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Despite reports of sex steroid receptor and COX2 expression in desmoid‐type fibromatosis, responses to single agent therapy with anti‐estrogens and non‐steroidal anti‐inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co‐express these targets. Clearly, further understanding of the signaling pathways deregulated in desmoid tumors is essential for the development of targeted molecular therapy. Transforming growth factor–β (TGFβ) and bone morphogenetic proteins (BMP) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGFβ superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and six samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGFβ family signaling pathways, β–catenin, sex steroid hormone receptors and COX2 were assessed using immunohistochemistry; patterns of co–expression were explored via correlational statistical analyses. In addition to β–catenin, immunoreactivity for phosphorylated SMAD2/3 (indicative of active TGFβ signaling) and COX2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD1/5/8 were detected in only a minority of cases. Transforming growth factor–β receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor–β was present in all cases studied. Transforming growth factor–β signaling appears to be activated in desmoid‐type fibromatosis and phosphorylated SMAD2/3 and COX2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor–β and COX2 co‐expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX2 inhibitors should be considered.

We examined Ki-67 heterogeneity within single and between synchronous liver metastases of small intestine neuroendocrine tumors. There were 27 patients (10 men and 17 women) with two or more liver metastases. The Ki-67 index was used to classify the tumors into World Health Organization grade 1, 2, or 3. The association between Ki-67 heterogeneity and tumor size of liver metastases was analyzed. Correlation of tumor grade with patient survival was also evaluated. Primary tumors from 20 patients were graded, including 17 grade 1 and three grade 2. A total of 188 liver metastases were resected, including 122 (65%) grade 1, 47 (25%) grade 2, and 19 (10%) grade 3. The highest tumor grade was grade 1 in 10 (37%), grade 2 in nine (33%), and grade 3 in eight (30%) patients. Patients with one or more grade 3 liver lesions had a shorter progression-free survival compared with those with grade 1/2 tumors (P < .001). A positive association was found between tumor size and Ki-67 index (P = .04), as well as between tumor size and intratumoral Ki-67 heterogeneity (P < .001). Intratumoral and intertumoral Ki-67 heterogeneity is common and positively correlated with tumor size. The presence of one or more grade 3 liver lesions predicts a worse prognosis.

Expression of the p63 tumor suppressor protein has been reported in the mononuclear stromal cells of giant cell tumor of the bone, which may represent osteoblast-precursor cells. Only a limited number of osteoblastic tumors have been studied for p63 expression thus far. We therefore examined whether p63 may serve as a marker for osteoblastic differentiation in osteosarcomas or as a differential diagnostic marker to distinguish osteoblastoma from osteosarcoma. Immunohistochemical stains for p63 were performed on a tissue microarray containing 71 chemotherapy naïve biopsy samples of osteosarcoma, 21 whole sections of osteosarcoma, and 8 osteoblastomas. Nuclear p63 was detected in seven of eight osteoblastomas but was restricted to stromal cells within primitive, immature-appearing areas of osteoid deposition. Although only 7 of 71 (10 %) biopsy samples of osteosarcoma represented on the tissue microarray were positive for p63, 7 of 21 (33 %) osteosarcomas were positive when whole tissue sections were evaluated. Although p63 is detected in most osteoblastomas, it is also observed in a significant subset of osteosarcomas, severely limiting its utility in distinguishing between benign and malignant osteoblastic tumors. The relatively low prevalence of p63 expression in osteosarcoma would also seem to preclude its use as a marker of osteoblastic differentiation in skeletal sarcomas.

Objectives: We examined Ki-67 heterogeneity within single and between synchronous liver metastases of small intestine neuroendocrine tumors. Methods: There were 27 patients (10 men and 17 women) with two or more liver metastases. The Ki-67 index was used to classify the tumors into World Health Organization grade 1, 2, or 3. The association between Ki-67 heterogeneity and tumor size of liver metastases was analyzed. Correlation of tumor grade with patient survival was also evaluated. Results: Primary tumors from 20 patients were graded, including 17 grade 1 and three grade 2. A total of 188 liver metastases were resected, including 122 (65%) grade 1, 47 (25%) grade 2, and 19 (10%) grade 3. The highest tumor grade was grade 1 in 10 (37%), grade 2 in nine (33%), and grade 3 in eight (30%) patients. Patients with one or more grade 3 liver lesions had a shorter progression-free survival compared with those with grade 1/2 tumors (P < .001). A positive association was found between tumor size and Ki-67 index (P = .04), as well as between tumor size and intratumoral Ki-67 heterogeneity (P < .001). Conclusions: Intratumoral and intertumoral Ki-67 heterogeneity is common and positively correlated with tumor size. The presence of one or more grade 3 liver lesions predicts a worse prognosis.

Despite reports of sex steroid receptor and COX 2 expression in desmoid‐type fibromatosis, responses to single agent therapy with anti‐estrogens and non‐steroidal anti‐inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co‐express these targets. Clearly, further understanding of the signaling pathways deregulated in desmoid tumors is essential for the development of targeted molecular therapy. Transforming growth factor–β ( TGF β) and bone morphogenetic proteins ( BMP ) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGF β superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and six samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGF β family signaling pathways, β–catenin, sex steroid hormone receptors and COX 2 were assessed using immunohistochemistry; patterns of co–expression were explored via correlational statistical analyses. In addition to β–catenin, immunoreactivity for phosphorylated SMAD 2/3 (indicative of active TGF β signaling) and COX 2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD 1/5/8 were detected in only a minority of cases. Transforming growth factor–β receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor–β was present in all cases studied. Transforming growth factor–β signaling appears to be activated in desmoid‐type fibromatosis and phosphorylated SMAD 2/3 and COX 2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor–β and COX 2 co‐expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX 2 inhibitors should be considered.

This chapter explains how carcinoid tumors arise from neuroendocrine cells. They comprise part of a larger group of cancers referred to as neuroendocrine tumors, which include islet cell tumors, large cell neuroendocrine tumors, atypical carcinoids and small cell carcinomas. Carcinoid tumors can arise anywhere in the body. Typical carcinoids are composed of monotonously similar cells with round nuclei, pink granular cytoplasm, and few mitosis. Serotonin, tachykinins and prostaglandins all activate receptors which result in smooth muscle contraction and vasodilatation. Secretion of these neuropeptides usually occurs in concert. For instance, the amount of tachykinin secretion in patients with carcinoid tumors correlates with the rate of serotonin secretion. Serotonin, tachykinins and prostaglandins all activate receptors which result in smooth muscle contraction and vasodilatation. Secretion of these neuropeptides usually occurs in concert. For instance, the amount of tachykinin secretion in patients with carcinoid tumors correlates with the rate of serotonin secretion. Somatostatin binds to somatostatin receptors expressed on 80% of carcinoid tumors.

An all-oral regimen of etoposide and cyclophosphamide was developed for use in poor-prognosis extensive disease small-cell lung cancer. Limited pharmacokinetic sampling was used to derive a pharmacodynamic model predictive of myelosuppression early in the course of therapy. Eligible patients were chemotherapy-naive and had extensive disease small-cell lung cancer with either SWOG performance status 2 or serum albumin <3.5 g/dl. The first cohort (n = 18) received etoposide orally at 50 mg daily and cyclophosphamide orally at 50 mg daily days 1-14 every 28 days. Due to good hematologic tolerance, the second cohort (n = 39) received both agents orally at 50 mg twice daily days 1-14 every 28 days. Plasma etoposide levels were determined in samples drawn at baseline, and at 1 h, 2 h, and 23.5 h (trough) after the first dose. Linear regression analysis was used to determine pharmacokinetic and demographic parameters predictive of myelosuppression. A total of 173 treatment cycles were delivered. Patients on the daily regimen had a 22% response rate (complete and partial), a 22% unconfirmed response rate, and a 5-month median survival, while patients on the twice-daily regimen had a 28% response rate (complete and partial), a 13% unconfirmed response rate, and a 7-month median survival. Granulocytopenia and alopecia were the most common toxicities seen. Significant granulocytopenia could be predicted for the twice-daily regimen according to the formula ln(AGC nadir)=7.80 - 1.88(trough), with an increased incidence of granulocytopenia if the etoposide trough value was >/=1.49 microg/ml. Oral etoposide and oral cyclophosphamide given days 1-14 every 28 days is well tolerated and results in an acceptable response rate and median survival in poor-prognosis (poor performance status or low serum albumin) extensive disease small-cell lung cancer. A trough etoposide level obtained within 24 h of starting therapy can predict severe granulocytopenia.

Carcinoid tumor can arise anywhere in the body. About 70% originate within three organs: the appendix, the small intestine, and the rectum. Most appendiceal carcinoids are small, do not cause symptoms, and are diagnosed incidentally during appendectomy. Larger tumors are found more frequently with small bowel than with appendiceal carcinoids. Most small bowel carcinoids occur in the ileum. Carcinoids may cause mesenteric fibrosis with partial bowel obstruction. Patients may have abdominal symptoms for months before diagnosis. Half of the rectal carcinoids are found incidentally at routine sigmoidoscopy. Rectal carcinoids do not secrete serotonin and are not associated with the carcinoid syndrome. The most dramatic manifestation of carcinoid tumors is the carcinoid crisis. This is observed in patients who have more intense syndromes associated with foregut carcinoids or increased 5-hydroxyindole acetic acid. Treatment of localized carcinoid tumors is surgical resection. Carcinoids smaller than 2 cm are usually cured.

Background Clinical trials are essential to advancing cancer treatments, yet fewer than 10% of adults with cancer enroll in trials, and many studies fail to meet accrual targets. Artificial intelligence (AI) could improve identification of appropriate trials for patients, but sharing AI models trained on protected health information remains difficult due to privacy restrictions. Methods We developed MatchMiner-AI, an open-source platform for clinical trial search and ranking trained entirely on synthetic electronic health record (EHR) data. The system extracts core clinical criteria from longitudinal EHR text and embeds patient summaries and trial \"spaces\" (target populations) in a shared vector space for rapid retrieval. It then applies custom text classifiers to assess whether each patient-trial pairing is a clinically reasonable consideration. The pipeline was evaluated on real clinical data. Results Across retrospective evaluations on real EHR data, the fine-tuned pipeline outperformed baseline text-embedding approaches. For trial-enrolled patients, 90% of the top 20 recommended trials were relevant matches (compared to 17% for the baseline model). Similar improvements were noted for patients who received standard-of-care treatments (88% of the top 20 matches were relevant, compared to 14% for baseline). Text classification modules demonstrated strong discrimination (AUROC 0.94-0.98) for evaluating candidate patient-trial space pair eligibility; incorporating these components consistently increased mean average precision to ~ 0.90 across patient- and trial-centric use cases. Synthetic training data, model weights, inference tools, and demonstration frontends are publicly available. Conclusions MatchMiner-AI demonstrates an openly accessible, privacy-preserving approach to distilling a clinical trial matching AI pipeline from LLM-generated synthetic EHR data.