"Stromatogenesis" and tumor progression

"Stromatogenesis" is the formation of new stroma occurring, in parallel with the neoplastic process, at sites of active tumor invasion, i.e., at the free surface of a developing exophytic tumor, at the invading tumor front of an advancing endophytic tumor, and at sites of tumor metastasis, wherein the newly formed stroma disrupts the continuity of normal structures, cleaving paths for the invading tumor cells. Stroma is also present at the heart of the tumor, but only as a secondary event following tumor advancement and subsequent incorporation of its periphery into inner tumor areas. The new stroma, composed of stromal cells and extracellular matrix (ECM), is loose and edematous at the expanding tumor fronts, and rather dense in central tumor areas and sites of tumor metastasis. The stromal cells facing tumor invasion are intensely proliferating (high MIB-1 index) spindle-shaped cells, alpha-smooth muscle actin positive, and loaded with thymidine phosphorylase (TP) and SPARC (secreted protein acidic and rich in cysteine). The associated ECM is rich in collagen III, SPARC, and new blood vessels (CD31) but is depleted of collagen I and fibronectin. These constitutional changes render stromatogenesis amenable to tumor cell invasion and are, in cases of incipient neoplasia, a prospective criterion of early stromal invasion. Other stromal cell or ECM constituents, such as the lactate dehydrogenase-5 (LDH-5), the acidic fibroblast growth factor (aFGF), the basic FGF (bFGF), and the collagens II and IV, remain unchanged, and others are negative: myosin, desmin, S-100 protein and epidermal growth factor receptor (EGFR). The mechanism of stromatogenesis is obscure but is probably stimulated by specific stromatogenic growth factors, released by neoplastic and inflammatory cells. It appears that the process is neither neoplastic nor reactive, but rather is a, hereto unexplained, phenomenon of host's complicity in tumor progression.     

Successful response in a case of severe pustular psoriasis after interleukin‐1β inhibition

Generalized pustular psoriasis (GPP) is a severe type of psoriasis accompanied by systemic and often life‐threatening manifestations. The efficacy of the interleukin (IL)‐1 antagonist anakinra in cases of GPP underscores the role of IL‐1 in disease pathogenesis. We present a case of a middle‐aged man who developed an abrupt and severe form of GPP with severe eosinophilia and cholestatic hepatitis. The patient received salvage treatment with a combination of glucocorticoids, hydroxyurea and imatinib, while administration of the IL‐1 inhibitor anakinra resulted in remission of hepatitis and a significant skin improvement. However, due to persistent hypersensitivity skin reactions, anakinra was withdrawn and replaced with the anti‐IL‐1β antagonist canakinumab. As a result of canakinumab, the patient's skin completely cleared, while no systemic manifestations recurred. After 1 year of continuous canakinumab therapy, the patient remained virtually free of symptoms, while the drug was well tolerated.     

Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study.

PURPOSE: Amifostine (WR-2721) is an important cytoprotective agent. Although intravenous administration is the standard route, pharmacokinetic studies have shown acceptable plasma levels of the active metabolite of amifostine (WR-1605) after subcutaneous administration. The subcutaneous route, due to its simplicity, presents multiple advantages over the intravenous route when amifostine is used during fractionated radiotherapy. PATIENTS AND METHODS: Sixty patients with thoracic, 40 with head and neck, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled onto a randomized phase II trial to assess the feasibility, tolerance, and cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine 500 mg, diluted in 2.5 mL of normal saline, was injected subcutaneously 20 minutes before each radiotherapy fraction. RESULTS: The subcutaneous amifostine regimen was well tolerated by 85% of patients. In approximately 5% of patients, amifostine therapy was interrupted due to cumulative asthenia, and in 10%, due to a fever/rash reaction. Hypotension was never noted, whereas nausea was frequent. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (P <.04). The delays in radiotherapy because of grade 3 mucositis were significantly longer in the group of patients treated with radiotherapy alone (P <.04). Amifostine significantly reduced the incidence of acute perineal skin and bladder toxicity (P <.0006). CONCLUSION: Subcutaneous administration of amifostine is well tolerated, effectively reduces radiotherapy's early toxicity, and prevents delays in radiotherapy. The subcutaneous route is much simpler and saves time compared with the intravenous route of administration and can be safely and effectively applied in the daily, busy radiotherapy practice.     

Total and caspase-cleaved cytokeratin 18 in chronic cholecystitis: A prospective study

Background  

Cell death mode has been studied in cancer, autoimmune, and neurodegenerative diseases. In this study, apoptosis and necrosis are investigated for the first time in patients with chronic calculous cholecystitis.     

Endometrial adenocarcinoma: beliefs and scepticism

The incidence of endometrial adenocarcinoma is high in North America and northern Europe, and low in Asia and Africa. This variance in frequency rates occurred in the late 1970s and its real cause has remained in question since. There is a widespread belief that endometrial adenocarcinomas associated with endometrial hyperplasia have a much better prognosis than those related to endometrial atrophy. This view is, in general terms, true but only because a high proportion of tumors arising from an atrophic endometrium are of serous/papillary, clear cell, or Grade 2-3 endometrioid carcinomas, in contrast to those developing from a hyperplastic endometrium, which are nearly all G1 endometrioid adenocarcinomas. These adenocarcinomas have, however, an excellent prognosis, no matter whether they are related to hyperplasia or atrophy, and taxonomically they form a single tumor group. In this regard, it is most reasonable to separate endometrial carcinomas into low- and high-grade tumors. The first are formed solely of G1 or "authentic" endometrioid adenocarcinomas, i.e., endometrioid neoplasms composed in their entirety of glandular elements without having traces of nonsquamous solid components. The high-grade tumors are formed of both endometrioid Grade 2-3 adenocarcinomas and nonendometrioid carcinomas-all of particularly aggressive behavior. The question of grading endometrioid adenocarcinomas in a precise and reproducible way becomes obvious. It is also believed that endometrial adenocarcinomas associated with endometrial hyperplasia are estrogen-primed, while those related to endometrial atrophy are deprived of hormonal stimulation. However, as we have shown in this laboratory recently, estrogen stimulation may be very common in endometrial neoplasms developing in an atrophic endometrium. For indeed most, if not all, postmenopausal atrophic endometria harboring adenocarcinomas contain actively proliferating glands, with high Ki-67 proliferation index, high epidermal growth factor receptor (EGFR) activity, high microvessel density (MVD), and rich in estrogen and progesterone receptors (ER and PR), indicative of a continuous low-level estrogenic stimulation. That there is a number of endometrial carcinomas that tend to develop in a milieu of antiestrogenic domination, following treatment for breast carcinoma, this may well represent a form of breast-endometrial hereditary disease and, certainly, merits further investigation.     

Phytobezoars as a cause of small bowel obstruction associated with a carcinoid tumor of the ileocecal area

Carcinoid tumors are slowly growing malignant neoplasms associated with an indolent clinical course. About 60% of such tumors are located within the gastrointestinal tract. We describe an unusual case of small bowel obstruction associated with a carcinoid tumor of the ileum. A 70-year-old woman was presented with abdominal pain, vomiting, and clinical signs of mechanical bowel obstruction. X-ray and CT-scan of the abdomen showed hydroaeric levels and the presence of intraluminal hyperdense "stones", presumably of gallbladder origin. A diagnostic laparotomy revealed that a large part of the terminal ileus was edematous, with prominent evidence of intestinal loop adhesions. The edematous part of the ileum was resected. Incision of the intestinal wall revealed a 2-cm soft mass at 8 cm from the ileocecal valve, where the presence of ten fruit pits obstructed the intestinal cavity. Histopathological examination confirmed the diagnosis of a carcinoid tumor. An interesting case of small-bowel obstruction with a double cause is presented: an ileal carcinoid and fruit pit bezoars. The pathophysiology of the obstruction is discussed.     

Differential assessment of vascular survival ability and tumor angiogenic activity in colorectal cancer.

BACKGROUND: The process of new vessel formation during neoplastic transformation and growth (neoangiogenesis) comprises proliferation, sprouting, and migration of endothelial cells within normal tissues adjacent to the tumor. These new vessels are directed toward the tumor invading edge and provide the bed for the subsequent growth of new tumor layers. We previously showed various degrees of decreasing vascular density in tumor layers once these lose contact with the normal tissue. This suggests that, apart from angiogenic factors, vascular survival factors contribute equally to the structure of the tumoral vasculature. This "vascular survival" potential can be assessed by comparatively examining the vascular density in peripheral and inner tumor areas. EXPERIMENTAL DESIGN: Using immunohistochemistry with the anti-CD31 monoclonal antibody, we assessed the tumor angiogenic activity (TAA) and vascular survival ability (VSA) in a sample of 242 patients with Dukes' stage A (90 patients), B (73 patients), and C (79 patients) colorectal cancer treated with surgery alone. RESULTS: Overall, High TAA and VSA were significantly related with poor prognosis (P = 0.03; hazard ratio, 1.9 and P = 0.001; hazard ratio, 2.7, respectively). In multivariate analysis, VSA was revealed as the most potent and independent prognostic factor (P = 0.0001; t ratio, 4.5), followed by vascular invasion (P = 0.0001; t ratio, 4.4) and stage (P = 0.01; t ratio, 2.5). Tumors with high TAA and high VSA had a significantly higher risk to develop liver metastasis (P = 0.0003). CONCLUSIONS: Assessment of VSA in addition to TAA provides additional important prognostic information in patients with colorectal cancer and can be a useful tool in the recruitment of patients who would benefit from angiostatic versus angiotoxic therapies.     

Prognostic role of angiogenesis in operable carcinoma of the gallbladder

The prognostic significance of intratumoral angiogenesis was investigated in 62 patients with stage I-III carcinomas of the gallbladder treated with simple cholecystectomy. Microvessel density (MVD) was assessed immunohistochemically, using the alkaline phosphatase/anti-alkaline phosphatase method and the monoclonal antibody CD31. The mean MVD was 30.5 vessels per x 200 optical field. Using the thirty-third and the sixty-sixth percentile, the patients were grouped into three MVD categories: low (MVD 9-18; 20 patients), medium (MVD 19-31; 20 patients), and high (MVD 32-86; 22 patients). A high MVD was more frequent in well-differentiated adenocarcinomas compared with moderately and poorly differentiated tumors (p = 0.04), but there was no statistically significant association between MVD and T stage, or patients' age or sex. Multivariate analysis, including MVD, T stage, and histologic grade, showed that MVD was a significant independent prognostic factor in carcinomas of the gallbladder (p = 0.001, t ratio 3.3). It is believed that the assessment of intratumoral angiogenesis in patients with operable gallbladder carcinomas may be useful in predicting prognosis and, perhaps, in decision making for postoperative adjuvant treatment.