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A 6-yr-old boy underwent a total body Ga-67 citrate imaging study because of a large mass of Hodgkin's lymphoma in the left neck and the left anterior chest wall region. The images showed intense uptake in the left neck extending anteroinferiorly to the left upper chest wall corresponding to the left neck and chest region. In addition, there was mild cervical-upper thoracic scoliosis with convexity to the right and mild scoliosis of the lower lumbar scoliosis with concavity to the left. After three cycles of chemotherapy, in the follow-up Ga-67 citrate total body images seven months after his first Ga-67 citrate imaging, the intense uptake in the left neck and the left upper chest wall had been resolved and the scoliosis of the cervical-thoracic and lower lumbar spine had also been reversed to normal. This case shows that a Ga-67 citrate imaging study is useful for first diagnosis and subsequent monitoring of the therapeutic effects in a follow-up imaging. Also Ga-67 citrate imaging provided evidence that the scoliosis had been reversed. [ABSTRACT FROM AUTHOR]

Abstract: Objective. : To determine the presenting symptoms, gynecologic manifestations, and optimal intraoperative management of women with primary appendiceal cancer. Methods. : A multi-institutional investigation was performed to identify female patients with primary appendiceal cancer who were treated from 1990 to present. Results. : Forty-eight women with primary appendiceal cancer were identified from the tumor registries of participating institutions. The most common symptoms were abdominal pain (40%) and bloating (23%), but only 8% experienced rectal bleeding. Serum CEA was elevated (>2.5 U/ml) in 67% of patients, and serum Ca-125 was elevated (>35 U/ml) in 50% of patients. Thirty-one patients (65%) presented with a right adnexal or right lower quadrant mass and were operated on initially by a gynecologic oncologist. Ovarian involvement by metastatic appendiceal cancer was documented in 18 patients (38%). All of these patients underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging, but only 8 had a right hemicolectomy at the time of initial surgery. Forty-one patients (85%) presented with advanced stage appendiceal cancer (Stage III or IV) and 19 patients (46%) received postoperative chemotherapy, most commonly with a combination of 5-FU/Leukovorin. Following surgery, 22 patients (46%) experienced disease progression or recurrence, and 14 have died of disease. The most common sites of recurrence were abdominal or pelvic peritoneum (18), colon (2), and ovary (2). Patient survival was 70% at 2 years, and 60% at 5 years. Conclusion. : Women with primary appendiceal cancer frequently present with ovarian metastases, and initial surgical intervention is often performed by a gynecologic oncologist. All patients with mucinous epithelial ovarian cancer should undergo appendectomy at the time of surgical staging. The appendix should be examined intraoperatively, and if appendiceal carcinoma is identified, a right hemicolectomy and appropriate surgical staging should be considered. [Copyright &y& Elsevier]

Abstract: Objective. : To determine the efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC). Methods. : A retrospective multi-institutional investigation was performed to identify surgically staged patients with Stage I UPSC who were (1) treated after surgery with 3–6 courses of platinum-based chemotherapy without radiation from 1990–2003, and (2) followed for a minimum of 12 months, or until recurrence. Results. : Six patients (IA—2, IB—3, IC—1) were treated with carboplatin (AUC 6) or cisplatin (50 mg/m2) alone. One patient recurred to the vagina, was treated with chemo-radiation, and is alive and well at 122 months. One patient recurred to the lung, liver, and brain, and died of disease at 24 months. The remaining 4 patients are alive with no evidence of disease 15–124 months (mean 62 months) after treatment. Two patients (IB-1, IC-1) were treated with cisplatin (50 mg/m2) and cyclophosphamide (1000 mg/m2), and both are alive and well with no evidence of disease 75 and 168 months after treatment. Twenty-one patients (IA—5, IB—13, IC—3) were treated with a combination of carboplatin (AUC 6) and paclitaxel (135 mg/m2–175 mg/m2). One patient recurred to the vagina after 3 cycles of carboplatin/paclitaxel, and was treated with chemo-radiation. She is now without evidence of disease 10 months after treatment. At present, all 21 patients with Stage I UPSC treated following surgical staging with carboplatin/paclitaxel chemotherapy are alive and well with no evidence of disease 10–138 months (mean 41 months) after treatment. Conclusion. : Combination carboplatin/paclitaxel chemotherapy following surgery is effective in the treatment of Stage I UPSC. [Copyright &y& Elsevier]

Background: There are a number of equally efficacious chemotherapy options for the treatment of women with endometrial cancer, all of which work in only a subset of those women with this disease. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. Such an assay should yield response rates similar to those found in treated patient populations. The purpose of this investigation was to determine whether the patterns of in vitro tumor response rates as determined by ChemoFx are consistent with expected population response rates., Methods: Nine hundred twenty-three tumor specimens from patients with high-risk early-stage, advanced stage, or recurrent endometrial cancer were sent for testing with the ChemoFx drug response marker from August 2, 2006, to August 31, 2009. Tumors were categorized as responsive (R), intermediately responsive (IR), or nonresponsive to each drug or combination tested. Response rates from clinical trials were identified and compared with the corresponding in vitro response rates., Results: Of the 923 specimens received, 759 (82%) were successfully tested by ChemoFx. Of these, 755 were tested for at least 1 of 5 National Comprehensive Cancer Network-recommended endometrial cancer drugs. The response rates (R+IR) for these drugs were as follows: 66% carboplatin-paclitaxel, 48% carboplatin, 37% cisplatin, 23% doxorubicin, and 36% paclitaxel. Moreover, 20% of tumors were pan-sensitive (R or IR) to all 5 regimens tested, 27% were pan-resistant (nonresponsive), and 53% showed different degrees of response to different drugs., Conclusions: ChemoFx in vitro response rates were consistent with published population response rates, and the ChemoFx drug response marker may provide clinically useful information to better optimize individual chemotherapy for treatment of women with endometrial cancer.

The decision whether to proceed with complete axillary node dissection based on sentinel node status is clear for patients with negative or macrometastatic disease. However, the course of action based on sentinel node micrometastasis remains controversial. We reviewed 358 cases from 6/1999 to 7/2003. All sentinel nodes were evaluated at three levels by frozen section, touch preparation, and scrape preparation. Micrometastasis was defined as tumor deposits between 0.2 and 2 mm. Size, grade, and lymphvascular invasion of the primary tumor, as well as number, status, size of metastatic disease, and presence of extranodal capsular extension of sentinel and nonsentinel nodes were recorded. Of the 358 cases, 89 had positive sentinel nodes, 29 of which represented micrometastases. Only one (3%) of the 29 cases contained a nonsentinel node with macrometastasis. In 60 of the 89 cases sentinel nodes contained macrometastases. Of these, 38 cases (63%) had metastatic tumor in nonsentinel nodes. Intraoperative consult was performed in 53 of the 89 cases with positive sentinel nodes. Only 1 of the 19 (5%) intraoperative consult cases with micrometastatic sentinel nodes had positive nonsentinel nodes, while 21 of 34 (62%) of macrometastatic sentinel nodes at intraoperative consult had tumor in nonsentinel nodes. No single variable studied discriminated between micro- vs macrometastatic disease. At intraoperative consult, macrometastatic disease was present in all three diagnostic preparations, while diagnostic material in micrometastatic sentinel nodes was usually present in only one modality. This analysis suggests that the risk of finding tumor in nonsentinel nodes differs significantly between cases with micro (3%)- vs macro (63%)-metastatic disease in sentinel nodes. This holds true for cases assessed by intraoperative consult. Considering the known morbidity of complete axillary dissection, assessments of risk vs benefit of undertaking this procedure should be performed on a case-by-case basis in patients with sentinel node micrometastases.

The ribonucleotide reductase inhibitor hydroxyurea (HU) has demonstrated some benefit as a component of drug cocktails for the treatment of HIV-1 infection. However, HU is notoriously myelosuppressive and often administered only as salvage therapy to patients with late-stage disease, potentially exacerbating the bone marrow toxicity of HU. In this report we have compared the antiviral effects of HU and two novel RR inhibitors trimidox (3,4,5-trihydroxybenzamidoxime) and didox (3,4-dihydroxybenzohydroxamic acid) in combination with didanosine (2,3-didoxyinosine; ddI) in the LPBM5 MuLV retrovirus model (murine AIDS). We also evaluated the effects of these drug combinations on the hematopoietic tissues of LPBM5 MuLV-infected animals. The combination of RR inhibitors and ddI was extremely effective (DX>TX>HU) in inhibiting development of retrovirus-induced disease (splenomegaly, hypergammaglobulinemia, activated B-splenocytes and loss of splenic architecture). In addition, relative levels of proviral DNA were significantly lower in combination drug-treated animals compared to infected controls. Evaluation of femur cellularity, numbers of marrow-derived myeloid progenitor cells (CFU-GM and BFU-E) and peripheral blood indices revealed that TX and DX in combination with ddI were well-tolerated. However, treatment with HU and ddI induced moderate myelosuppression. These data demonstrate that RR inhibitors in combination with ddI provide significant protection against retroviral disease in murine AIDS. Moreover, the novel RR inhibitors TX and DX appear to be more effective and less myelosuppressive than HU when administered with ddI in this model.

Purpose: To determine if circadian timed (CT) chemotherapy results in improved response, progression-free survival (PFS), overall survival (OS), and lower toxicity, when compared with standard timed (ST) chemotherapy., Materials and Methods: Eligibility criteria were stage III, IV, or recurrent endometrial cancer with poor potential for cure by radiation therapy or surgery; measurable disease; and no prior chemotherapy. Therapy was randomized to schedules of ST doxorubicin 60 mg/m2 plus cisplatin 60 mg/m2, or CT doxorubicin 60 mg/m2 at 6:00 am plus cisplatin 60 mg/m2 at 6:00 pm. Cycles were repeated every 3 weeks to a maximum of eight cycles., Results: The ST arm included 169 patients, and the CT arm included 173 patients. The objective response rate (complete responses plus partial responses) was 46% in the ST group compared with 49% in the CT group (P =.26, one tail). Median PFS and OS were 6.5 and 11.2 months, respectively, in the ST group; and 5.9 and 13.2 months, respectively, in the CT group (PFS: P =.31; OS: P =.21, one tail). Median total doses were 209 mg/m2 doxorubicin and 349 mg/m2 cisplatin in the ST group, versus 246 mg/m2 doxorubicin and 354 mg/m2 cisplatin in the CT group. Grade 3 or 4 leukopenia occurred in 73% of patients in the ST arm and in 63% of patients in the CT arm. There were eight treatment-related deaths., Conclusion: In this trial, no significant benefit in terms of response rate, PFS or OS, or toxicity profile was observed with CT doxorubicin plus cisplatin in patients with advanced or recurrent endometrial carcinoma.

We evaluated the ability of a short course of treatment with the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) and two novel RR inhibitors Trimidox (TX) and Didox (DX) to influence late-stage murine retrovirus-induced lymphoproliferative disease. LPBM5 murine leukaemia virus retrovirus-infected mice were treated daily with HU, TX or DX for 4 weeks, beginning 9 weeks post-infection, after development of immunodeficiency and lymphoproliferative disease. Drug effects on disease progression were determined by evaluating spleen weight and histology. Effects on haematopoiesis were determined by measuring peripheral blood indices (white blood cells and haematocrit) and assay of femur cellularity and femoral and splenic content of colony-forming units granulocyte-macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E). HU, TX and DX partially reversed late-stage retrovirus-induced disease, resulting in spleen weights significantly below pre-treatment values. Spleen histology was also improved by RR inhibitor treatment (DX>TX>HU). However, as expected, HU was significantly myelosuppressive, inducing a reduction in peripheral indices associated with depletion of femoral CFU-GM and BFU-E. In contrast, although TX and DX were moderately myelosuppressive, both drugs were significantly better tolerated than HU. In summary, short-term treatment in late-stage murine retroviral disease with HU, TX or DX induced dramatic reversal of disease pathophysiology. However, the novel RR inhibitors TX and DX had more effective activity and significantly less bone marrow toxicity than HU.

The purpose of this study was to assess the physical response of skin to laser resurfacing in a real-time, quantitative fashion. The study was designed to assess skin contraction from two opposite standpoints. First, change in tension was measured during laser application while samples were held at constant length. Second, change in length of a sample under no tension was measured during laser treatment. These two disparate analyses represent the two possible extremes of the clinical situation in which skin exists under some tension with some laxity to allow for decrease in length. A custom apparatus with digital interface for skin tension measurements was used to produce single sample tracings of change in skin tension with laser treatment. Length change was measured for individual samples by continuous sonomicrometer readings. Individual sample data were then plotted in a time versus tension/length graph. Skin contracts immediately to a peak level and then relaxes to a sustained plateau level for both CO2 and erbium:YAG lasers. Increased contraction was noted when the beam penetrated into the dermis. Greater peak and plateau contraction is observed after the beam has penetrated into the dermis. Skin contraction varies directly with energy for CO2 and erbium:YAG laser. Findings were similar when skin tension was measured with the sample held at constant length and when length change was measured with the sample under no tension. Char left on the skin after a pass with CO2 laser substantially decreases skin contraction. High-density settings with CO2 laser yield pulse stacking, which effectively irradiates the same portion of tissue with char on it. Skin contraction varies inversely with computer pattern density settings for CO2 laser due to this pulse stacking effect. Density has little effect on skin contraction for the erbium:YAG laser because little char is generated. Histologic analysis identified a zone of coagulated dermis that correlates linearly with skin contraction.

Transforming growth factor beta (TGF-beta) can promote late stage tumor progression in a number of model systems. In the present study, we have examined whether expression of a truncated soluble extracellular domain of TGF-beta type III receptor (sRIII) in human breast cancer MDA-MB-231 cells can antagonize the tumor-promoting activity of TGF-beta by sequestering active TGF-beta isoforms that are produced by the cancer cells. The secretion of sRIII reduced the amount of active TGF-beta1 and TGF-beta2 in the conditioned medium. This led to a significant reduction of the growth-inhibitory activity of the medium conditioned by sRIII-expressing cells on the growth of mink lung epithelial CCL64 cells in comparison with the medium conditioned by the control cells. The tumor incidence and growth rate of all of the three sRIII-expressing clones studied were significantly lower than those of the control cells in athymic nude mice. Four of five control cell-inoculated mice showed spontaneous metastasis in the lung, whereas none of the sRIII-expressing cell-inoculated mice had any lung metastasis. Thus, our results suggest that the sRIII may be used to antagonize the tumor-promoting activity of TGF-beta.

This article reviews the "state of practice" with regard to sentinel lymph node biopsy, a new and evolving technique currently used most commonly for staging of malignant melanoma and adenocarcinoma of the breast. Sentinel lymph node biopsy has the potential to both increase the accuracy of lymph node sampling as a prognostic tool and to decrease the need for unnecessary and morbid extensive lymph node dissection in such patients. The need for close cooperation and planning involving the surgeon and pathologist is stressed, and gross room tissue handling, radiation safety, microscopic examination, and the use of ancillary diagnostic techniques are discussed.

A method is described that permits the selection of spontaneously transformed mammary epithelial colonies from an untransformed mouse mammary epithelial cell line, NMuMG, and utilizes a long-term anchorage-independent growth of the transformants on soft agarose. These transformed cells (NMuMG-ST) are shown to be distinguishable from the untransformed cells by morphology, growth characteristics, induced carcinomas when transplanted into nude mice and ability to metastasize. This transformed phenotype displayed focal, multilayer growth and higher saturation density in comparison with the untransformed phenotype. Transplanted tumors as well as metastatic lung tumors in nude mice were adenocarcinomas morphologically similar to typical mammary tumors in humans. This selection procedure of mutant mammary cells from an immortalized cell line derived from normal mammary glands could be very useful to identify the genomic biomarkers in the growth regulation and malignant progression of breast cancer.

The role of surgery in the treatment of Stage I and II non-Hodgkin's thyroid lymphoma (NHTL) is not well defined. At our institution, we have treated seven patients (six women and one man) with NHTL during the past 6 years. Three patients (43%) had a prior history of thyroid disease, usually lymphocytic thyroiditis. Clinical symptoms included a rapidly enlarging neck mass (86%), dysphagia (71%), dyspnea (71%), and hoarseness (71%). Five patients (71%) had hypothyroidism; one patient, hyperthyroidism; and one patient, normal thyroid function. Five patients underwent fine-needle aspiration (FNA) at our institution. In three instances, FNA results were indicative of NHTL; the remaining FNA tests yielded no diagnosis. Surgical procedures were varied: incisional biopsy (n = 4), limited tumor debulking with tracheostomy (n = 2), and thyroidectomy (n = 1). Each of the seven patients was found to have large cell lymphoma. Treatment consisted of combination chemotherapy with consolidative irradiation. All tumors dramatically decreased in size soon after the initiation of therapy. One patient refused radiotherapy. All patients except one are still alive (median follow-up, 24 months). In conclusion, 1) a diagnosis of NHTL, although rare, should be considered when patients have rapidly growing goiters; 2) FNA is a useful first step in diagnosing NHTL; 3) NHTL is exquisitely sensitive to both chemotherapy and radiation; 4) surgical intervention is generally confined to incisional biopsy with occasional limited pretracheal tumor debulking; and 5) when a biopsy is obtained from a patient suspected of having NHTL, immediate processing by the pathologist is recommended so that material can be obtained for special studies as needed.

Objectives: To determine whether a very small focus of prostate cancer in a needle biopsy specimen correlates with organ-confined disease or with favorable disease parameters., Methods: Of 598 needle biopsies of the prostate performed from January 1990 through June 1994, 49 specimens (8.2%) contained a microscopic focus (less than 2 mm in length of the entire biopsy core specimen) of adenocarcinoma. For these 49 patients, the clinical and pathologic features were correlated., Results: Of these 49 patients, 27 (55.1%) underwent either radical prostatectomy, with or without pelvic lymph node dissection (26), or pelvic lymph node dissection alone (1). Seven of these 27 patients (25.9%) had extraprostatic disease: lymph node involvement (1), positive surgical margins (5), or seminal vesicle invasion (1). Ten of the 49 patients (20.4%) underwent radiotherapy, and 12 (24.5%) chose hormonal therapy. The pathologic stage for these 22 patients could not be ascertained. However, despite the limited amount of disease in the biopsy specimen, 2 patients treated with radiotherapy suffered a relapse (mean interval to recurrence, 11.5 months), and 3 patients treated with hormonal therapy (early or delayed) had bony metastasis at the time of diagnosis. Overall, 12 of the 49 patients (24.5%) had unfavorable disease (as defined by extraprostatic disease on pathologic specimen, relapse after radiotherapy, or bony metastasis at the time of diagnosis)., Conclusions: These findings suggest that a microscopic focus of prostatic adenocarcinoma in a needle biopsy specimen, per se, does not predict the pathologic stage or the biologic behavior of a tumor.

We studied the expression of p53 gene product in pancreatic adenocarcinomas of the usual ductal type to determine its relationship to cigarette smoking and its usefulness as an independent prognostic indicator. Twenty-six resection specimens of pancreatic adenocarcinoma were examined by immunohistochemistry using an antigen retrieval solution and monoclonal PAb1801 and polyclonal CM1 antibodies on paraffin-embedded material. Specific nuclear p53 expression for both PAb1801 and CM1 was identified in seven cases (27%). In all cases immunoreaction was confined to neoplastic cells. Three of four (75%) tumors from patients who had never smoked showed immunoreaction, whereas only three of 14 (21%) tumors from smokers showed positive staining. Cases with positive staining had shorter mean survival (6.3 mo) than cases that failed to stain (9.8 mo), but the difference was not statistically significant in this small study. There was no statistically significant association between p53 immunoreactivity and other clinicopathologic parameters. Our findings indicate that abnormalities of p53 gene in pancreatic adenocarcinomas may not be directly related to cigarette smoking. Those patients who survived the longest tended to have tumors negative for p53 immunostaining. p53 immunoreaction may be a useful feature in distinguishing adenocarcinoma from chronic pancreatitis in small biopsies.

To investigate the etiologies for discrepancies between cervicovaginal smear and corresponding cervical biopsy results, 615 patients with cytologic diagnoses of dysplasia or malignancy during 1 year were reviewed. Sixty-nine patients (11%) were identified in which the cytologic and histologic diagnoses differed. Utilizing an algorithm developed for the study, these cases were assigned an etiologic category for discrepancy: colposcopic biopsy or cytologic sampling, cytologic screening, histotechnical processing, histologic or cytologic interpretation. The most common cause for a discrepancy was colposcopic biopsy sampling (36 cases, 51%). There were nine errors (13%) in biopsy interpretation, with seven underdiagnoses and two overdiagnoses. Eight errors (11%) in cytologic interpretation occurred with half of these representing underdiagnoses. The other causes for discrepancy were less common--cytologic sampling (6 cases), histotechnical processing (3 cases), cytologic screening (2 cases), and a combination of factors (5 cases). Use of this algorithm allows laboratories to identify problem areas and design specific corrective protocols to improve diagnostic accuracy and patient care.

Histologic grading of adenocarcinoma of the prostate gland is a reliable predictor of extension and metastasis. Studies involving correlation of grade between biopsy and prostatectomy specimens have traditionally involved biopsies using a large-bore (14-gauge) cutting needle. However, common practice has shifted to the use of biopsy cores with a smaller caliber (18 gauge). This study was undertaken to determine the degree of correlation of tumor grade between 18-gauge core biopsy samples and excised glands. Sixty-seven patients with stage A or B adenocarcinoma of the prostate gland who had previously undergone 18-gauge core biopsy, who underwent radical prostatectomies, were studied. The Gleason score was determined by referred consensus among three pathologists. There was exact agreement between biopsy and excision in 39 cases (58%), whereas 24 cases (36%) differed by one digit. Three cases (4.5%) were undergraded, and one case (1.5%) was overgraded by two or more points. Only six tumors (8.9%) would have been incorrectly specified by the degree of differentiation. Discrepancies in grade of two points or more were not more frequent in cases with a small tumor volume (< or = 10%) in the biopsy specimens. We concluded that with careful histologic evaluation, the grade of tumor identified in these smaller biopsy cores correlates well with that seen at prostatectomy.

Background: Primary small cell carcinoma of the head and neck is rare. Although the larynx is the most prevalent site of head and neck small cell carcinoma (SCC), this report will concentrate on SCC of the major salivary glands and paranasal sinuses. In all, 33 cases of paranasal sinus and 43 cases of major salivary gland SCC have been reported in the literature., Methods: We report two patients, one with submandibular gland SCC and the other with maxillary sinus SCC. A literature review of all known paranasal sinus and major salivary gland SCC with inclusion of data from these two new cases is undertaken. Discussion of all past and present cases concentrates on sites of metastasis, treatment, and survival., Results: Paranasal sinus SCCs predominantly arise from the nasal cavity, whereas the parotid gland is the primary site in three fourths of major salivary gland SCCs. One half of major salivary gland and three fourths of paranasal sinus SCCs have only local disease at presentation. Both patients in this report developed bone marrow metastases, a feature heretofore not observed in SCC from these primary sites. The patient with maxillary sinus SCC developed the syndrome of inappropriate antidiuretic hormone (SIADH)., Conclusion: The paranasal sinus and major salivary glands are rare primary sites for SCCs. Long-term survival with local therapy in patients with local disease can occur, but in patients with metastatic disease survival mirrors metastatic pulmonary SCC.

Objective: The utility of an antibody to proliferating cell nuclear antigen (PCNA), a growth-specific nuclear protein, was assessed as a prognostic variable for prostatic adenocarcinoma. Its expression was correlated with established prognostic indicators, including tumor grade, stage, prostatic-specific antigen (PSA), and percent of tumor in the gland at excision., Methods: Forty archival needle biopsies containing a minimum of four hundred tumor cells were analyzed. Immunoperoxidase staining of paraffin sections was performed for PCNA (PC10) after pretreatment in antigen retrieval solution. A proliferative index (PI) for each case was derived using image analysis with measurement of at least four hundred twenty-five nuclei., Results: PI values ranged from 2.4 to 31.3 percent. Mean PI values varied significantly (ANOVA, p = 0.005) among cases with dominant Gleason grade (DGG) of 3 (mean PI = 9.3%), 4 (mean PI = 13.7%), and 5 (mean PI = 18.8%). By t test, significant differences were noted for PI in cases with DGG 2 and 3 versus those with DGG 4 and 5 (p = 0.0065). PI for cases with DGG 3 versus 5 showed significant difference (p = 0.0017). Tumors of Gleason scores 5 to 7 differed significantly from those with scores 8 to 10 (p = 0.014). A statistical relationship for PI and PSA, clinical stage, and percent tumor at resection could not be established by linear regression., Conclusions: These findings suggest that additional study of the PI, as determined by PCNA immunohistochemistry and image analysis, may be warranted to determine its usefulness as an adjunctive parameter in prostate adenocarcinoma. This technique may be particularly useful in needle biopsies where limited tumor may render assessment of grade difficult.

Fifty-six specimens of gastric carcinoma were examined for the localization of HER-2/neu oncoprotein (HER-2/neu) and epidermal growth factor receptor (EGFR) by immunohistochemistry using polyclonal antibodies on paraffin-embedded material. Strong membrane staining for HER-2/neu was noted in 14 cases (25%), all of which were of the intestinal type. Only cytoplasmic staining was found in an additional 21 cases (37.5%), including seven diffuse tumors. Twenty-four cases (nine diffuse and 15 intestinal) showed cytoplasmic staining with accentuation on the cell membrane for EGFR. Patchy staining was common for HER-2/neu, while EGFR immunoreactivity was always diffuse. Twenty cases (35.7%) showed positive staining for both, 15 cases (26.8%) for HER-2/neu only, four cases (7.1%) for EGFR only, and 17 cases (30.4%) for neither. Expression of HER-2/neu was more commonly associated with intermediate-grade and high-stage tumors. Cases with positive (either membrane or cytoplasmic) staining for HER-2/neu showed poorer overall mean survival (308 days) than cases that failed to stain (763 days). The EGFR-positive cases showed shorter mean survival (387 days) than the negative cases (547 days), but this difference did not reach statistical significance. The EGFR positivity did not further reduce survival in HER-2/neu-positive cases (362 days). The results of this study support the hypothesis that the expression of HER-2/neu may be a significant predictor of prognosis in patients with gastric carcinoma. Our findings also suggest that expression of these two closely related protooncogenes in malignant and benign gastric tissues is independent of each other and that EGFR does not potentiate the oncogenic effect of HER-2/neu.

Adenocarcinoma accounts for a small percentage of neoplasms arising within the renal pelvis. We describe a mucinous adenocarcinoma of the renal pelvis that occurred in a 57-year-old woman. Investigation of the recent literature reveals an additional 12 cases of adenocarcinoma of the renal pelvis reported since 1980. These 13 cases are summarized in detail, for a total of 59 cases of adenocarcinoma of the renal pelvis documented in the English-language literature. These tumors can be subdivided into three major histologic types: tubulovillous, mucinous, and papillary non-intestinal. The tubulovillous and mucinous tumors are morphologically similar to intestinal tumors accounting for 71.5% and 21.5% of cases, respectively. They are believed to arise in foci of intestinal metaplasia. Only three cases (7%) were of the nonintestinal, nonmucinous, papillary subtype. These rare tumors are notable for their morphologic similarity to Bellini or collecting duct carcinoma, but a specific morphologic precursor has not been identified. Of the three subtypes, tumors of tubulovillous morphology confer the worst prognosis with 70% of patients dying within 5 years. Thirty-three percent of mucinous tumors and none of the papillary nonintestinal tumors were fatal.

Five previously unreported cases of congenital epulis of the newborn are presented. All five cases were on the anterior maxillary alveolar ridge. Four were removed at 2 days of age and one at 7 weeks. Light microscopy demonstrated large eosinophilic granular cells within vascular fibrous connective tissue. Immunohistochemical studies revealed a positivity for vimentin and neuron specific enolase. Cytogenetic evaluation performed on one case was normal. Estrogen and progesterone receptors were absent in the one case so studied. Electron microscopy demonstrated tumor cells that were filled with autophagosomes. Cellular organelles were significantly reduced and inversely related to the number of cytoplasmic autophagosomes. Many of the autophagosomes contained collagen precursors. Poorly formed junctional complexes were seen. Occasional tumor cells demonstrated long processes that contained contractile microfilaments, pinocytosis, and areas of exocytosis. These studies suggest the tumor cells represent early mesodermal cells that express pericytic and myofibroblastic features that undergo cytoplasmic autophagocytosis.

Clinical acute graft-versus-host disease (aGVHD) was correlated with alterations in PBL phenotype and skin immunohistology in 52 patients transplanted with HLA-identical bone marrow. Concurrent with the emergence of aGVHD, there was a profound decrease in absolute number of CD3- T cells and an increase in CD3-CD16+, CD56+ (a subset of which coexpress CD8+ "dim") NK cells in the PBL. CD4+ T and CD20+ B lymphocytes failed to recover within 90 days in the patients with grades II-IV aGVHD. Ex vivo partial T cell depletion, in itself, did not significantly impair T cell recovery as compared to that in non-T-depleted recipients unless aGVHD occurred. Although leukocytic cellular infiltration in the skin was generally sparse, CD16+ NK lymphocytes were significantly increased in grades II-IV aGVHD. By contrast, there was no significant increase in CD3+, CD4+, or CD8+ lymphocytes in these lesions as compared to skin biopsies obtained from BMT patients without aGVHD or from normal skin. Taken together, these findings suggest that NK cells may be important in the pathogenesis of human aGVHD.

Lymphangiomyomatosis (LAM) is a progressive disease afflicting women of childbearing age. LAM remains a rare disease, unfamiliar to many clinicians. It usually poses a diagnostic dilemma for the primary physician, possibly resulting in a delayed or missed diagnosis, unnecessary operative intervention, and inappropriate therapy. LAM is characterized microscopically by abnormal smooth muscle proliferation causing gradual obstruction of small airways, lymphatics, and vasculature. The proliferation eventually results in a characteristic clinical syndrome of progressive dyspnea, recurrent pneumothorax, chylous effusion, and hemoptysis. Despite a variety of treatment regimens developed since the first description of LAM, patient survival has not improved appreciably. Most patients die within 10 years of the time of diagnosis. This report presents a patient with LAM and a review of the literature.

Murine AIDS (MAIDS) is a disease that shows many similarities to human HIV infection. The etiological agent of MAIDS is a defective murine leukemia virus that seems to be able to induce disease in the absence of viral replication. This animal model has been useful in stimulating the search of answers to questions and the formation of new hypotheses related to human AIDS. The monovalent cation lithium can influence a number of immunohematopoietic cell types and cellular processes where proliferation and differentiation occur. We describe here the result of in vivo studies investigating the effect of lithium treatment on MAIDS-infected mice. Viral control and lithium-treated animals were monitored for survival and development of MAIDS pathology. MAIDS animals treated with lithium demonstrated a marked reduction in their development of lymphadenopathy and splenomegaly. Both MAIDS control and lithium-treated virus-infected mice developed evidence of lymphoma; however, the involvement was much more massive both at the gross and microscopic levels in the MAIDS control compared with the lithium-treated mice. These data suggest that lithium may be effective in modulating murine immunodeficiency virus infection and raise important questions related to the potential role lithium may play in the pathophysiological processes associated with retroviral infections.

Granulocyte macrophage-colony-stimulating factor (GM-CSF) has shown promise as a means of alleviating leukopenia associated with a wide variety of disorders. It is currently undergoing evaluation as an adjunct to bone marrow transplantation but its use in patients with metabolic disorders, such as Hurler's syndrome (HS), has not been explored. We followed bone marrow morphology in a 2-year-old male with HS who received up to 8 micrograms/kg GM-CSF per day because of failure of allogeneic bone marrow engraftment. Both premortem and postmortem bone marrow sampling revealed almost complete replacement of the marrow space by sheets of histiocytes demonstrating metachromatic cytoplasmic granules. Such cells were present in far greater numbers than are usually seen in untreated patients with HS or patients with HS undergoing successful bone marrow transplantation without GM-CSF. Moreover, the in vitro culture of bone marrow from a second HS patient showed a GM-CSF dose-related increase in colony formation up to a dose of 250 units/ml. Microscopic examination of these colonies showed a high percentage of histiocytes identical to those seen in the patient's bone marrow. These observations suggest that caution should be exercised when considering administration of CSFs to patients with HS and similar metabolic storage diseases.

A patient with signet ring adenocarcinoma of the stomach with metastatic disease to the breast treated at our institution is presented and added to the 14 cases reported in the literature. A review of the common clinical features and possible mechanisms of metastases is given. While the majority of patients present with symptoms referable to their gastric malignancy, the patient in this case initially sought treatment because of her breast mass. Metastatic deposits within the breast may be difficult to distinguish from primary breast carcinoma. For this reason, immunohistochemistry utilizing carcinoembryonic antigen (CEA), C-ERB B-2, and gross cystic protein were used in this case to confirm an extramammary source. In order to prevent unnecessary breast surgery and provide proper treatment of the gastric primary, the patient's complete clinical presentation must be used to guide diagnostic evaluation.

An unusual case of angiotrophic lymphoma diagnosed initially in the uterus is described. Immunohistochemical studies documented the intravascular tumor cells in the myometrium to be of B lymphocytic origin. The patient's bone marrow was hypercellular, and cytogenetic studies of the aspirate revealed a subpopulation of cells with multiple clonal chromosomal abnormalities. To our knowledge, this is the first case to document abnormal cytogenetic findings in this uncommon malignancy.

Treatment with human recombinant interleukin-2 (rIL-2) is associated with multiple organ dysfunctions, including hepatic and cardiac toxicities. We present a rabbit model that may be highly suited to investigations of these organ toxicities. Rabbits were treated with rIL-2 at a dose of 3 x 10(6) Cetus units/kg/day in divided doses every 8 h for 9-11 doses. Control animals received either excipient or 5% dextrose in water. Treatment with rIL-2 resulted in hepatic and myocardial infiltration by lymphocytes and mononuclear cells. Monoclonal antibody-staining techniques revealed a high percentage of T lymphocytes. It remains to be shown whether these infiltrates are responsible for the respective organ toxicities or represent merely an epiphenomenon of rIL-2 treatment.

Human recombinant interleukin-2 (rIL-2), with or without lymphokine-activated killer cells, has been shown to mediate tumor regressions in animals and in humans. A well-recognized adverse effect of rIL-2 is the development of a generalized vascular leak syndrome that involves the pulmonary microvasculature. We present a rabbit model for the study of rIL-2 pulmonary toxicity that closely reflects the human situation. Rabbits were treated with rIL-2 (Cetus) by two dose/schedule schemata. Separate control groups received rIL-2 excipient (Cetus) or 5% dextrose in water (D5W). In a short-term model, animals were treated with 10(6) Cetus units of rIL-2 in five bolus injections of 200,000 Cetus units each. In a long-term model, rabbits were treated with 3 (x) 10(6) Cetus units/kg of rIL-2 daily in three divided doses every 8 h for 9-11 doses (a schedule analogous to one used in human trials). Following treatment, animals were killed and examined for evidence of pulmonary toxicity. Among the treatment and control groups, there was no evidence of pulmonary leukostasis as determined by mean alveolar septal wall granulocytes per high power field or mean lung myeloperoxidase activity per gram of tissue. While there were no differences among the three treatment groups with regard to pulmonary edema formation (wet/dry weights), there was a tendency toward statistically significant differences between the rIL-2 and control groups. Pulmonary vascular permeability was assessed using i.v.-administered [125I]rabbit serum albumin (RSA) and expressed as mean bronchoalveolar lavage fluid/plasma [125I]RSA ratios. The rIL-2-treated animals had significantly increased pulmonary extravasation of [125I]RSA compared to controls, but there were no differences between the excipient- and D5W-treated controls. Lungs from rIL-2-treated (but not controls) animals displayed marked ultrastructural changes by electron microscopy in the arteriolar segment to include intracellular and subcellular blebs throughout the arteriole with separation of endothelial cells from basement membrane, interstitial edema, endothelial adhesion, and transmigration of lymphocytes into interstitium. Immunoperoxidase stains using an antirabbit T-cell monoclonal antibody demonstrated significant T-cell infiltration into the pulmonary interstitium of rIL-2-treated animals compared to controls. The long-term treatment model described appears to be highly suited for studies of rIL-2-induced pulmonary toxicity.

The authors present an example of mycosis fungoides which was initially diagnosed from a palatal biopsy. The distinctive nuclear morphology of the tumor cells, with a discussion of their diagnostic importance, is presented. The advantages of plastic-embedded formalin-fixed tissue are delineated.

Terminal transferase (TdT) activity and antigen have been measured in 267 specimens of human bone marrow and peripheral blood by using a biochemical assay for enzymatic activity and an immunofluorescence test for antigen. Oligo p(dA)50 and dGTP were used as reagents in the biochemical assay and either rabbit anti-calf TdT or rabbit anti-human TdT was used as the primary antibody for immunofluorescence. Because both false-positive and false-negative detection of TdT antigen occurs, the biochemical assay of TdT activity is considered the standard against which immunofluorescence assays must be measured. If specimens of cells contained TdT activity, then the immunofluorescence detected antigen in 91% of cases (rabbit anti-calf TdT) and 95% of cases (rabbit anti-human TdT). When no TdT activity was detected, the immunofluorescence test was positive in 7.8% of cases (rabbit anti-calf TdT) and 5.2% of cases (rabbit anti-human TdT). When air-dried slices were shipped by air mail to a distant location before being stained for immunofluorescence, TdT antigen was detected in only 33% of matched pair cases which contained TdT activity. From this study, the authors conclude that with current methodology, immunofluorescence tests for TdT antigen must be carried out on slides prepared in the testing laboratory and that such tests are reliable in more than 90% of cases. However, because a small percentage of results are false positives and false negatives, the authors suggest that if a patient's clinical response is not consistent with the immunofluorescence TdT result, an enzymatic assay for TdT activity be carried out.

The obese Zucker rodent appears to lack a significant induction response after phenobarbital pretreatment. Induction of the hepatic cytochrome P-450 system with phenobarbital is known to enhance acetaminophen hepatotoxicity. The purpose of this study was to evaluate the influence of phenobarbital enzyme induction on acetaminophen hepatotoxicity in the obese and lean Zucker rodent. A preliminary study was performed evaluating the pharmacokinetics of acetaminophen in both the obese and lean Zucker rats. Data were utilized to calculate appropriate loading doses of acetaminophen during the subsequent hepatotoxicity study. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received appropriate placebo solutions. Serum hepatic transaminase enzymes and histologic evidence of hepatocellular necrosis were utilized to evaluate hepatic damage after p.o. administration of 1300 mg of acetaminophen to both obese and lean Zucker rats. Obese Zucker control animals had approximately 2.5 times the total hepatic glutathione content compared to their lean control (164.9 +/- 43.2 vs. 65.3 +/- 18.4 mumol/whole liver). Obese Zucker animals receiving only acetaminophen showed a trend toward a reduced incidence of hepatocellular necrosis compared to similarly treated lean littermates. Obese Zucker rodents pretreated with phenobarbital had an even more pronounced resistance to acetaminophen-induced hepatocellular necrosis (P less than .01) when compared to similarly treated lean littermates. Thus, acetaminophen hepatotoxicity is reduced in the obese Zucker rat and pretreatment with phenobarbital offers further protection against hepatocellular damage. We suggest that the previously unrecognized increase in hepatic glutathione plays a major role in the resistance of the obese Zucker rat to acetaminophen hepatotoxicity.

An unusual cytoplasmic distribution of terminal deoxynucleotidyl transferase (TdT) antigen in leukemic cells from two patients who had chronic myelogenous leukemia in blastic phase is described. In most leukemic cells that contain TdT, the intracellular location has been reported to be exclusively nuclear. The cells from these two patients demonstrated TdT staining in both the nucleus and the cytoplasm. The pattern is remarkably similar to that observed in thymocytes, in which bright cytoplasmic staining may also be seen. In the immunofluorescence procedures for detection of TdT in blasts from patients who have chronic myelogenous leukemia, significant cytoplasmic staining should not be mistaken for nonspecific absorption of immunoglobulins or specimen deterioration.

Pseudolymphoma is an uncommon benign lesion of the stomach that poses a difficult problem in diagnosis and management. The clinical manifestations and endoscopic, radiologic, and biopsy findings are not generally helpful in making this diagnosis preoperatively. Histologic examination of the lesion is the only reliable method that distinguishes pseudolymphoma from true lymphoma. Distinguishing histologic features of pseudolymphomas are (1) formation of true germinal centers, (2) presence of a polymorphous inflammatory infiltrate, and (3) absence of lymph nodal involvement by lymphoma. We report four cases and review the literature to illustrate the features of pseudolymphoma. Subtotal gastric resection is done for diagnostic as well as for therapeutic purposes. Distinction of these benign lesions from malignant lymphomas is important so that unnecessary radical surgery and postoperative radiation therapy or chemotherapy are avoided.

We have evaluated a new solid phase enzyme immunoassay (EIA) for detection of terminal deoxynucleotidyl transferase (TDT). The EIA is greater than 100 times more sensitive than previously used tests for enzyme activity. In 284 clinical specimens of human peripheral blood and bone marrow, the EIA detected TdT antigen in 97% of peripheral blood and 100% of bone marrow samples that were positive for enzymatic activity. The excellent sensitivity and specificity of this new test suggests that it can be used in clinical situations where quantitative TdT measurements are desired.