Richard K. Sibley

Helicobacter pylori Infection and the Risk of Gastric Carcinoma

BACKGROUND Infection with Helicobacter pylori has been linked with chronic atrophic gastritis, an inflammatory precursor of gastric adenocarcinoma. In a nested case-control study, we explored whether H. pylori infection increases the risk of gastric carcinoma. METHODS From a cohort of 128,992 persons followed since the mid-1960s at a health maintenance organization, 186 patients with gastric carcinoma were selected as case patients and were matched according to age, sex, and race with 186 control subjects without gastric carcinoma. Stored serum samples collected during the 1960s were tested for IgG antibodies to H. pylori by enzyme-linked immunosorbent assay. Data on cigarette use, blood group, ulcer disease, and gastric surgery were obtained from questionnaires administered at enrollment. Tissue sections and pathology reports were reviewed to confirm the histologic results. RESULTS The mean time between serum collection and the diagnosis of gastric carcinoma was 14.2 years. Of the 109 patients with confirmed gastric adenocarcinoma (excluding tumors of the gastroesophageal junction), 84 percent had been infected previously with H. pylori, as compared with 61 percent of the matched control subjects (odds ratio, 3.6; 95 percent confidence interval, 1.8 to 7.3). Tumors of the gastroesophageal junction were not linked to H. pylori infection, nor were tumors in the gastric cardia. H. pylori was a particularly strong risk factor for stomach cancer in women (odds ratio, 18) and blacks (odds ratio, 9). A history of gastric surgery was independently associated with the development of cancer (odds ratio, 17; P = 0.03), but a history of peptic ulcer disease was negatively associated with subsequent gastric carcinoma (odds ratio, 0.2; P = 0.02). Neither blood group nor smoking history affected risk. CONCLUSIONS Infection with H. pylori is associated with an increased risk of gastric adenocarcinoma and may be a cofactor in the pathogenesis of this malignant condition.

Malignant small cell tumor of the thoracopulmonary region in childhood. A distinctive clinicopathologic entity of uncertain histogenesis

This report describes a unique clinicopathologic entity characterized as a malignant small cell tumor of the thoracopulmonary region in 20 children and adolescents (average age 14.5 years). There was a female predilection (75%) for this tumor which appeared to originate in the soft tissues of the chest wall or the peripheral lung. The neoplasm tended to recur locally and did not seem to disseminate as widely as some of the other small cell tumors of childhood (rhabdomyosarcoma, Ewings sarcoma, neuroblastoma and malignant lymphoma). However, the median survival was only 8 months. Electron microscopy of 3 cases suggested a neuroepithelial derivation, but, at the present, the histogenesis remains a subject for further investigation.

RANTES chemokine expression in cell-mediated transplant rejection of the kidney

RANTES (regulated upon activation, normal T cell expressed and secreted) is a chemotactic cytokine (a chemokine) for memory T lymphocytes, monocytes, and eosinophils. RANTES expression was studied in renal allograft biopsy specimens. Although RANTES was not expressed in samples taken one hour after transplantation, or in native renal biopsy specimens from patients with cyclosporin nephrotoxicity, it was expressed during cell-mediated transplant rejection. RANTES mRNA was detected in infiltrating mononuclear cells and renal tubular epithelium, and RANTES protein was localised to mononuclear cells, tubular epithelium, and vascular endothelium. This suggests RANTES has a role in allograft rejection.

Primary neuroendocrine (Merkel cell?) carcinoma of the skin. I. A clinicopathologic and ultrastructural study of 43 cases.

The clinical and pathologic features of 43 cases of primary neuroendocrine carcinoma of the skin are reported. These tumors arise in the dermis and subcutaneous tissues of elderly individuals. The head and neck are the most common primary sites followed by the lower and upper extremities and trunk. Characteristic histologic features include round cells with scanty amphophilic cytoplasm and vesicular nuclei with multiple small nucleoli. The cells are arranged in sheets, solid nests, or anastomosing trabeculae. Collections of perinuclear intermediate filaments, cytoplasmic dense-core membrane- bound secretory granules, complex intercellular junctions, and cytoplasmic spinous processes are the principal fine structural features. These ultrastructural findings are similar to those of the normal cutaneous Merkel cell. The natural history of this neoplasm is characterized by local recurrence in 30% of cases, regional lymph node metastases in 65% of cases, and distant metastases in 40%. One-third of the patients were dead because of their tumors. Treatment of extensive local or distant metastastic disease with chemotherapy or radiotherapy resulted in only short-term palliative response.

Recurrence of Disease in Pancreas Transplants

In a series of 200 pancreas transplants with 6 mo to >9 yr of follow-up, recurrence of disease was identified as the cause of graft failure in 8 cases, all in non- or minimally immunosuppressed recipients of transplants from identical twin (n = 3) or HLA-identical sibling (n = 5) donors. Recurrence of disease was defined as selective loss of β-cells; other endocrine cell types persisted and appeared normal within the islets of the graft. Isletitis was present in islets with residual β-cells during the evolution of the process in all nonimmunosuppressed and in some immunosuppressed recipients, but isletitis resolved in all cases in which β-cell destruction was complete and also resolved in some cases in which residual β-cells were retained after the introduction of or an increase in immunosuppression. Recurrence of disease can be prevented by immunosuppression, and 2 recipients of identical twin grafts and 12 recipients of grafts from HLA-identical siblings had functioning grafts as of March 1988, the longest >7 yr. The process has not been observed in patients in whom full-dose immunosuppression has been used, including HLA-identical siblings, and this may be the reason no cases of recurrence of disease have been identified in recipients of cadaveric grafts. Alternatively, the observations are consistent with, but not proof of, the hypothesis that recurrence of disease (autoimmune isletitis leading to diabetes) is a major histocompatibility complex-restricted phenomenon.

Cellular profile and cytokine production at prosthetic interfaces: STUDY OF TISSUES RETRIEVED FROM REVISED HIP AND KNEE REPLACEMENTS

The tissues surrounding 65 cemented and 36 cementless total joint replacements undergoing revision were characterised for cell types by immunohistochemistry and for cytokine expression by in situ hybridisation. We identified three distinct groups of revised implants: loose implants with ballooning radiological osteolysis, loose implants without osteolysis, and well-fixed implants. In the cemented series, osteolysis was associated with increased numbers of macrophages (p = 0.0006), T-lymphocyte subgroups (p = 0.03) and IL-1 (p = 0.02) and IL-6 (p = 0.0001) expression, and in the cementless series with increased numbers of T-lymphocyte subgroups (p = 0.005) and increased TNF alpha expression (p = 0.04). For cemented implants, the histological, histochemical and cytokine profiles of the interface correlated with the clinical and radiological grade of loosening and osteolysis. Our findings suggest that there are different biological mechanisms of loosening and osteolysis for cemented and cementless implants. T-lymphocyte modulation of macrophage function may be an important interaction at prosthetic interfaces.

Acquired immune tolerance to cadaveric renal allografts. A study of three patients treated with total lymphoid irradiation

The advent of new immunosuppressive drug regimens has produced a substantial improvement in organ-allograft survival during this decade.1 2 3 4 5 However, the treatment of organ-transplant recipien...

Primary neuroendocrine (Merkel cell?) carcinoma of the skin. II. An immunocytochemical study of 21 cases.

Twenty-one examples of neuroendocrine carcinoma of the skin were examined by the unlabeled antibody enzyme method for several neural hormones and peptides, carcinoembryonic antigen, S-100 protein, neuron- specific enolase, and three intermediate filaments: neurofilament, glial fibrillary acidic protein, and cytokeratin. Vasoactive intestinal polypeptide from two sources reacted with the neoplastic cells of four (18%) and seven (32%) of the cases, and pancreatic polypeptide reacted with scattered cells of one case. Neuron-specific enolase reactivity occurred in 50% of the cases. Neurofilament (70, 150, 200 kilodaltons) was strongly positive in 40% of the tumors whereas neurofilament (200 kilodaltons) was negative. Two monoclonal anticytokeratin antibodies of 54 kilodaltons and 44-54 kilodaltons reacted in 77% and 64% of the cases, respectively, in a distribution similar to the neurofilament. Sections reacted with antisera against cytokeratins of higher molecular weight were negative. The demonstration of vasoactive intestinal polypeptide, pancreatic polypeptide, neurofilament, and neuron-specific enolase is evidence of the neuroendocrine nature of this neoplasm.

Neuroendocrine (Merkel cell) carcinoma of the skin. A histologic and ultrastructural study of two cases.

The clinical, histologic, and ultrastructural features of two cases of a primary cutaneous neuroendocrine neoplasm probably arising from Merkel cells are presented and compared with previously reported examples. This recently described tumor arises in the dermis of elderly individuals, is often locally aggressive, may metastasize to regional lymph nodes, and eventually may cause death. Microscopically, sheets of primitive cells fill and expand the dermis. Ultrastructural study of our cases revealed morphologic similarities to normal cutaneous Merkel cells, including peripherally situated dense-core neurosecretory-like granules, zonula adherens-type intercelluar junctions, prominent Golgi apparatus, and varying numbers of mitochondria and rough endoplasmic reticulum. This unusual tumor is readily confused with cutaneous lymphoma and various undifferentiated primary or metastatic neoplasms by conventional light microscopy. The definitive diagnosis can be made only by electron-microscopic examination.

Chronic injury of human renal microvessels with low-dose cyclosporine therapy

Physiologic and morphologic techniques were used to study kidneys of cardiac transplant recipients treated with either low-dose (low-CsA) or high-dose (high-CsA) cyclosporine. After 12 months both low-CsA (4.6 +/- 0.4) and high-CsA (6.3 +/- 0.3 mg/Kg/24 hr, p less than 0.01) were associated with azotemia and hypertension; GFR with each regimen was depressed below values in a third group treated without CsA (no-CsA) by 40-47%, while corresponding renal vascular resistance was elevated greater than 2-fold (P less than 0.01). Morphologic changes in both CsA groups included an obliterative arteriolopathy with downstream collapse or sclerosis of glomeruli. Determination of renal arcuate vein occlusion pressure revealed an increasing renal artery-to-peritubular capillary pressure gradient between 1 and 12 months of CsA therapy. Fractional clearances of dextrans of graded size were elevated at each time compared with the no-CsA group. Analysis of dextran transport with an isoporous membrane model indicates that transglomerular hydraulic pressure difference (delta P) approximated 39 with no-CsA, but was reduced with low-CsA therapy to about 30 at 1 month, and about 34 mmHg after 12 months. We conclude that chronic CsA therapy induces constriction and eventual occlusion of afferent arterioles, causing downstream glomerular damage that is irreversible. Low versus high dosage of CsA confers only marginal protection against this serious microvascular injury.