiliary tract. However, due to the growing number of screening colonoscopy procedures, polypoid neural lesions of the colon are being recognised increasingly and range from benign tumours to high-grade malignant neoplasms. Morphological variability of neural tumours can be wide, although some entities share pathological features, and, as such, these lesions can be diagnostically challenging. We review the spectrum of pathology of neural tumours in the gastroenteropancreaticobiliary tract, with the goal of providing a practical approach for practising surgical pathologists.

Microcarcinoid arising in patients with long-standing ulcerative colitis: histological analysis.

Some case reports of neuroendocrine tumors and neuroendocrine carcinoma associated with ulcerative colitis (UC) have been published. Most neuroendocrine tumor cases are small lesions corresponding to microcarcinoids (MCs). However, published case reports have presented findings of MCs as single-case reports. Thus, the frequency of MCs is still unclear. In this study, we described the clinical and morphological features of 14 cases of UC-associated MCs and estimated the frequency of MCs. Consecutive patients with UC who underwent complete removal of the large intestine were assessed, and 135 patients were selected. Of the 135 cases, 14 cases (10.4%) in which MC lesions were observed histologically were classified as the MC group, and the remaining 121 cases were classified as the control group. Seven cases in the MC group (50%) exhibited colitic cancer. No cases in either group had distinct carcinoid tumors. All MC lesions were located in the rectum, and the sizes ranged from 0.1 to 5.5 mm. Eight cases (57%) had multiple MC lesions. The frequency of MCs in UC was estimated to be 10.4%. Most cases of MC were quite unlikely to develop into clinically distinct carcinoid tumors. Thus, when MC lesions remain microscopic, they may not represent true neoplasms, which require immediate surgical resection. Because MC often arose in cases with UC complicated by dysplasia or cancer, patients with UC whose rectal biopsies reveal MC may be at high risk of colitic cancer.

Neuroendocrine liver metastases: Vascular patterns on triple-phase MDCT are indicative of primary tumour location.

PURPOSE: To re-evaluate and compare CT features of neuroendocrine liver metastases (NLM) from pancreatic (p) and enteric (e) gastroenteropancreatic (GEP) tumours. MATERIAL AND METHODS: From 2006-2013, all patients with proven GEP-neuroendocrine tumours (NETs) with at least one NLM, no previous treatment were included. On unenhanced, arterial and portal phases, NLMs were characterized as hypo-, iso- or hyperattenuating in consensus by 2 radiologists blinded to clinical data. Enhancement patterns (EP) corresponded to the combination of arterial/portal CT attenuation. RESULTS: 78 patients (43 men, 55%, mean 56±13 yo) and 559NLMs were analyzed. pNLMs were more frequently hypoattenuating on unenhanced CT than eNLMs (72% vs. 57%, p<0.001). 70% of the lesions were hypervascular with no significant difference between pNLMs and eNLMs (p=0.32). eNLMs were more frequently hypoattenuating on portal phase than pNLMs (88% vs. 56%, p<0.001). eNLMs were more frequently hyper/hypo than pNLMs (56% vs. 28%, p<0.001). pNLMs were more frequently hyper/iso than eNLMs (33% vs. 8%, p<0.001). Other NLMs showed various patterns, including hypo/hypo in 12%. CONCLUSION: Most NLMs of GEP tumours are hypervascular but the enhancement pattern on multiphasic CT depends on the primary tumour. These differences are helpful when the primary tumour has not been diagnosed.

Human epididymis protein 4 immunostaining of malignant ascites differentiates cancer of Müllerian origin from gastrointestinal cancer.

BACKGROUND: An accurate diagnosis of cancer of Müllerian origin is required before the initiation of treatment. An overlap in clinical presentation and cytological, histological, or imaging studies with other nongynecological tumors does occur. Therefore, immunocytochemistry markers are used to determine tumor origin. Human epididymis protein 4 (HE4) is overexpressed in tissue of epithelial ovarian cancer (EOC). It has shown to be a sensitive and specific serum marker for EOC and to be of value for the differentiation between EOC and ovarian metastases of gastrointestinal origin. The objective of the current study was to evaluate HE4 immunocytochemistry in malignant ascites for differentiation between cancer of Müllerian origin, including EOC, and adenocarcinomas of the gastrointestinal tract. METHODS: Cytological specimens of 115 different adenocarcinomas (45 EOCs, 46 cases of gastric cancer, and 24 cases of colorectal cancer) were stained for HE4, paired box 8 (PAX8), and other specific markers. RESULTS: 91% of the ascites samples from patients with EOC stained for both HE4 and PAX8. The 4 samples without HE4 staining were a clear cell carcinoma, a low-grade serous adenocarcinoma, an undifferentiated adenocarcinoma, and a neuroendocrine carcinoma. All high-grade serous adenocarcinomas (n = 37, 100%) stained with HE4, compared with 94% that stained positively for PAX8. In cases of gastric or colorectal cancer, 25% and 21% of cases, respectively, stained positive for HE4. No PAX8 staining was observed in colorectal or gastric adenocarcinomas. CONCLUSIONS: HE4 staining in ascites is feasible and appears to have a high sensitivity for high-grade serous ovarian cancer. HE4 is a useful addition to the current panel of immunocytochemistry markers for the diagnosis of EOC and for differentiation with gastrointestinal adenocarcinomas. Cancer Cytopathol 2017;125:197-204. © 2016 American Cancer Society.

Prognostic significance of the frequency of primary cilia in cells of small bowel and colorectal adenocarcinoma.

PURPOSE: The primary cilium is a solitary, sensory, immotile microtubule-based structure that arises from the centrosome and is projected from the surface of most human cell types. It has been hypothesized that primary cilia could serve as a tumor suppressor organelle. The objective of this pilot study was to investigate the presence and frequency of primary cilia in cells of small bowel and colorectal adenocarcinoma and to evaluate the prognostic significance of their frequency. METHODS: The presence of primary cilia in cells in samples of small bowel (8 patients) and colorectal adenocarcinoma (32 patients) was evaluated. The primary cilia of cells were immunofluorescently labeled using primary monoclonal anti-acetylated agr;-tubulin antibody and cell nuclei were labeled using DAPI. RESULTS: Primary cilia were identified in all examined specimens. The median frequency of primary cilia was 0.49% in cells of small bowel cancer and 0.22% in cells in colorectal cancer. Overall survival according to frequency of primary cilia in all intestinal adenocarcinomas was significantly longer in patients with higher frequency (≥ 0.187) than in patients with lower frequency of primary cilia (< 0.187) in univariate analysis (p=0.007) and also in the Cox proportional hazard model (p=0.032). Overall survival according to frequency of primary cilia in colorectal adenocarcinoma was significantly longer in patients with higher frequency (≥ 0.187) than in patients with lower frequency of primary cilia (< 0.187) (p=0.028). CONCLUSIONS: The present pilot study provides the first evidence of the prognostic significance of the frequency of primary cilia in small bowel and colorectal adenocarcinoma. Because of significantly higher median frequency of primary cilia in the rare small bowel adenocarcinoma than in the frequent colorectal adenocarcinoma (p<0.001), the results of this study support a potential role for primary cilia as a biomarker in these types of cancer.

Jejunitis and brown bowel syndrome with multifocal carcinogenesis of the small bowel.

This is the first report describing a case where prolonged, severe malabsorption from brown bowel syndrome progressed to multifocally spread small bowel adenocarcinoma. This case involves a female patient who was initially diagnosed with chronic jejunitis associated with primary diffuse lymphangiectasia at the age of 26 years. The course of the disease was clinically, endoscopically, and histologically followed for 21 years until her death at the age 47 due to multifocal, metastasizing adenocarcinoma of the small bowel. Multiple lipofuscin deposits (so-called brown bowel syndrome) and severe jejunitis were observed microscopically, and sections of the small bowel showed dense lymphoplasmacytic infiltration of the lamina propria as well as blocked lymphatic vessels. After several decades, multifocal nests of adenocarcinoma cells and extensive, flat, neoplastic mucosal proliferations were found only in the small bowel, along with a loss of the mismatch repair protein MLH1 as a long-term consequence of chronic jejunitis with malabsorption. No evidence was found for hereditary nonpolyposis colon carcinoma syndrome. This article demonstrates for the first time multifocal carcinogenesis in the small bowel in a malabsorption syndrome in an enteritis-dysplasia-carcinoma sequence.

SATB2 is a sensitive marker for lower gastrointestinal well-differentiated neuroendocrine tumors.

Special AT-rich sequence binding protein-2 (SATB2) is selectively expressed in the lower gastrointestinal tract mucosa and has been identified as a sensitive marker for colorectal adenocarcinomas. The goal of this study was to investigate the expression of SATB2 in well-differentiated neuroendocrine tumors to explore its potential as a diagnostic marker for hindgut well-differentiated neuroendocrine tumors. Immunohistochemical staining with a monoclonal antibody to SATB2 was performed on full tissue blocks in 167 well-differentiated neuroendocrine tumors of various origins. The staining was semi-quantitatively scored as 0 (no tumor cell staining), 1+ (1-25%), 2+ (26-50%), 3+ (51-75%) and 4+ (76-100%). Positive SATB2 staining was seen in 17% foregut (14/84, 12/66 primary and 2/18 metastatic), 12% midgut (3/22, 3/18 primary and 0/7 metastatic), and 90% hindgut (52/58, 44/49 primary and 8/9 metastatic) well differentiated neuroendocrine tumors. Most hindgut well-differentiated neuroendocrine tumors (41/58) showed 4+ staining. The specificity of SATB2 for foregut, midgut and hindgut well-differentiated neuroendocrine tumors was 34%, 54% and 84%, respectively. Our results indicate that SATB2 is a sensitive marker for hindgut well-differentiated neuroendocrine tumors though it is not entirely specific. SATB2 should be included in the immunohistochemical panel in working out metastatic well-differentiated neuroendocrine tumor of an unknown origin.

Surgery of upper GI gastrointestinal stromal tumors: our experience, prognostic analysis.

BACKGROUND/AIMS: To review our treatment experience of gastrointestinal stromal tumors (GISTs) of the upper gastrointestinal tract and identify the prognostic factors that influence tumor recurrence. METHODOLOGY: Data of 46 consecutive patients with upper GI GISTs who underwent surgery from 1988 to 2011 were reviewed. The overall and disease-free survival rates and influence of clinicopathologic variables on disease-free survival rate were evaluated. RESULTS: The median age was 64 years (range, 20-86 years). R0 resections were performed in 43 (93.5%) patients. With a median follow-up time of 33 months (1-275 months), there were 5 (10.9%) recurrences and 2 mortalities in the high-risk group. The overall survival and recurrence-free survival rates at 5 years were 92.1% and 84.6%, respectively. Male gender, tumor size of >10 cm, high numbers of mitotic figures, R1 resection, high risk according to the Joensuu criteria, and a Ki-67 index of >10% were associated with a poor prognosis. CONCLUSIONS: Surgical resection of low- and intermediate-risk GISTs has excellent results. High counts of mitotic figures, male gender, incomplete resection, large tumor size, and a high Ki-67 index are associated with a poor prognosis.

Clinical characteristics and prognostic factors of gastroenteropancreatic neuroendocrine tumors: a single center experience in China.

BACKGROUND/AIMS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a unique subgroup of tumors in the digestive system but with great clinical heterogeneity. The information on clinical characteristics and prognostic factors of Chinese patients is rather limited. METHODOLOGY: We retrospectively analyzed the clinical features, prognostic factors of this disease in a consecutive cohort (N=294) between January 2007 and December 2012. RESULTS: Functioning tumors accounted for 9.2%. Rectum was the most predominant GEP-NETs locations. Abdominal pain occurred in 46.5% patients which was the most common initial symptom. G1, G2 and G3 tumors accounted for 41.5%, 34.7% and 23.8%, respectively. Endoscopy provided the highest detection rate of 95.7%. Consistence between endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNAB) and surgically obtained histological Ki-67 index was 36.4%. Serum CgA test showed a 80.0% consistence with the tissue biopsy. The median follow up duration was 2.8 years (0.02-5.90 years), the median survival was 4.8 years, overall 5-year survival rate was 69.6%. We found colonic localization, tumor size larger than 20 mm, G3 tumor and metastasis were associated with worse outcome (p<0.05). CONCLUSION: We found both consistence and differences in GEP-NETs characteristics between our study and previous reports.

NKX6-1 Is a Novel Immunohistochemical Marker for Pancreatic and Duodenal Neuroendocrine Tumors.

NKX6-1 is a homeobox transcription factor participating in the development and regulation of endocrine function of pancreatic islets. This study evaluated the potential use of NKX6-1 as a diagnostic marker for well-differentiated neuroendocrine tumors (WDNETs). In total, 178 primary and 26 metastatic WDNETs of different origins were analyzed through immunohistochemistry for NKX6-1, TTF-1, CDX2, ISL1, and polyclonal PAX8. NKX6-1 was expressed in 36 of the 44 (82%) primary pancreatic WDNETs, 12 of the 18 (67%) primary duodenal WDNETs, and rarely in pulmonary, gastric, and appendiceal WDNETs. The specificity of using NKX6-1 as a marker for pancreatic and duodenal WDNETs is 93%. Of the 26 metastatic WDNETs, NKX6-1 was expressed only in the tumors of pancreatic origin (sensitivity: 63%, specificity: 100%). The combinatorial use of NKX6-1, CDX2, TTF-1, and ISL1 distinguished WDNETs of different origins with high specificity. Our results indicated that the inclusion of NKX6-1 in an immunohistochemical panel will be beneficial for identifying the primary sites of WDNETs.

Detection of intestinal cancer by local, topical application of a quenched fluorescence probe for cysteine cathepsins.

Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional colonoscopy readily detects the majority of premalignant lesions, which exhibit raised morphology. However, lesions that are flat and depressed are often undetected using this method. Therefore, there is a need for molecular-based contrast agents to improve detection rates over conventional colonoscopy. We evaluated a quenched fluorescent activity-based probe (qABP; BMV109) that targets multiple cysteine cathepsins that are overexpressed in intestinal dysplasia in a genetic model of spontaneous intestinal polyp formation and in a chemically induced model of colorectal carcinoma. We found that the qABP selectively targets cysteine cathepsins, resulting in high sensitivity and specificity for intestinal tumors in mice and humans. Additionally, the qABP can be administered by either intravenous injection or by local delivery to the colon, making it a highly valuable tool for improved detection of colorectal lesions using fluorescence-guided colonoscopy.

Evaluation of cytotoxic and apoptotic effects of individual and mixed 7-ketophytosterol oxides on human intestinal carcinoma cells.

Phytosterol oxidation products (POPs) are constituents of the human diet. Definitive information on the toxic or biological effects of POPs is limited and in some cases contradictory. This study evaluates the cytotoxicity of four individual 7-ketophytosterol oxides, including 7-ketositosterol (7K-SI), 7-ketocampesterol (7K-CA), 7-ketobrassicasterol (7K-BR), 7-ketostigmasterol (7K-ST), and a mixture of 7-ketophytosterols (7K-MIX) toward a human intestinal carcinoma (HIC) cell line. Results showed that all tested compounds reduced cell proliferation in a dose-dependent manner; especially 7K-SI and 7K-CA exhibited higher activities. Both compounds increased early apoptotic cells and caused cell cycle arrest in the G1 phase with cell accumulation in the S phase. No evidence of cell death was observed induced by 7K-ST and 7K-MIX. Furthermore, 7K-SI, 7K-CA, and 7K-BR induced apoptosis by enhancing caspase-3 activity and the modulatory effects of Bcl-2, while 7K-ST and 7K-MIX did not involve caspase-3 activation and Bcl-2 down-regulation.