Pathologic Basis of Diseaseby Stanley L. Robbins is really the fourth edition of hisPathology. Appropriate updating and addition enhance the otherwise identical format, sequence, writing, and illustrations. So many medical students have benefited from this source that it may be the best known general book in the field. I recommend it even more now. Like his former texts, this will be enjoyed for its readability. He clearly lays out a great deal of information. When he includes minutiae, the reasons are clear and one feels that all the material is pertinent. Robbins keeps the whole field in perspective—that is, he does not dwell so long or so heavily on pathologic anatomy or pathogenesis as to tempt the reader to overlook clinical presentation or prognosis. A great strength of the subject of pathology is that it bonds strongly with many other medical sciences and specialties and thus occupies the

Pathologic Basis of Disease

Tumor necrosis factor or tumor promoting factor

Cachexia is a syndrome characterized by wasting of skeletal muscle and contributes to nearly one-third of all cancer deaths. Cytokines and tumor factors mediate wasting by suppressing muscle gene products, but exactly which products are targeted by these cachectic factors is not well understood. Because of their functional relevance to muscle architecture, such targets are presumed to represent myofibrillar proteins, but whether these proteins are regulated in a general or a selective manner is also unclear. Here we demonstrate, using in vitro and in vivo models of muscle wasting, that cachectic factors are remarkably selective in targeting myosin heavy chain. In myotubes and mouse muscles, TNF-α plus IFN-γ strongly reduced myosin expression through an RNA-dependent mechanism. Likewise, colon-26 tumors in mice caused the selective reduction of this myofibrillar protein, and this reduction correlated with wasting. Under these conditions, however, loss of myosin was associated with the ubiquitin-dependent proteasome pathway, which suggests that mechanisms used to regulate the expression of muscle proteins may be cachectic factor specific. These results shed new light on cancer cachexia by revealing that wasting does not result from a general downregulation of muscle proteins but rather is highly selective as to which proteins are targeted during the wasting state.

/pdf/cancer-cachexia-is-regulated-by-selective-targeting-of-1xkh2kvjj3.pdf

Cancer cachexia is regulated by selective targeting of skeletal muscle gene products

The present invention relates to methods and reagents useful for modulating gene expression in various applications such as therapeutic, diagnostic, target assessment and genome discovery applications. Specifically, the present invention relates to synthetic chemically modified small nucleic acid molecules capable of mediating RNA interference (RNAi) to a target nucleic acid sequence, such as short interfering nucleic acids (siNA), short interfering RNA (siRNA), double stranded RNA (dsRNA). ), MicroRNA (miRNA), and short hairpin RNA (shRNA) molecules. Small nucleic acid molecules are useful in the treatment of any disease or condition that responds to regulation of gene expression in a cell, tissue or organism.

RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING CHEMICALLY MODIFIED SHORT INTERFERING NUCLEIC ACID (siNA)

Skeletal muscle atrophy and weakness are thought to be stimulated by tumor necrosis factor alpha (TNF-alpha) in a variety of chronic diseases. However, little is known about the direct effects of TNF-alpha on differentiated skeletal muscle cells or the signaling mechanisms involved. We have tested the effects of TNF-alpha on the mouse-derived C2C12 muscle cell line and on primary cultures from rat skeletal muscle. TNF-alpha treatment of differentiated myotubes stimulated time- and concentration-dependent reductions in total protein content and loss of adult myosin heavy chain (MHCf) content; these changes were evident at low TNF-alpha concentrations (1-3 ng/ml) that did not alter muscle DNA content and were not associated with a decrease in MHCf synthesis. TNF-alpha activated binding of nuclear factor kappaB (NF-kappaB) to its targeted DNA sequence and stimulated degradation of I-kappaBalpha, an NF-kappaB inhibitory protein. TNF-alpha stimulated total ubiquitin conjugation whereas a 26S proteasome inhibitor (MG132 10-40 microM) blocked TNF-alpha activation of NF-kappaB. Catalase 1 kU/ml inhibited NF-kappaB activation by TNF-alpha; exogenous hydrogen peroxide 200 microM activated NF-kappaB and stimulated I-kappaBalpha degradation. These data demonstrate that TNF-alpha directly induces skeletal muscle protein loss, that NF-kappaB is rapidly activated by TNF-alpha in differentiated skeletal muscle cells, and that TNF-alpha/NF-kappaB signaling in skeletal muscle is regulated by endogenous reactive oxygen species.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.12.10.971

Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-κB activation in response to tumor necrosis factor α

The present study was undertaken to evaluate the relationship between serum tumor necrosis factor (TNF) and cachexia in patients with prostate cancer TNF levels were determined in 110 serum samples from prostate cancer patients by an enzyme immunoassay Serum TNF activity was positive in 76% of the patients with relapsed disease, whereas only 11% of the untreated patients and 0% of the patients in remission as a result of endocrine therapy were positive The serum total protein and albumin levels, hemoglobin levels, and body mass index of the patients with elevated serum TNF levels were significantly lower (P < 005) than the corresponding values in patients with undetectable serum TNF levels The serum TNF levels of patients with serum albumin levels of <35 g/dl, serum total protein levels of <70 g/dl, hemoglobin levels of <110 g/dl, and a body mass index of <21 kg/m2 were significantly higher (P < 005) than the values in their respective counterparts There was a significant correlation between the detectability of serum TNF and performance status (P < 005) Patients with elevated serum TNF levels had a significantly higher mortality rate (P < 005) than those with undetectable serum TNF levels These findings suggest that TNF may be one of the factors contributing to the complex syndrome of cachexia in patients with prostate cancer

https://clincancerres.aacrjournals.org/content/clincanres/4/7/1743.full.pdf

Association between tumor necrosis factor in serum and cachexia in patients with prostate cancer

Background:

Clinical differential diagnosis between malignant and benign tumors is important in order to select a therapeutic strategy for a primary retroperitoneal tumor.

Methods:

The clinical findings and radiological features of 25 patients with primary retroperitoneal tumors were retrospectively evaluated to find those signs that might contribute to the preoperative distinction between benign and malignant tumors.

Results:

Of 25 primary retroperitoneal tumors, 15 were benign. This may reflect the increased number of incidentally found small benign tumors. There were significant associations between the presence of symptoms and malignancy (P< 0.05), between irregular margins on imaging and malignancy (P< 0.05) and between the absence of calcification and malignancy (P< 0.05). Malignant tumors were significantly larger than benign tumors (11.45 ± 1.90 cm vs. 5.31 ± 0.43 cm). A retroperitoneal tumor scoring system was developed to distinguish primary retroperitoneal benign tumors from their malignant counterparts based on the: 1) maximum diameter equal to or larger than 5.5 cm, 2) presence of symptoms, 3) absence of calcification, 4) presence of irregular margins, and 5) presence of cystic degeneration or necrosis. A significant correlation was found between the incidence of malignant tumors and the total retroperitoneal tumor score (P < 0.05).

Conclusion:

This study suggests that the size of tumor, the presence of symptoms, irregular margins, and the absence of calcification may be valuable predictors of primary retroperitoneal malignant tumor.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1442-2042.1997.tb00282.x

Differential Diagnosis of Primary Benign and Malignant Retroperitoneal Tumors

This study was undertaken to evaluate the relationship between serum tumor necrosis factor (TNF) and coagulopathy in patients with prostate cancer. TNF levels in 104 sera obtained from 101 prostate cancer patients were determined using an enzyme immunoassay. Serum levels of fibrin/fibrinogen degradation product E fragment (FDP) and plasma levels of fibrin degradation product d-dimer in patients with elevated serum TNF levels were 1221.95 ± 375.94 ng/ml and 27.34 ± 9.81 µg/ml, which were significantly higher than those (FDP, 94.35 ± 13.17 ng/ml; d-dimer, 1.03 ± 0.20 µg/ml) in patients with undetectable serum TNF levels ( P < 0.01). In addition, patients with elevated serum TNF levels showed significant increases in plasma levels of thrombin-antithrombin-III complex and plasmin-α2-antiplasmin inhibitor complex and a significantly higher incidence of positive plasma soluble fibrin monomer complex than did those with undetectable serum TNF levels. The percentage of prothrombin time was significantly decreased in the group with elevated serum levels of TNF. Serum levels of TNF were significantly elevated in patients with serum FDP levels of ≥200 ng/ml than in those with serum FDP levels of <200 ng/ml (3.91 ± 0.45 versus 2.17 ± 0.08 units/ml) and in patients with plasma d-dimer levels of ≥2 µg/ml than in those with plasma d-dimer levels of <2 µg/ml (3.82 ± 0.48 versus 2.10 ± 0.06 units/ml). These results suggest that TNF may be one of the pathogenetic factors that could explain the occurrence of coagulopathy in patients with prostate cancer.

https://cancerres.aacrjournals.org/content/canres/55/21/4881.full.pdf

Tumor Necrosis Factor and Coagulopathy in Patients with Prostate Cancer

Purpose/Methods: We report on a case of retroperitoneal benign schwannoma treated by laparoscopic surgery. Results/Discussion: The difficulties of diagnosis and the advantages of laparoscopic management are discussed.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1442-2042.1999.06222.x

Laparoscopic treatment of retroperitoneal benign schwannoma.

It is difficult to explain ectopic thyroid beneath the diaphragm because during the development the thyroid descends from the tongue to the anterior of the trachea. A few cases of ectopic lesions have been reported in the literature for abdominal organs including the adrenal glands, but the mechanism by which the thyroid components migrate into the abdomen has been poorly understood. A 54-year-old woman was diagnosed as having an adrenal mass. Laparoscopic adrenalectomy was carried out. Microscopically, the mass was composed of normal adrenal and ectopic thyroid tissues. We herein describe the fourth case reported of ectopic thyroid in the adrenal gland.

/pdf/ectopic-thyroid-in-an-adrenal-mass-a-case-report-1suttpn661.pdf

Munehisa Ueno

Papers

Association between tumor necrosis factor in serum and cachexia in patients with prostate cancer

Differential Diagnosis of Primary Benign and Malignant Retroperitoneal Tumors

Tumor Necrosis Factor and Coagulopathy in Patients with Prostate Cancer

Laparoscopic treatment of retroperitoneal benign schwannoma.

Ectopic thyroid in an adrenal mass: a case report