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The underutilized practice of photographing anatomic pathology specimens from surgical pathology and autopsies is an invaluable benefit to patients, clinicians, pathologists, and students. Photographic documentation of clinical specimens is essential for the effective practice of pathology. When considering what specimens to photograph, all grossly evident pathology, absent yet expected pathologic features, and gross-only specimens should be thoroughly documented. Specimen preparation prior to photography includes proper lighting and background, wiping surfaces of blood, removing material such as tubes or bandages, orienting the specimen in a logical fashion, framing the specimen to fill the screen, positioning of probes, and using the right-sized scale.

The underutilized practice of photographing anatomic pathology specimens from surgical pathology and autopsies is an invaluable benefit to patients, clinicians, pathologists, and students. Photographic documentation of clinical specimens is essential for the effective practice of pathology. When considering what specimens to photograph, all grossly evident pathology, absent yet expected pathologic features, and gross-only specimens should be thoroughly documented. Specimen preparation prior to photography includes proper lighting and background, wiping surfaces of blood, removing material such as tubes or bandages, orienting the specimen in a logical fashion, framing the specimen to fill the screen, positioning of probes, and using the right-sized scale.

Cervical cancer is known to metastasize primarily by the lymphatic system. Dissemination through lymphatic vessels represents an early step in regional tumor progression, and the presence of lymphatic metastasis is associated with a poor prognosis. In patients who have undergone a radical hysterectomy, lymphovascular space invasion (LVSI), assessed on hematoxylin and eosin-stained slides, is a major factor for adjuvant therapy in patients with cervical cancer. With the advent of a lymphatic endothelial cell-specific marker, such as D2-40, it is now possible to distinguish between blood and lymphatic space invasion (LSI). In this study, the utility of D2-40 was assessed for the detection of lymphatic vessel density (LVD) and identification of LSI. The expressions of vascular endothelial growth factor receptor-3 (VEGFR-3), VEGF-C, tyrosine receptor kinase-2, and angiopoietin-1 were assessed by immunohistochemical methods on 50 patients with squamous cell carcinoma of the cervix. Clinicopathologic characteristics, including pelvic lymph node metastasis, were correlated with the above histochemical findings. We found that lymphangiogenesis, measured by an increase in peritumoral LVD, was significantly associated with positive lymph node status ( .005). VEGFR-3 expression was significantly associated with LVD (P< .05). D2-40 staining verified LSI (P= .03) and surpassed that of hematoxylin and eosin-identified LVSI (P= 54). In conclusion, lymphangiogenic markers, specifically LVD quantified by D2-40 and VEGFR-3, are independently associated with LSI and lymph node metastasis in patients with early squamous cell carcinoma of the cervix treated with radical hysterectomy and pelvic lymphadenectomy.

Radioiodinated phospholipid ether analogues have shown a remarkable ability to selectively accumulate in a variety of human and animal tumors in xenograft and spontaneous tumor rodent models. It is believed that this tumor avidity arises as a consequence of metabolic differences between tumor and corresponding normal tissues. The results of this study indicate that one factor in the tumor retention of these compounds in tumors is the length of the alkyl chain that determines their hydrophobic properties. Decreasing the chain length from C12 to C7 resulted in little or no tumor accumulation and rapid clearance of the compound in tumor-bearing rats within 24 h of administration. Increasing the chain length had the opposite effect, with the C15 and C18 analogues displaying delayed plasma clearance and enhanced tumor uptake and retention in tumor-bearing rats. Tumor uptake displayed by propanediol analogues NM-412 and NM-413 was accompanied by high levels of liver and abdominal radioactivity 24 h postinjection to tumor-bearing rats. Addition of a 2-O-methyl moiety to the propanediol backbone also retarded tumor uptake significantly. A direct comparison between NM-404 and its predecessor, NM-324, in human PC-3 tumor bearing immune-compromised mice revealed a dramatic enhancement in both tumor uptake and total body elimination of NM-404 relative to NM-324. On the basis of imaging and tissue distribution studies in several rodent tumor models, the C18 analogue, NM-404, was chosen for follow-up evaluation in human lung cancer patients. Preliminary results have been extremely promising in that selective uptake and retention of the agent in tumors is accompanied by rapid clearance of background radioactivity from normal tissues, especially those in the abdomen. These results strongly suggest that extension of the human trials to include other cancers is warranted, especially when NM-404 is radiolabeled with iodine-124, a new commercially available positron-emitting isotope. The relatively long physical half-life of 4 days afforded by this isotope appears well-suited to the pharmacodynamic profile of NM-404.

Diclofenac is a nonsteroidal anti‐inflammatory drug (NSAID) widely prescribed for pain and inflammation. Theoretically, the gastrointestinal (GI) complications of diclofenac could be minimized by administering a diclofenac resinate formulation, such as Flotac, where GI mucosal contact with free NSAID is minimized by its complexing with the cholestyramine resin. The objective of the present study was to investigate the influence of cholestyramine co‐treatment on diclofenac enteropathy in fed rats and diclofenac gastropathy in fasted rats. Male Sprague‐Dawley rats were gavaged with diclofenac (50 mg/kg), diclofenac (50 mg/kg) plus cholestyramine (50 mg/kg), or an equivalent amount of Flotac, a 1:1 wt/wt mixture of diclofenac and cholestyramine presently used in human therapeutics in Mexico. Ulceration of the GI tract, serum proteins, and bile salts were assessed at 3, 12, or 24 h. Cholestyramine alone produced no detectable alterations in small intestinal integrity or serum bile salts levels. Fed rats given Flotac or diclofenac plus cholestyramine showed patterns of small intestinal ulceration and serum protein decline that were similar to rats given only diclofenac. Thus, no influence on enteropathy was detected. In contrast, fasted rats given Flotac showed a modest reduction in the number and length of gastric lesions compared to rats given diclofenac. The observed attenuation of gastric lesions with Flotac is consistent with a role for direct cytotoxicity in NSAID gastropathy. Drug Dev. Res. 64:19–27, 2005. © 2005 Wiley‐Liss, Inc.

Pallister-Killian syndrome (PKS), a rare disorder, is characterized by tissue-limited or tissue-specific mosaicism. The characteristic chromosome abnormality associated with PKS is i(12p), which is seen predominantly in skin fibroblast cultures. Diagnosis of i(12p) has been carried out on buccal smears before and was shown to be an easy and feasible method. All previously published studies used α-satellite probes for the diagnosis and as such have several pitfalls. Our approach, using dual-color, locus-specific probes, has high specificity and sensitivity for the diagnosis of i(12p). Using statistical analysis, we have also confirmed that the signal pattern in interphase nuclei is consistent with isochromosome 12p.

Intraoperative somatosensory evoked potential (SSEP) monitoring was performed in eight children who had undergone an acute deformity correction in the lower extremities using external fixation. Five patients showed stable evoked potentials during surgery and had no neurologic complications postoperatively. Three patients experienced evoked potential abnormalities. In one patient, 60° external rotation of the foot produced significant SSEP changes. The reduction of rotation to 40° resulted in tibial but not peroneal SSEP recovery. Peroneal nerve deficit was noted postoperatively. The second patient showed substantial SSEP attenuation after 45° correction of distal tibial valgus. However, spontaneous recovery of the response occurred, which allowed maintenance of the achieved correction. In a third patient, significant SSEP changes occurred after 90° external rotation and 10 mm medial translation of the distal femur. Total release of translation allowed 75° external rotation without SSEP abnormalities. Neither of the latter two patients had peripheral nerve deficits postoperatively. Intraoperative SSEP monitoring thus helps to define a neurologically safe limit of acute deformity correction.

Hepatobiliary cystadenomas (HBCs) with mesenchymal stroma (MS) are rare cystic neoplasms occurring exclusively in women. Hepatobiliary cystadenoma consists of a mucin‐producing cyst lining epithelium underlined by a dense MS cell layer. In the current study, the authors review the fine needle aspiration cytology of HBC with MS and identify characteristic cytologic features that suggest such an uncommon neoplasm on aspirates.A search of the histopathology files at the University of Texas Medical Branch at Galveston for the interval of January 1992 through December 2000 yielded four cases of HBC having both cytologic and histologic specimens. The cytologic features of the aspirates were reviewed and correlated with the clinical history, radiologic findings, and the histopathology of the excised specimens.All four patients were middle‐aged women (mean age, 48.5 years) who presented with epigastric pain radiating to the back, due to large cystic lesions in the right liver lobe (three patients) or the left liver lobe (one patient). Aspiration cytology revealed chronic inflammatory exudate in all cases, along with occasional aggregates of bland, cuboidal‐columnar epithelial cells (in three cases), which rarely arranged in papillary clusters. No significant atypia, evidence of malignancy, or MS cells were identified on the aspirates. HBC with MS was confirmed histologically on the excised specimens in all cases.By ensuring adequate sampling and correlating with consistent clinical and radiologic findings, a diagnosis of HBC or cystic hepatobiliary neoplasm can be suggested on the basis of aspiration cytology. Cancer (Cancer Cytopathol) 2002;96:37–42. © 2002 American Cancer Society. DOI 10.1002/cncr.10315

The effect of inhaled benzene on embryonal and fetal development was assessed in mice and rabbits. CF-1 mice and New Zealand white rabbits were exposed to 0 or 500 ppm of benzene for 7 hr per day from days 6 through 15 (mice) and 6 through 18 (rabbits) of gestation. Little evidence of maternal toxicity was seen in either species. Although some signs of embryonal toxicity were observed in both mice and rabbits, a teratogenic effect was not discerned in either species inhaling 500 ppm of benzene.

It was initially reported that lipopolysaccharide (LPS)-unresponsive C3H/HeJ mice are refractory to LPS at the B-lymphocyte level, but more recently it has been shown that other cells are similarly unaffected. The current study was undertaken to study an in vivo LPS-modulated disease process involving macrophage-T cell interactions. Adult CBA/J and C3H/HeJ mice were used as spleen donors, and graft versus host reactions were induced in BALB/c neonates. Prior LPS treatment of CBA/J adults decreased the ability of their spleen cells to cause fatal graft versus host disease in BALB/c neonates, whereas no difference was found between injection of spleen cells from normal or LPS-treated C3H/HeJ mice. Similar results were obtained with these cell types when the mouse spleen mixed leukocyte culture system was used. In a carbon clearance assay for stimulation of the reticuloendothelial system with LPS, it was found that the rate of phagocytosis was significantly increased in BALB/c and CBA/J mice 72 h after inoculation of LPS. No stimulation was seen in rate of carbon uptake in the C3H/HeJ animals after treatment with phenol-extracted LPS or with butanol-extracted LPS. An LPS-induced protective serum factor was produced only in the LPS-responsive CBA/J mice and was specific for the syngeneic cells.

The pharmacokinetics and metabolism of 1,4-dioxane were determined in four healthy male volunteers exposed to 50 ppm dioxane vapor for 6 hr. Samples of blood and urine collected during and after the exposure were analyzed for dioxane and its metabolite β-hydroxyethoxyacetic acid (HEAA) by gas chromatography-mass spectrometry. A pharmacokinetic model with associated parameters was constructed to describe the fate of dioxane and HEAA in humans. The model was compared to a model constructed previously for dioxane in rats. This comparison facilitates assessment of the hazard to humans of dioxane exposure by extrapolation of toxicological information obtained in rats.The dynamics of dioxane uptake and elimination in humans could be described by a one-compartment open-system model with zero-order uptake and first-order elimination. The half-life for elimination of dioxane was 59 + 7 min; 99.3% of the elimination was by metabolism of dioxane to HEAA, and 0.7% was by excretion of dioxane in the urine. Dioxane and HEAA were detectable in the urine until 6 and 18 hr after cessation of exposure, respectively. The total absorbed dose of dioxane during the 6 hr period was 5.4 ±1.1 mgjkg, although the maximum amount of dioxane in the body at any one time was 1.2 ± 0.2 mg/kg and occurred at the end of the exposure. At 6 hr the amount of dioxane in the body had reached over 99% of the steady-state amount. A simulation of repeated daily exposures to 50 ppm dioxane for 8 fir/day indicated that dioxane would never accumulate to concentrations above those attained after a single 8 hr exposure as long as the exposure concentration of dioxane was 50 ppm or less. Lack of accumulation of dioxane on repeated exposure is a critical point since saturation of the metabolism of dioxane at high dosage levels to rats has been shown to lead to toxicity. The results of the study conducted in human volunteers support the conclusion that exposure to the current threshold limit value of 50 ppm dioxane in the workplace will not cause adverse effects, even when the exposure is on a continuous or repeated basis.

Background.Keratinocyte growth factor-2 (KGF-2) also described as fibroblast growth factor-10 (FGF-10) is a newly identified member of the fibroblast growth factor family. KGF-2 is 96% identical to the recently identified rat FGF-10 and specifically stimulates growth of normal human epidermal keratinocytes. The present study was undertaken to examine the effects of topically applied KGF-2 in an incisional wound healing model. KGF-2 treatment resulted in an improvement in incisional wound healing as characterized by an increase in breaking strength, collagen content, and epidermal thickness.

Rats and hamsters were exposed to the dust of pulverized asbestos pipe covering at an average concentration of 85 mg/m3 for 6 h/d, 5 d/wk, for 7 mo, followed by a lifetime observation period. In rats, the pulmonary responses were alveolar adenomatous proliferation, nonprogressive fibrosis, squamous metaplasia, and a substantial incidence of pulmonary carcinoma formation. A smaller group of hamsters exposed under these conditions experienced an earlier onset of mortality than control hamsters, which were not subjected to the exposure regimen. Although this prevented conclusive evaluation of the pulmonary response in this species, no pulmonary neoplasms were noted in the surviving hamsters.

Methylene Chloride: A Two-Year Inhalation Toxicity and Oncogenicity Study in Rats and Hamsters. BUREK, J. D., NITSCHKE, K. D., BELL, T. J., WACKERLE, D. L., CHILDS, R. C., BEYER, J. E., DITTENBER, D. A., RAMPY, L. W., AND MCKENNA, M. J. (1984). Fundam. Appl. Toxicol. 4, 30–47. A long-term study was conducted to determine the possible chronic toxicity and oncogenicity of methylene chloride. Rats and hamsters were exposed by inhalation to 0, 500, 1500, or 3500 ppm of methylene chloride for 6 hr per day, 5 days a week, for 2 years. No exposure-related cytogenetic effects were present in male or female rats exposed to 500, 1500, or 3500 ppm. Females rats exposed to 3500 ppm had an increased mortality rate while female hamsters exposed to 1500 or 3500 ppm had decreased mortality rates. Carboxyhemoglobin values were elevated in rats and hamsters exposed to 500, 1500, or 3500 ppm with the percentage increase in hamsters greater than in rats. Minimal histopathologic effects were present in the livers of rats exposed to 500, 1500, or 3500 ppm. Decreased amyloidosis was observed in the liver and other organs in hamsters exposed to 500, 1500, or 3500 ppm. While the number of female rats with a benign tumor was not increased, the total number of benign mammary tumors was increased in female rats in an exposure-related manner. This effect was also evident in male rats in the 1500- and 3500-ppm exposure groups. Finally, male rats exposed to 1500 or 3500 ppm had an increased number of sarcomas in the ventral neck region located in or around the salivary glands. Therefore, in this 2-year study, some effects were observed in male and female rats exposed to 500, 1500, or 3500 ppm of methylene chloride. In contrast, hamsters exposed to the same exposure concentrations had less extensive spontaneous geriatric changes, decreased mortality (females), and lacked evidence of definite target organ toxicity.

Chronic Toxicity and Oncogenicity Study on Inhaled Vinylidene Chloride in Rats. QUAST, J. F., MCKENNA, M. J., RAMPY, L. W., AND NORRIS, J. M. (1986). Fundam. Appl. Toxicol. 6, 105–144. Male and female Sprague—Dawley rats (Spartan substrain) were exposed to vinylidene chloride (VDC) by inhalation for 18 months to assess chronic toxicity and oncogenic potential of the subject test material. Interim sacrifices were performed at 1, 6, and 12 months. Rats were exposed to VDC concentrations of 10 and 40 ppm for 6 hr/day, 5 days/week for the first 5 weeks of the study. Based upon the absence of observable treatment-related effects among rats sacrificed after 1 month of exposure, the exposure concentrations were increased to 25 and 75 ppm VDC. Exposures were continued at these concentrations through the 18th month of the study after which the surviving animals were held until 24 months and then sacrificed. Cytogenetic evaluations were performed on a separate group of animals, four rats/sex, exposed to 0, 25, or 75 ppm VDC for 6 months. There were no exposure-related changes in the following parameters: mortality, appearance and demeanor, body weight data, clinical chemistry determinations, hematologic evaluations, urinalysis, or cytogenetic evaluation of bone marrow preparations. A target organ effect, characterized by hepatocellular fatty change in the midzonal region of the hepatic lobule which was minimal in severity, was observed in both male and female rats of both the 25- and 75-ppm exposure groups as early as the 6-month interim sacrifice. The midzonal fatty change was also observed at the 12-month sacrifice but no indication of progression of this lesion in either severity or incidence was apparent. During the last 6 months of the study, after exposures had been discontinued, this effect was no longer discernible; therefore this alteration was readily reversible. The incidences of several tumors and/or tumor types were statistically increased or decreased in VDC-exposed rats when compared to their respective control groups; none of these differences were judged to be attributable to VDC exposure.

Metabolism of Acrylate Esters in Rat Tissue Homogenates. R.R. Miller, J.A. Ayres, L.W. Rampy and M.J. McKenna. (1981). Fundam. Appl. Toxicol. 1:410–414. Methyl, ethyl and butyl acrylate were hydrolyzed to acrylic acid in rat liver, kidney and lung homogenates. The rates of hydrolysis of the various esters in these in vitro studies were comparable; hydrolysis rates were approximately 20 times higher in liver homogenates than in kidney or lung homogenates. The esters also disappeared rapidly when added to blood in vitro. However, the disappearance in blood was not associated with the appearance of acrylic acid. Ethyl acrylate was found to react spontaneously with GSH in vitro and this reaction was catalyzed greatly by enzymes in 100 000 x g liver supernatant. Acrylic acid did not react with GSH in vitro. Ethyl acrylate, but not acrylic acid, depletes non-protein sulfhydryls when added to blood in vitro. Thus, the disappearance of acrylate esters in blood in vitro could be due at least in part to binding with non-protein sulfhydryls in red blood cells rather than to hydrolysis.

Methylene Chloride: A 2-Year Inhalation Toxicity and Oncogenicity Study in Rats. Nit-schke, K. D. Burek, J. D., Bell, T. J., Kociba, R. J., Rampy, L. W. and McKenna, M. J. (1988). Fundam. Appl. Toxicol. 11, 48-59. Male and female Sprague-Dawley rats were exposed to 0, 50, 200, or 500 ppm methylene chloride for 6 hr/day, 5 days/week for 2 years. Blood carboxyhemoglobin levels were elevated in a dose-dependent (less than linear) manner in rats exposed to 50–500 ppm methylene chloride Histopathologic lesions related to methylene chloride exposure were confined to the liver and mammary tissue of rats. An increased incidence of hepatocellular vacuolization was observed in male and female rats exposed to 500 ppm methylene chloride. Female rats exposed to 500 ppm methylene chloride also had an increased incidence of multinucleated hepatocytes and number of spontaneous benign mammary tumors/ tumor-bearing rat (adenomas, fibromas, and fibroadenomas with no progression toward malignancy); the incidence of benign mammary tumors in female rats exposed to 50 or 200 ppm methylene chloride was comparable to historical control values. No increase in the number of any malignant tumor type was observed in rats exposed to concentrations as high as 500 ppm methylene chloride. Additional groups of female rats were exposed to 500 ppm methylene chloride for the first 12 months or the last 12 months of the 24-month study. The response observed in female rats exposed to 500 ppm for the first 12 months was the same as that observed in female rats exposed to 500 ppm for 2 years. Conversely, the response observed in female rats exposed to 500 ppm during the last 12 months of the study was similar to that observed in control animals. Based upon the results of this study, the no-adverse-effect level for chronic inhalation exposure of Sprague-Dawley rats was judged to be 200 ppm methylene chloride.