Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease.

Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.

Uterine papillary serous carcinoma: evaluation of long-term survival in surgically staged patients.

OBJECTIVE: Earlier studies have demonstrated that the uterine papillary serous carcinoma (UPSC) variant of endometrial carcinoma has a high recurrence rate, even when disease is apparently confined to the uterus. The current study evaluated survival in patients with surgically staged UPSC. METHODS: Patients with UPSC were identified from surgical pathology files and charts were retrospectively reviewed. Only patients who had undergone a TAH-BSO, lymph node dissection, and peritoneal cytology were included. RESULTS: The FIGO stages of the 36 patients were 12 Stage I (4 IA, 4 IB, 4 IC), 2 Stage IIB, 13 Stage III (5 IIIA, 8 IIIC), and 9 Stage IV. Of the 14 Stage I/II patients, 6 did not receive adjuvant therapy, 5 received whole pelvic radiation (WPXRT), and 3 received whole abdominal radiation therapy (WART); after a median follow-up interval of 50 months only 2 (14%) of these Stage I/II patients have developed a recurrence. Both of the recurrences were in Stage IC patients who received radiation; 1 recurred in the radiation field. Of the 5 Stage IIIA patients, 3 patients declined therapy and 2 were treated with WART; 3 patients, including the 2 who received radiation therapy, are alive without disease. Of the 8 Stage IIIC patients, 2 declined postoperative therapy, 2 received WART, and 4 received WPXRT with an extended field to include paraaortic nodes. Four of the 6 Stage IIIC patients treated with curative intent are without evidence of disease and 1 died of unrelated causes after a median follow-up interval of 48 months. Both of the Stage IIIC patients who declined treatment recurred. Of the 9 patients with Stage IV disease, 8 have died of disease. CONCLUSION: Women with UPSC have a good prognosis when surgical staging confirms that disease is confined to the uterus (Stage I/II). Surgical findings can also be used to tailor adjuvant radiation treatments. Further study is required to define the optimal treatment for women with metastatic UPSC.

A retrospective review of paclitaxel-associated gastrointestinal necrosis in patients with epithelial ovarian cancer.

Seven patients with gastrointestinal necrosis following paclitaxel chemotherapy are reported. Four of seven patients had platinum refractory disease, while 3/7 patients received primary paclitaxel therapy. Complications occurred 5 to 16 days following paclitaxel therapy. The most common clinical presentation was fever (7/7 patients), neutropenia (6/7 patients), and abdominal pain (6/7 patients). All seven patients developed gastrointestinal necrosis following the first cycle of paclitaxel chemotherapy. The exact mechanism by which this complication occurs is poorly understood. We postulate that gastrointestinal necrosis may be the result of a direct drug effect on the gastrointestinal epithelium and might involve a synergistic interaction between compromised bowel and paclitaxel-induced mitotic arrest. We observe that the incidence of gastrointestinal necrosis in patients with platinum refractory disease is 4 of 108 patients (3.7%). The incidence of this complication in patients receiving primary paclitaxel at our institution is 3 of approximately 128 patients (2.3%). Eighteen cases to date have been identified in the literature. A high index of suspicion of this complication should be considered for patients presenting with neutropenic fever and abdominal pain following paclitaxel chemotherapy.

Phase II study of high-dose cisplatin, etoposide, and cyclophosphamide for refractory ovarian cancer.

OBJECTIVES: A phase II trial of high-dose cyclophosphamide, etoposide, and cisplatin was done. STUDY DESIGN: Forty-eight patients with progressive or persistent disease and previous cisplatin-based chemotherapy and no paclitaxel therapy were entered for treatment on the basis of two cycles of cyclophosphamide (4500 mg/m2), etoposide (750 mg/m2), and cisplatin (120 mg/m2). RESULT: Seventy-four cycles were delivered. Six patients died during treatment (12.5%). Of 28 with measurable disease, there was a 25% response rate and 32% had stable disease. Median time to recurrence and survival were significantly different for minimal versus bulky disease (p = 0.0089, p = 0.0008, log rank) and for platinum-sensitive versus platinum-resistant disease (p = 0.18, p = 0.0012, log-rank). The number of prior regimens was not correlated with time to progression or survival. CONCLUSION: This study shows little advantage for high-dose protocols except for patients with a response to platinating agents and minimal residual disease.

The use of intraoperative radiation therapy in radical salvage for recurrent cervical cancer: outcome and toxicity.

OBJECTIVE: Our purpose was to evaluate the contribution of intraoperative radiation therapy in the management of recurrent cervical cancer. STUDY DESIGN: Twenty-two patients were treated with electron beam intraoperative radiation therapy for recurrent cervical cancers that were confined to the pelvis but were too extensive to be adequately treated by radical surgery alone. All patients underwent extensive surgical dissection for exposure and maximal tumor resection. Doses of intraoperative radiation therapy ranged from 14 to 27.8 Gy (median 22 Gy). Twelve patients received intraoperative radiation therapy to address gross residual disease, and 10 patients were treated for microscopically positive or close surgical margins. RESULTS: The five-year disease-specific survival and local control rates were 43% and 48%, respectively. There were trends toward better local control and disease-specific survival in patients with microscopic residual disease compared with those with gross residual disease. Seven patients had peripheral neuropathy related to treatment, and four of these cases resolved. CONCLUSION: In carefully selected cases intraoperative radiation therapy contributes to radical salvage of patients with recurrent cervical cancer involving the pelvic wall.

Role of expanded clay and porous ceramic amendments on plant establishment in minespoils.

Greenhouse experiments were conducted to examine the impact of expanded clay (Turface) or porous ceramic (Isolite) amendments on germination, biomass production, plant Zn concentration, and Zn accumulation by Festuca arundinacea grown in mine tailings. Because previous studies have demonstrated that fertilization is essential for plant growth in these tailings, manure was also added to the tailings. Plant growth and germination were greatest if the expanded clay was added topically to the tailings. To a lesser extent, plant growth and germination was also stimulated by topical additions of porous ceramic. However, no benefit was observed if either amendment was mixed into the top 10 cm of the mine tailings. The concentration of Zn in F. arundinacea tissues was lowest if the expanded clay was added topically to the mine tailings. Roots growing in the layer of clay or ceramic amendment appeared to be smaller, finer, and more abundant than the large, coarse roots found throughout the tailings-manure mixture. These results suggest that topical application of an expanded clay or porous ceramic product will increase seed germination and improve plant establishment and growth in contaminated minespoils.

Primary central nervous system recurrence after paclitaxel therapy for epithelial ovarian malignancy.

Paclitaxel is currently being utilized to treat neoplasms which have a significant incidence of central nervous system metastases. It is, however, unclear as to whether paclitaxel crosses the blood-brain barrier. In this report, the authors describe a patient with refractory epithelial ovarian cancer treated with paclitaxel at 135 mg/m2/24 hr every 21 days. The patient achieved a complete clinical response of all abdominal and pelvic disease, but simultaneously developed central nervous system metastases. Paclitaxel was effective against the patient's abdominal and pelvic disease but was not protective against central nervous system metastasis.

Uterine papillary serous carcinoma: patterns of metastatic spread.

Uterine papillary serous carcinoma (UPSC) is a distinct histologic type of endometrial cancer which is associated with a high relapse rate and poor prognosis. Between 1983 and 1993, 50 patients with UPSC of the endometrium were surgically staged. Thirty-three patients had pure UPSC and 17 had UPSC admixed with other histologies. Extrauterine disease was found in 36 women (72%). Lymph node metastases were present in 36% of women without myometrial invasion, 50% with inner one-half invasion, and 40% with outer one-half invasion. Similarly, the presence of intraperitoneal disease or positive washings did not correlate with increasing myometrial invasion. Grade and histology (mixed vs pure) were also not predictive of extrauterine disease. Patients with lymphatic/vascular space invasion (LVSI) were more likely to have extrauterine disease (85%); however, even without LVSI the incidence of extrauterine disease was 58% (P = 0.05). Unlike endometrioid adenocarcinomas, grade and depth of myometrial invasion were not significant predictors for extrauterine disease. This study reinforces the need for complete surgical staging in all patients with UPSC regardless of depth of invasion.

Uterine smooth-muscle tumors of uncertain malignant potential.

OBJECTIVE: To determine whether tumors meeting the criteria of Hendrickson and Kempson for uterine smooth-muscle tumors of uncertain malignant potential have a natural history different from those of leiomyomas and leiomyosarcomas. METHODS: Tumors with five to ten mitoses per ten high-power fields and with mild or moderate cellular atypia were classified as tumors of uncertain malignant potential. Tumors with two to four mitoses per ten high-power fields and severe cellular atypia would also be classified as tumors of uncertain malignant potential, but we had no tumors that fell into this latter group. Forty-seven women with leiomyosarcoma or smooth-muscle tumors of uncertain malignant potential were identified. Paraffin-embedded blocks were recut, and hematoxylin and eosin-stained sections were studied for mitotic counts and cellular atypia. Statistical analysis used chi 2, Fisher exact test, Student t test, and Kaplan-Meier life table analysis. RESULTS: Fifteen tumors were classified as uncertain malignant potential and 32 as leiomyosarcomas. The patients with leiomyosarcoma were significantly older and more likely to present with extrauterine disease. Those with tumors of uncertain malignant potential had a 5-year disease-free survival of 66% and overall survival of 92%, compared to 28 and 40%, respectively, for leiomyosarcomas; these differences were statistically significant. Patients with tumors of uncertain malignant potential tended to have a protracted clinical course after development of recurrence, and several survived longer than 5 years with metastatic disease. CONCLUSIONS: Patients with five to ten mitoses per ten high-power fields and mild to moderate cellular atypia had a prognosis significantly better than that of patients with leiomyosarcomas. In this group, only 27% developed a recurrence, and after recurrence they tended to have a protracted course. Some of these tumors do have a very aggressive course, and the term "uncertain malignant potential" is appropriate.

Paclitaxel (Taxol) treatment for refractory ovarian cancer: phase II clinical trial.

OBJECTIVE: Our aim was to determine the efficacy and toxicity of paclitaxel in the treatment of refractory and platinum-resistant epithelial ovarian cancer. STUDY DESIGN: Eligibility required three prior failed chemotherapy regimens and documented platinum resistance. One hundred patients with advanced ovarian cancer received paclitaxel 135 mg/m2 over 24 hours every 21 days with optional granulocyte colony-stimulating factor support. RESULTS: Paclitaxel was generally well tolerated. In four patients bowel perforation or fistula developed. After three cycles 34% of patients had stable disease and 25% of patients demonstrated a response, either partial or complete. After six cycles 24% of patients continued to respond. To date, six patients have achieved a complete response. CONCLUSION: A 25% response rate in patients with refractory ovarian cancer was observed, which was durable to six cycles.

The influence of mycorrhizal symbiosis and fertilizer amendments on establishment of vegetation in heavy metal mine spoil.

Biomass production of Andropogon gerardii and Festuca arundinacea was assessed in mine tailings (chat), a material containing high levels of zinc. The effects of organic and inorganic fertilizer amendments, the addition of an expanded clay material, and mycorrhizal fungi on the revegetation of chat were assessed. Plant growth in chat was best with mycorrhizal inoculation combined with nitrogen (either organic or inorganic) and phosphorus fertilization. Plant growth was also achieved if the chat material was amended with expanded clay and N and P fertilizer. However, the biomass produced in contaminated soil did not equal that of similarly fertilized uncontaminated soil. Regression analysis and canonical discriminate analysis revealed significant differences in the responses of the two plant species to the various chat amendments. Although F. arundinacea generally produced greater biomass than A. gerardii, it tended to accumulate more zinc in the shoots than A. gerardii. Therefore, if plant cover is to be used as forage or if wind-blown plant dry matter is of concern, A. gerardii may be more appropriate than F. arundinacea for revegetation of these toxic sites. Alternatively, if maximum plant cover is of primary importance to reduce wind or water erosion from contaminated soils, F. arundinacea may be the species of choice.

Effects of mycorrhizae and other soil microbes on revegetation of heavy metal contaminated mine spoil.

The effects of mycorrhizal fungi and other soil microorganisms on growth of two grasses, Andropogon gerardii Vitm. and Festuca arundinacea Schreb., in heavy metal-contaminated soil and mine tailings were investigated. A. gerardii is highly dependent on mycorrhizal fungi in native prairie, while F. arundinacea is a facultative mycotroph and relies on mycorrhizal symbiosis only in extremely infertile soils. Regardless of microbial amendments, neither plant species was able to establish and grow in the mine tailings. Both plant species grew in the moderately contaminated or non-contaminated soils, although A. gerardii grew in these soils only when mycorrhizal. Other soil microbes significantly improved growth of A. gerardii only in uncontaminated soil, but to a lesser extent than mycorrhizae. Although F. arundinacea was more highly colonized by mycorrhizal fungi than A. gerardii, neither microbial amendment affected growth of fescue in any soil. In several treatments mycorrhizal fungi adapted to uncontaminated soil stimulated plant growth more than mycorrhizae adapted to the moderately contaminated soil. However, mycorrhizal fungi adapted to contaminated soil did not increase the productivity of plant growth in contaminated soil more than fungi adapted to uncontaminated soil. A. gerardii plants inoculated with mycorrhizal fungi retained more Zn in roots than in shoots, confirming earlier reports that mycorrhizal fungi alter the translocation pattern of heavy metals in host plants. In contrast, mycorrhizae did not affect translocation patterns in F. arundinaceae, suggesting that the mycorrhizal dependence of a plant species is correlated with the retention of metals in roots. The correlation between mycorrhizal dependence of a plant species and mycorrhizal alteration of translocation pattern may also explain the inconsistent reports of mycorrhizal effects on translocation of heavy metals in plants. Plant response to mycorrhizal symbiosis may therefore provide a useful criterion for the selection of the plant species to be used in revegetation of contaminated sites.

Combined radiotherapy and chemotherapy in the management of local-regionally advanced vulvar cancer.

PURPOSE: To determine, in a retrospective single institutional study, the role of concurrent radiotherapy and chemotherapy in the treatment of local-regionally advanced vulvar cancer. METHODS AND MATERIALS: From 1984 to 1991, 20 patients with locally extensive primary or recurrent carcinoma of the vulva were treated with initial combined radiotherapy and chemotherapy. Seven patients had Federation Internationale de Gynecologie et d'Obstretrique Stage III disease, 10 had Stage IV disease, and three were treated for recurrent disease. None of these patients were considered candidates for primary radical vulvectomy and groin node dissection. Median radiation doses to regions of microscopic disease and gross tumor were 40 Gy (range 30-54 Gy) and 54 Gy (34-70.4 Gy), respectively. All patients received 2 or 3 cycles of 5-Fluorouracil concurrently with radiotherapy. In addition, five patients received Cis-platinum, and one Mitomycin-C. Median at-risk follow-up interval was 37 months. RESULTS: Ten patients had complete resolution of tumor to initial chemoradiotherapy, and eight of these have remained free of tumor relapse. Eight other patients had partial responses, with tumor bulk reduced by > 50%, while the remaining two patients had local-regionally progressive disease. Six of the patients with partial responses had residual tumor successfully resected, although four subsequently recurred. For the entire group of 20 patients, the actuarial 3- and 5-year local control rates were 48% each, and the corresponding disease-specific survival rates were 59% and 49%. There was a suggestion that better local control was obtained in patients who received gross tumor radiation doses > or = 50 Gy. Skin reaction was the major acute toxicity and responded well to conservative management. Long-term sequalae were limited to skin and subcutaneous atrophy. CONCLUSION: These results indicate that initial combined radiotherapy and chemotherapy is effective in the management of advanced vulvar cancer.

Deoxyribonucleic acid analysis by flow cytometry of uterine leiomyosarcomas and smooth muscle tumors of uncertain malignant potential.

OBJECTIVES: The histologic distinction of uterine benign leiomyomas from leiomyosarcomas is difficult. Ploidy analysis and measurement of the proliferative rate were examined to determine if they could distinguish malignant from benign tumors and if they were independent prognostic factors. STUDY DESIGN: Paraffin-embedded blocks were recut and prepared for flow cytometry with the technique of Hedley. Mitotic counts and tumor grading were performed on an adjacent hematoxylin and eosin-stained section. Statistical analysis was carried out with chi 2 life-table, and Cox model analysis. RESULTS: There were 33 patients with deoxyribonucleic acid histograms that were acceptable for analysis. Fourteen tumors were diploid and 19 were aneuploid. There were no significant differences in the clinical characteristics between the patients with diploid tumors and those with aneuploid tumors. Aneuploid tumors were more likely to have cellular atypia (p = 0.085). There was a strong correlation between the percentage of cells in the S phase and the mitotic count (p = 0.0001). Increasing mitotic count, increasing S phase, presence of extrauterine disease, and postmenopausal status were all adverse prognostic factors. However, when multivariant analysis with a Cox model was used, only S phase and presence of extrauterine disease were adverse factors. Diploid tumors have a better overall survival (p = 0.0658) but a similar disease-free survival. In those patients who ultimately have relapses, diploid tumors have a significantly longer interval from relapse to death (p = 0.0045). CONCLUSIONS: Neither ploidy analysis nor measurement of the proliferative rate will distinguish a benign from a malignant course in an individual patient; however, ploidy is predictive of survival from time of disease progression and proliferative rate is the strongest predictor of overall survival. The time-proven reliability of mitotic count in the diagnosis of smooth muscle tumors reflects its ability to predict proliferative rate.

The utility of immunocytochemistry in invasive adenocarcinoma of the cervix.

OBJECTIVES: The purpose of the study was to evaluate the utility of immunocytochemistry in the management of cervical adenocarcinoma. Patterns of reactivity to various immunocytochemical markers were correlated with clinically known risk factors for recurrence. STUDY DESIGN: A retrospective evaluation of 55 patients with invasive cervical adenocarcinoma was conducted. Monoclonal antibodies were generated against various human intermediate filament proteins and tested on fixed, paraffin-embedded tissue by the avidin-biotin complex immunoperoxidase method. Dako V9 antivimentin antibodies and two anticytokeratin antibodies, 35 beta H11 and 34 beta E12, were used. Polyclonal antibodies to carcinoembryonic antigen and antibodies to epithelial membrane antigen were used. RESULTS: Of 55 patients, 50 (91%) had positive epithelial membrane antigen antibodies in tumor cells. Tissue from patients with cervical adenocarcinoma demonstrated positivity for 35 beta H11 antibodies in 46 of 53 patients (87%) and positivity for 34 beta E12 antibodies in 15 of 54 patients (28%). Vimentin antibodies were negative in all except one patient. Carcinoembryonic antigen-positive antibodies were detected in 37 of 55 patients (67%). This study also demonstrated consistent negative expression of vimentin in invasive cervical adenocarcinoma. Carcinoembryonic antigen expression rates were 50% and 75% for patients with small tumors (less than or equal to 2 cm) and large tumors (greater than 2 cm), respectively (p less than 0.01). Patients with carcinoembryonic antigen expression are at increased risk for recurrence and also sustain reduced survival potential. CONCLUSIONS: Patients with cervical adenocarcinoma and carcinoembryonic antigen expression are at increased risk for recurrence. We speculate that immunocytochemistry may detect lymph node micrometastases otherwise unsuspected by conventional microscopy.

Gynecologic radiotherapy fields defined by intraoperative measurements.

Whole-pelvis radiation therapy has been traditionally delivered through fields, the dimensions of which have been determined by convention and based largely on textbook anatomic landmarks. Since July 1986, 100 patients have had intraoperative retroperitoneal measurements carried out at the time of radical surgery in an effort to examine this anatomic basis for field dimensions. Structural measurements of the pelvic and paraaortic arterial branches were made in reference to the lumbosacral prominence to correlate with lymphatic pathways. The mean level of the aortic bifurcation was found to be 6.7 cm above the lumbosacral prominence. The mean level of the bifurcation of the common iliac artery was 1.7 cm above this reference point on the right and 1.4 cm above on the left. Both common iliac bifurcations were cephalad to the level of the lumbosacral prominence in 87% of patients. In only three patients were both bifurcations located below this level. Transverse pelvic dimension measurements demonstrated a width of 12.3 cm at the level of the obturator fossa and of 13.0 cm at the most inferior outside width of the external iliac arteries. To establish a simple external reference which could assist in defining radiotherapy field widths, the maximal separation of the femoral arteries at the level of inguinal ligaments was measured and averaged 14.6 cm. These data suggest that conventional fields frequently fail to correspond to true anatomic landmarks and that to optimally cover the lymphatics in radiotherapy, fields should, ideally, be based on intraoperative measurements. If such surgical guides are not available, we would suggest that standard whole-pelvis radiotherapy for cervical cancers should employ anterior and posterior fields with widths of at least 16 cm which will fully include the bifemoral separation. A superior border at the L4-L5 interspace is required to cover lymphatic pathways to the mid-common iliac nodal level. It may also be convincingly pointed out that the attachments of the uterosacral and cardinal ligaments are clearly posterior to the rectosigmoid, mandating lateral fields that should encompass the entire anterior sacral silhouette.