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Purpose Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer characterized by early metastasis, resistance to therapy, and a high mortality rate. Little is known about the biology of these tumors. Smaller studies suggest that Her-2/neu may be involved in the tumorigenesis of this disease. The purpose of this study was to evaluate the protein expression and gene amplification of Her-2/neu in UPSC and to determine its prognostic value. Patients and Methods Tumor tissue from 68 patients with UPSC treated at The University of Texas M.D. Anderson Cancer Center from 1989 to 2002 was available. Her-2/neu expression was evaluated by immunohistochemistry (IHC). Overexpression was defined as complete membrane staining in greater than 10% of the cells. In tumors with overexpression of Her-2/neu by IHC, fluorescence in situ hybridization (FISH) was performed to assess gene amplification. Clinical and pathologic information was obtained from medical records. Results Twelve (18%) of 68 tumors demonstrated Her-2/neu overexpression. Of these, only two showed gene amplification. When evaluating all 68 patients, Her-2/neu overexpression was associated with a poorer overall survival (OS; P = .008). In our multivariate Cox proportional hazards models, Her-2/neu IHC overexpression, lymph node status, and stage were each associated with OS (P ≤ .05). Conclusion Positive IHC overexpression of Her-2/neu was seen in 18% of UPSCs but was rarely correlated with Her-2/neu gene amplification. Overexpression of Her-2/neu was associated with a worse overall prognosis. The use of trastuzumab (Herceptin; Genentech, South San Francisco, CA) in women with UPSC should be further evaluated in a clinical trial setting.

Purpose Patients with completely resected high-risk endometrial cancer have a risk of disease recurrence even with the addition of adjuvant pelvic radiotherapy (RT). A Phase II study was completed by the Radiation Therapy Oncology Group to assess the safety and toxicity of chemotherapy when combined with pelvic RT for these patients. Methods and materials Eligibility requirements included a total abdominal hysterectomy and bilateral salpingo-oophorectomy with Grade 2 or 3 endometrial adenocarcinoma with >50% myometrial invasion, stromal invasion of the cervix, or pelvic-confined extrauterine disease. This study was designed to administer 4500 cGy in 25 fractions to the pelvis, along with cisplatin (50 mg/m2) on Days 1 and 28. Vaginal brachytherapy with a low-dose-rate applicator (1 × 20 Gy to the surface) or high-dose-rate applicator (3 × 6 Gy to the surface) was performed after external beam RT. Four courses of cisplatin (50 mg/m2) and paclitaxel (175 mg/m2) were given at 4-week intervals after RT completion. Results Forty-six patients were entered between October 1997 and April 1999. Two patients were ineligible (one with previous bladder cancer and one who had undergone surgery >8 weeks before the start of RT). Follow-up ranged from 6.9 to 48.8 months (median, 28.7 months). The disease was Stage III, II, and I in 66%, 16%, and 18% of patients, respectively. Two patients were not assessable because of incomplete treatment data. The protocol completion rate was 98% (41 of 42 assessable patients). Acute toxicity during RT/chemotherapy was Grade 1 in 27%, Grade 2 in 43%, Grade 3 in 27%, and Grade 4 in 2%. During adjuvant chemotherapy, the toxicity was Grade 1 in 7%, Grade 2 in 7%, Grade 3 in 21%, and Grade 4 in 62%. Severe toxicity was primarily hematologic. Chronic toxicity was Grade 1 in 20%, Grade 2 in 39%, Grade 3 in 16%, and Grade 4 in 2%, including 1 patient with a Grade 4 small bowel complication. At 24 months, the pelvic recurrence, regional recurrence, distant recurrence, disease-free survival, and overall survival rate was 2%, 3%, 17%, 83%, and 90%, respectively. Conclusion This treatment protocol demonstrated an excellent treatment completion rate and expected toxicity. Longer follow-up is needed to assess the outcome. To assess the efficacy of this adjuvant treatment program, a Phase III trial (Radiation Therapy Oncology Group 9905) was designed with high-risk uterine-confined disease to be randomized between pelvic RT alone and pelvic RT with chemotherapy.

Circulating insulin-like growth factors (IGFs) and their binding proteins have been associated with increased risk of breast, prostate, colon, and lung cancer. To examine the association of IGFs and endometrial cancer risk, we measured the plasma levels of IGF-1, IGF-2, and IGF binding protein 3 (IGFBP-3) by ELISA in 80 women with endometrial cancer and 80 age-matched control subjects with no history of cancer. Mean plasma levels of IGF-2 were significantly higher in women with cancer versus controls (670 ng/ml versus 380 ng/ml, P < 0.001). In contrast, significantly lower mean plasma levels of IGF-1 (155 mg/ml versus 185 ng/ml, P < 0.01) and IGFBP-3 (1703 ng/ml versus 2170 ng/ml, P < 0.001) were observed among cases compared to the control group. Women in the highest quartile of IGF-2 were found to have 9.67 (95% confidence interval 3.29–28.43) times the risk of endometrial cancer than women in the lowest quartiles. Women in the highest quartile of IGFBP-3 were associated with a significantly decreased risk for developing endometrial cancer (odds ratio = 0.23, 95% confidence interval 0.09–0.60). These data suggest that increased plasma levels of IGF-2 and decreased levels of IGFBP-3 are associated with an increased risk of endometrial cancer. Further validation of these results is needed to determine the potential usefulness of risk assessment.

Objective . To evaluate patients with vulvar cancer who experienced a recurrence after undergoing lymphatic mapping and sentinel lymph node (SLN) biopsy. Methods . We reviewed the records of 52 patients who underwent vulvectomy and lymphatic mapping with blue dye for treatment of vulvar cancer at our institution from 1993 to 1999 and identified patients who experienced recurrent disease. Results . Fourteen (27%) of 52 patients experienced a recurrence. The patients' median age was 60 years (range 35–84 years). Nine patients had squamous lesions, four patients had melanoma, and one patient had Paget's disease with stromal invasion. Four tumors were stage T1, seven were T2, and three were T3. Eight lesions were located at the midline and six were lateral. Thirteen patients underwent superficial inguinal lymphadenectomy while one patient underwent SLN biopsy only. Postoperatively, seven patients underwent no further treatment, six underwent radiation therapy, and one patient underwent chemotherapy. The median follow-up was 46 months and the median disease-free interval was 21 months. Primary recurrence was in the vulva in eight patients (57%), in the groin in three patients (21%), and distant in three patients (21%). Nine of 32 (22%) squamous lesions recurred, four (57%) of seven melanomas recurred, and the sole patient with invasive Paget's recurred. Patient weight was found to be significantly different between patients who experienced a recurrence and those who did not ( P = 0.05). At least one SLN was identified in 46 (88%) of the 52 patients. One (17%) of six patients in whom no SLN was identified experienced a recurrence, and 13 (28%) of 46 patients in whom a SLN was identified experienced a recurrence ( P = 0.5). In the 41 patients with negative SLNs and negative non-SLNs, the recurrence rate was 24%; in the six patients with positive SLNs and negative non-SLNs, the recurrence rate was 40%; and in the five patients with positive SLNs and positive non-SLNs, the recurrence rate was 40% ( P = 0.6). No patients had a negative SLN and positive non-SLN. Of the three patients who experienced a recurrence in the groin, one had a negative SLN and negative non-SLN, one had a positive SLN and positive non-SLN, and one had no SLN identified and a negative non-SLN. Conclusions . This heterogeneous group of patients who underwent lymphatic mapping with blue dye had similar patterns of recurrence to reported series of patients who did not undergo lymphatic mapping. Groin relapse following a negative SLN biopsy is of concern and suggests that long-term follow-up data are required before lymphatic mapping and SLN biopsy alone can be considered standard treatment for patients with vulvar cancer.

The objective of this study was to investigate the cause of groin recurrence in patients with vulvar cancer who had negative nodes in their superficial inguinal lymphadenectomy (SIL) specimens.The records of patients with vulvar cancer treated at M. D. Anderson Cancer Center between 1986 and 1997 were reviewed to identify patients with squamous histology, clinical and surgical stage I or II, depth of invasion greater than 1 mm, and primary treatment consisting of radical wide excision and SIL. One hundred four patients met these criteria. Among these, nine experienced recurrent disease that involved one or both of the groins. All of the original hematoxylin and eosin (HE)-stained slides were reviewed by one pathologist (AM). Then, each paraffin block containing nodal tissue was recut at 40 microm intervals to obtain five sections for HE staining and two unstained sections to be used for cytokeratin immunostaining if necessary.The median age at diagnosis and primary surgery was 65 years and the median depth of invasion was 4 mm. Seven patients underwent bilateral, and two underwent unilateral, groin dissections. The median number of lymph nodes removed per groin was seven. The median time to recurrence was 22 months. A total of 785 additional HE-stained slides were prepared and examined at 100x and 400x magnification. No micrometastases were identified, and there were no other suspicious findings. Therefore, immunohistochemical staining was not performed. At recurrence, one patient had a biopsy only, and eight had attempted surgical resection. In two patients, tumor was identified in fibroadipose tissue only; no lymph nodes were identified. Among the other six patients, the median number of lymph nodes resected at the time of the recurrence was five (range 1 to 10). At last report, six patients had died and three were alive and free of disease. Median follow-up for survivors was 63 months (range 42 to 71).These data strongly suggest that groin relapse in patients with negative nodes on SIL is caused by metastatic disease in unresected inguinal nodes. SIL as performed on the patients in this study did not eliminate all sites of nodal metastasis.

Objective The aim of this study was to determine the efficacy of cisplatin, ifosfamide, and mesna in uterine malignant mixed mullerian tumor (MMMT) and to evaluate the expression of clinically relevant molecular markers. Methods Women with advanced or recurrent MMMT were treated every 28 days with cisplatin (75 mg/m 2 ), ifosfamide (1.2 gm/m 2 ), and mesna (240 mg/m 2 ). Treatment continued until disease progression or for six courses in the case of nonmeasurable disease. Immunohistochemical analysis for estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, C-kit, Abl, and PDGFR-β expression were performed. Results Sixteen patients received 1–10 cycles; 2 died of disease progression after 1 cycle; 3 stopped after 1 cycle because of toxicity. Of 6 with measurable disease, 2 had a partial response, 1 had stable disease (SD), and 3 had progression (RR 33%). Partial response durations were 6 and 9 months; SD duration was 6 months. Of 5 patients without measurable disease, 4 received 6 cycles; 1 received 4 cycles. Four died of recurrent disease and 1 was without disease 6.5 years after treatment. Thirty-six percent experienced at least one neutropenic G3 or G4 event. All experienced G1 gastrointestinal toxicity. Four required dose reductions. At 7.5 months, only 1 with measurable disease was still living. Immunohistochemical analyses revealed that 24% expressed ER or PR, 19% expressed HER-2/neu , and none expressed C-kit . However, 45% expressed Abl and 100% expressed PDGFR-β. Conclusions Although the combination of cisplatin, ifosfamide, and mesna in patients with MMMT had moderate activity, the high toxicity and short response duration in this uncommon, aggressive malignancy suggest that this regiment continues to be a disappointing treatment choice for uterine MMMT. HER-2/Neu , Abl , or PDGFR-β expression may be of value in order to investigate novel multimodality treatment strategies.

To determine the outcome of patients after radical radiotherapy (RT) for isolated vaginal recurrence of endometrial carcinoma and to determine the clinical and pathologic predictors of outcome.We reviewed the records of 91 patients treated at our institution between 1960 and 1997 with radical RT for vaginal recurrence after definitive surgery for endometrial carcinoma. Thirty-one percent of the patients received external beam RT (EBRT) alone, 12% received brachytherapy alone, and 57% received a combination. The median dose of radiation was 75 Gy (range 34-122). All end points were measured from the time of the first recurrence. The median duration of follow-up after recurrence was 58 months (range 1-289).The 2- and 5-year local control (LC) rate and overall survival rate was 82% and 75% and 69% and 43%, respectively. The median time from initial diagnosis of endometrial cancer to death from disease was 38 months. On univariate analysis, a dose to the relapse site ofor =80 Gy and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved LC. On multivariate analysis, only the type of treatment correlated significantly with LC (p = 0.03). On univariate analysis, Grade 1 or 2 vs. Grade 3 tumor and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved overall survival.RT provides excellent LC of isolated vaginal recurrences of endometrial carcinoma, particularly when high doses are given using a combination of EBRT and brachytherapy. However, distant metastases frequently develop despite local disease control, contributing to a 5-year overall survival rate of50%. For patients who have an isolated vaginal recurrence, the time from initial diagnosis of endometrial cancer to death from disease is usually3 years. For this reason, in studies of adjuvant RT, long-term follow-up is required to permit evaluation of the impact of treatment on survival.

Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are unusual neoplasms with histologic features that resemble those within ovarian Sertoli and granulosa cell tumors. We report the case of a 24-year-old woman with a UTROSCT presenting as a cervical mass, which on initial evaluation was thought to represent cervical adenocarcinoma. The patient's cervical biopsy specimen contained epithelioid cells arranged in tubules and anastomosing cords, without significant cellular atypia or mitotic activity. Because this morphology elicited a broad differential diagnosis, immunohistochemical studies were performed. The tumor was found to be diffusely positive for cytokeratin cocktail, calretinin, and desmin, focally positive for CK7 and SMA, and negative for EMA, CEA, inhibin, CD10, CK20, chromogranin, and synaptophysin. Ultrastructural examination revealed occasional gland-like lumens with cells joined by desmosomes and a continuous basal lamina. UTROSCTs have features that may cause them to be confused with more common tumors, especially in limited biopsy samples, and should be included in the differential diagnosis when a gland-forming neoplasm with an unusual appearance is identified in a cervical or endometrial biopsy specimen.

Our objective was to assess the value of lymphangiography in selecting patients for surgical staging of locally advanced cervical cancer. We reviewed our computerized database to identify patients with cervical cancer who had abnormal findings on lymphangiography and underwent retroperitoneal lymph node dissection between September 1991 and January 1996. The records of these patients were retrospectively reviewed, and the following data were retrieved: clinical tumor stage and findings on lymphangiography at surgery, and on pathologic examination of resected lymph nodes. The lymphangiograms were reviewed and reinterpreted in blinded fashion by two of the authors. The positive and negative predictive values of lymphangiography for the presence of lymph node metastases were calculated, with findings on pathologic examination of lymph nodes used as the gold standard. The positive and negative predictive values of surgeons' clinical assessments at surgery were also calculated. Fifty patients met the selection criteria and constituted the study population. Fourteen patients (28%) had histologically negative nodes, and 36 patients (72%) had lymph node metastases. Thirty-three patients had metastases to pelvic nodes, 1515 patients had metastases to common iliac nodes, and 1616 patients had metastases to para-aortic nodes. The positive predictive value of lymphangiography for lymph node metastases was 74% for pelvic nodes, 73% for common iliac nodes, and 88% for para-aortic nodes. The negative predictive value of lymphangiography for lymph node metastasis was 76% for common iliac nodes and 77% for para-aortic nodes. Overall, 46% of the patients selected for surgical exploration had histologic findings of either common iliac or para-aortic lymph node metastases; these findings led clinicians to extend radiation fields to cover the para-aortic lymph nodes. Lymphangiography is helpful in selecting patients with cervical cancer who have a high risk of common iliac or para-aortic lymph node metastasis. However, more accurate and more readily available noninvasive methods of evaluating cervical patients for the presence of regional disease continue to be needed.

Eukaryotic DNA replication requires the previous formation of a prereplication complex containing the ATPase Cdc6 and the minichromosome maintenance (Mcm) complex. Although considerable insight has been gained from in vitro studies and yeast genetics, the functional analysis of replication proteins in intact mammalian cells has been lacking. We have made use of adenoviral vectors to express normal and mutant forms of Cdc6 in quiescent mammalian cells to assess function. We demonstrate that Cdc6 expression alone is sufficient to induce a stable association of endogenous Mcm proteins with chromatin in serum-deprived cells where cyclin-dependent kinase (cdk) activity is low. Moreover, endogenous Cdc6 is sufficient to load Mcm proteins onto chromatin in the absence of cdk activity in p21-arrested cells. Cdc6 synergizes with physiological levels of cyclin E/Cdk2 to induce semiconservative DNA replication in quiescent cells whereas cyclin A/Cdk2 is unable to collaborate with Cdc6. Cdc6 that cannot be phosphorylated by cdks is fully capable of inducing Mcm chromatin association and replication. Mutation of the Cdc6 ATP-binding site severely impairs the ability of Cdc6 to induce Mcm chromatin loading and reduces its ability to induce replication. Nevertheless, the ATPase domain of Cdc6 in the absence of the noncatalytic amino terminus is not sufficient for either Mcm chromatin loading or DNA replication, indicating a requirement for this domain of Cdc6.

Acute respiratory infection (ARI) is a common diagnosis in outpatient and emergent care settings. Currently available diagnostics are limited, creating uncertainty in the use of antibacterial, antiviral, or supportive care. Up to 72% of ambulatory care patients with ARI are treated with an antibacterial, despite only a small fraction actually needing one. Antibiotic overuse is not restricted to ambulatory care: ARI accounts for approximately 5 million emergency department (ED) visits annually in the USA, where 52–61% of such patients receive antibiotics. Thus, an accurate test for the presence or absence of viral or bacterial infection is needed. In this review, we focus on recent research showing that the host-response (genomic, proteomic, or miRNA) can accomplish this task.

This is a report of 52 patients with vulvar cancer who were injected with isosulfan blue dye at the time of their primary surgical treatment. The intent was to identify the sentinel nodes, which are the first nodes to receive metastases from the primary tumor, All patients who had their primary surgical treatment for vulvar cancer at the authors' institutions between 1993 and 1999 were included in the study (N = 52; median age = 58 years, range = 18-92). After preparation for surgery and before the skin incision was made, 1 to 4 ml of isosulfan blue dye were injected into the dermis at the edge of the tumor closest to the groin. Bilateral injections were made when the tumor was located with 2 cm of the midline, Injection sites were massaged for 5 minutes, a deep groin incision was made, and the afferent lymphatic channel was identified. This channel was followed until one or more blue nodes were found. These sentinel nodes were excised and sent for gross histological examination. If the findings were suspicious, a frozen section analysis was done. All nonsentinel nodes were excised and examined separately. The blue dye disappeared within 45 minutes of injection. In 22 of the 52 patients (42%), tumor was diagnosed in the labium. Fourteen patients (27%) had disease in the clitoris. Other tumor sites included the perineum, fourchette, and Bartholin's gland. Squamous cell (67%) and adenocarcinoma (17%) were the most frequent tumor types. Melanoma and Paget's disease were also diagnosed (13 and 2%, respectively). Most patients (81%) underwent superficial inguinal lymphadenectomy. The others had inguinal femoral lymphadenectomy (12%) or sentinel lymph node biopsy (8%). Unilateral groin dissection was performed in the 25 women with lateral tumors and in 3 of the 27 women with a midline tumor. The other 24 patients had bilateral dissection. The blue dye was well tolerated by all patients. Forty-six patients (88%) had at least one sentinel node diagnosed. In all, 76 groin dissections were performed, and the sentinel node was identified in 57 of the dissected groins (75%). When incisional or excisional biopsy preceded the node mapping, the sentinel node could not be identified in 44% of the groin dissections. When only a punch biopsy was performed, the percentage of patients in whom no sentinel node was found was significantly lower (16%, P =.007). The tumor location also had a significant effect on the identification of sentinel nodes. Successful identification was made in 22 of the 25 of women with lateral tumors (88%) and 35 of the 51 women with midline tumors (65%) (P =.067). Sentinel nodes were less likely to be identified in the early years of the study (P =.034). In all, 556 nodes were removed from the 52 women (median = 7 per groin). A total of 83 sentinel nodes were identified (median = 1 in each groin, range = 1-4). Tumor metastases were found in the lymph nodes of 11 patients, 10 with involvement on one side and 1 with a midline tumor. No sentinel node was found in 2 of the 12 groins with metastases, both in patients enrolled during the first 2 years of the study. No false-positive nodes were seen. Since 1995, a successful sentinel node identification has been made in 100% of the patients with T 1 or T 2 primary vulvar squamous cell cancer who had clinically nonsuspicious nodes.

Objective. The aim of this study was to determine the effectiveness and toxicity of monthly treatment with intravenous paclitaxel for women with advanced or recurrent uterine papillary serous carcinoma (UPSC). Methods. Consenting women with histologically confirmed advanced (FIGO stage III or IV) or recurrent UPSC were treated on an Institutional Review Board approved protocol of a 24-h intravenous infusion of 200 mg/m 2 of paclitaxel every 3 weeks. Both measurable and nonmeasurable disease cases were enrolled. Treatment was continued until disease progression, patient intolerance, or (in women with nonmeasurable disease) completion of six courses. Results. Twenty patients received from 1 to 11 cycles of therapy. Two women died of disease after 1 cycle of therapy and were not evaluable for response. Among 13 women with measurable tumor receiving 2 or more cycles of therapy, 4 had a complete clinical response and 6 had a partial response (objective response rate, 77%). The median time to progression was 7.3 months (range, 2–21 months). All 3 remaining patients with measurable disease had stable disease for a median of 6 months. The 5 patients without evaluable disease received 5 to 6 cycles of adjuvant paclitaxel. Three developed recurrence (range, 4–10 months; median, 7.2 months). Neutropenia was the major toxicity. Eleven of the 20 patients required G-CSF support, and 9 were hospitalized for neutropenic fever. One woman had reversible cardiac symptoms, which might have been related to paclitaxel treatment. At the time of analysis (mean follow-up, 23 months; range, 4.3–59.9 months), 13 women had died of disease, 4 were alive with disease, and 2 were disease free. All 3 disease-free patients had been treated for nonmeasurable advanced stage disease. Conclusion. Paclitaxel appears to have excellent activity in the treatment of advanced or recurrent UPSC, an uncommon but aggressive malignancy. Longer survival appears to be more common among women with small-volume disease.

The minichromosome maintenance (MCM) proteins, together with the origin recognition complex (ORC) proteins and Cdc6, play an essential role in eukaryotic DNA replication through the formation of a pre-replication complex at origins of replication. We used a yeast two-hybrid screen to identify MCM2-interacting proteins. One of the proteins we identified is identical to the ORC1-interacting protein termed HBO1. HBO1 belongs to the MYST family, characterized by a highly conserved C2HC zinc finger and a putative histone acetyltransferase domain. Biochemical studies confirmed the interaction between MCM2 and HBO1 in vitro and in vivo. An N-terminal domain of MCM2 is necessary for binding to HBO1, and a C2HC zinc finger of HBO1 is essential for binding to MCM2. A reverse yeast two-hybrid selection was performed to isolate an allele of MCM2 that is defective for interaction with HBO1; this allele was then used to isolate a suppressor mutant of HBO1 that restores the interaction with the mutant MCM2. This suppressor mutation was located in the HBO1 zinc finger. Taken together, these findings strongly suggest that the interaction between MCM2 and HBO1 is direct and mediated by the C2HC zinc finger of HBO1. The biochemical and genetic interactions of MYST family protein HBO1 with two components of the replication apparatus, MCM2 and ORC1, suggest that HBO1-associated HAT activity may play a direct role in the process of DNA replication.

Author(s): Lee, Larissa J; Ratner, Elena; Uduman, Mohamed; Winter, Kathryn; Boeke, Marta; Greven, Kathryn M; King, Stephanie; Burke, Thomas W; Underhill, Kelly; Kim, Harold; Boulware, Raleigh J; Yu, Herbert; Parkash, Vinita; Lu, Lingeng; Gaffney, David; Dicker, Adam P; Weidhaas, Joanne | Abstract: ObjectiveTo explore the association of a functional germline variant in the 3'-UTR of KRAS with endometrial cancer risk, as well as the association of microRNA (miRNA) signatures and the KRAS-variant with clinical characteristics and survival outcomes in two prospective RTOG endometrial cancer trials.Methods/materialsThe association of the KRAS-variant with endometrial cancer risk was evaluated by case-control analysis of 467 women with type 1 or 2 endometrial cancer and 582 age-matched controls. miRNA and DNA were isolated for expression profiling and genotyping from tumor specimens of 46 women with type 1 endometrial cancer enrolled in RTOG trials 9708 and 9905. miRNA expression levels and KRAS-variant genotype were correlated with patient and tumor characteristics, and survival outcomes were evaluated by variant allele type.ResultsThe KRAS-variant was not significantly associated with overall endometrial cancer risk (14% controls and 17% type 1 cancers), although was enriched in type 2 endometrial cancers (24%, p = 0.2). In the combined analysis of RTOG 9708/9905, miRNA expression differed by age, presence of lymphovascular invasion and KRAS-variant status. Overall survival rates at 3 years for patients with the variant and wild-type alleles were 100% and 77% (HR 0.3, p = 0.24), respectively, favoring the variant.ConclusionsThe KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.

High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer, who had a positive second-look laparatomy or recurrent disease. Ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. Etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. Filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity.

mg/m 2 . In the second stage of the study, the doses of cisplatin and melphalan were fixed at 75 mg/m 2 and the MTD level, respectively, and the dose of paclitaxel was escalated. The planned dose escalation levels of paclitaxel were 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 225 mg/m 2 , and 250 mg/m 2 . G-CSF was administered for 12‐19 days with each cycle, and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points included clinical or surgical response, progression free survival, and survival. RESULTS. Between January 1993 and May 1996, 34 women with untreated advanced stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated with 192 cycles of therapy. The MTD of melphalan was 10 mg/m 2 , with the dose-limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose level of 200 mg/m 2 with a toxicity rate of , 33%. The clinical response rate was 80% in 29 patients with measurable disease. Of 11 patients who underwent second-look surgery, 5 (45%) had a surgical pathologic complete response. The median progression free survival was 16.8 months and the median survival was 32.8 months. CONCLUSIONS. The combination of intravenous melphalan, paclitaxel, and cisplatin was found to have acceptable toxicity and good activity. A Phase II study of this combination appears to be warranted. Cancer 1999;86:2291‐300. © 1999 American Cancer Society.

BACKGROUND The purpose of the current study was to evaluate the current practice of surgical staging of ovarian serous borderline tumors. METHODS Women with a diagnosis of ovarian serous borderline tumors whose pathology slides were sent to the M. D. Anderson Cancer Center for second-opinion diagnostic consultation between 1990–1996 were identified. The original pathology reports and M. D. Anderson Cancer Center consultation reports of 255 cases were reviewed for the frequencies of frozen-section analyses and staging biopsies, biopsy results, the specialty of the surgeon, and hospital type. RESULTS The majority (78%) of ovarian borderline tumors primarily were encountered and staged by general obstetrician-gynecologists. Overall, 66% of patients had at least 1 staging biopsy performed. Approximately 12% of subjects underwent complete surgical staging, defined as having biopsy samples taken from pelvic and abdominal peritoneum, omentum, and retroperitoneal lymph nodes. Gynecologic oncologists performed complete staging in 50% of cases, obstetrician-gynecologists performed complete staging in 9% of cases, and general surgeons performed complete staging in 0% cases. The overall frequency of a positive staging biopsy was 37%. Approximately 47% (80 of 169) of patients who underwent biopsies were upstaged as a result of positive biopsies, - with 41% (70 of 169) having extrapelvic spread. CONCLUSIONS Currently, surgical staging for women with ovarian serous borderline tumors remains inadequate, although a significant proportion of patients who undergo staging are noted to have extrapelvic spread. Cancer 1999;85:905–11. © 1999 American Cancer Society.

Objectives. To evaluate the efficacy of radiation therapy and potential prognostic factors in patients treated for pelvic recurrence of cervical carcinoma after radical hysterectomy. Materials. The records of 50 patients treated between 1964 and 1994 for an isolated pelvic recurrence of cervical carcinoma a median of 10.5 months after initial radical hysterectomy were retrospectively reviewed. Patients were categorized according to the extent of disease on clinical examination as group 1, mucosal involvement only (5); group 2, paravaginal extension (11); group 3, central recurrence with pelvic wall extension (13); and group 4, recurrences limited to the pelvic sidewall (21). Seven patients with group 3 or 4 disease who had a poor performance status were treated with palliative intent using hypofractionated radiotherapy. The remaining 43 patients were treated with curative intent, 33 with radiotherapy only and 10 with a combination of cisplatin-based chemotherapy and radiotherapy. Survival rates were calculated from the date of initial recurrence. Median follow-up of surviving patients was 109 months. Results. The overall 5-year survival rate was 33% for all 50 patients (median survival, 18 months), 39% for the 43 patients treated with curative intent, and 25% for patients with isolated sidewall recurrences treated with curative intent. The survival rate was 69% for patients with group 1 and 2 disease and 18% for those treated with curative intent for group 3 disease ( P = 0.07). The survival rate was better for patients with recurrent squamous carcinomas (51%) than for those with adenocarcinomas (14%) ( P = 0.05). Three group 4 patients who survived more than 5 years were treated with external-beam radiation alone. Eight-one percent of patients who had a second recurrence had evidence of disease progression. Three patients experienced late treatment complications. Conclusions. Patients who experience an isolated recurrence of cervical cancer after initial radical hysterectomy have an excellent prognosis if disease does not involve the pelvic wall. Occasional long-term survivors of recurrent disease involving the pelvic wall justify an aggressive treatment approach.

Background The objective of the current study was to update the authors' experience with patients with ovarian serous borderline tumors with invasive peritoneal implants to gain additional insight into the biologic behavior of these tumors and a better understanding of the effect of postoperative treatment. Methods Thirty-nine patients with ovarian serous borderline tumors with invasive peritoneal implants were identified through a retrospective review. Major endpoints selected for analysis were surgicopathologic response, time to recurrence, type of recurrence, progression free survival, and overall survival. Univariate and multivariate regression analyses also were performed. Results Median follow-up time was 111 months. Four of 7 evaluable patients who had second-look surgery (57%) had a response to chemotherapy. Twelve of 39 patients (31%) either developed progressive disease or had a recurrence. The median time from date of diagnosis to recurrence was 24 months. In 10 of these 12 patients with a recurrence, tissue was available; 9 had invasive low grade serous carcinoma and 1 had a recurrent borderline tumor. Macroscopic residual disease was the only factor studied that had a significant effect on survival; patients with no macroscopic residual tumor had a significantly better survival than those with any macroscopic residual tumor (P Conclusions Greater than 30% of patients with ovarian serous borderline tumors with invasive peritoneal implants will develop progressive or recurrent tumor, most commonly serous carcinoma. The presence of macroscopic residual disease appears to be the major predictor of recurrence and survival. However, in this study, the authors were unable to elucidate the role of postoperative therapy or the criteria for selection of patients for such therapy.

Sp1 is a ubiquitous activator of numerous TATA-containing and TATA-less promoters within the human genome. This transcription factor is distinct from several other mammalian activators because it cannot stimulate transcription of reporter genes when ectopically expressed in Saccharomyces cerevisiae . Here we report that in cultured cells from Drosophila melanogaster human Sp1 efficiently activates transcription from synthetic promoters containing TATA boxes, but not from promoters that contain an initiator instead of a TATA box. The inability of Sp1 to activate initiator-mediated transcription did not result from inactivity of the consensus initiator element used for the experiments, as other initiator functions were conserved in Drosophila cells. Interestingly, a difference between the Drosophila and human TFIID complexes was found to be responsible for the selective inability of Sp1 to activate initiator-mediated transcription in Drosophila; in a complementation assay with a TFIID-depleted HeLa cell extract both the Drosophila and human TFIID complexes supported TATA-mediated transcription, but only the human complex supported initiator-mediated transcription. These results suggest that a species-specific interaction is required for activation of TATA-less promoters by Sp1, revealing a difference in transcriptional activation mechanisms between vertebrates and invertebrates.

To evaluate the effectiveness of an outcomes-management program designed to provide high-quality patient care, generate data for outcomes research, and decrease costs in a managed-care environment.An outcomes-management program was launched in June 1994, based on the elimination of wasteful or ineffective therapies through the systematic development of practice guidelines and collaborative care paths, with concomitant definition of desired outcomes. Over 3 months, care paths were developed for our most common surgical procedures. A matched control outcomes study was undertaken for the most commonly performed gynecologic oncology procedure: total abdominal hysterectomy and oophorectomy with pelvic and para-aortic node sampling for endometrial cancer. Thirty consecutive women treated on the care path were compared with 29 matched controls accrued during the period of care-path planning and with 73 controls from the period preceding care-path planning. Patient satisfaction with care-path treatment was assessed by a survey sent 2 weeks after discharge.Median length of hospital stay decreased significantly, from 6 days before care-path planning to 4 days after care-path implementation (P.001). Median laboratory costs decreased by 74% (P.001), medication costs by 35% (P.001), room costs by 29% (P.001), and total hospital costs by 20% (P.002). Incremental improvements were observed during care-path planning. There were no readmissions for complications in the care-path group. According to the survey results, patient satisfaction with care was very high among care-path patients.A physician-driven outcomes-management program in an academic setting permits the delivery of high-quality care and supports outcomes research while decreasing costs.

Purpose: To evaluate the role of surgical debulking in patients with stage IV ovarian cancer. Methods: We conducted a retrospective review of patients with advanced epithelial ovarian cancer treated at M. D. Anderson Cancer Center. Eligible patients included women with stage IV disease treated with platinum-based chemotherapy. Surgical debulking was considered optimal if the diameter of the largest residual tumor was 2 cm or less. Survival analysis and comparisons were performed using the Kaplan–Meier method and the log-rank test. Results: One hundred eight women with stage IV ovarian cancer were identified. The extraperitoneal metastatic sites were the liver parenchyma in 16 patients, the pleura in 54 patients, a variety of other organs in 22, and two or more sites in the remaining 16. Median age of the patient population was 58 years (range 35–81 years). Surgery to reduce the primary tumor was performed in 100 patients. The procedures included salpingo-oophorectomy with or without hysterectomy in 94 patients, omentectomy in 90, small bowel resection in 4, large bowel resection in 23, and splenectomy in 2. At the completion of surgery, tumor reduction was considered optimal in 31 patients, suboptimal in 61, and undetermined in 8. The overall median survival for optimally debulked patients was 25 months compared to 15 months for suboptimally debulked patients (P< 0.02). The progression-free survival, on the other hand, was not statistically different between the two groups. Conclusion: Residual tumor seems to be an important prognostic factor in patients with stage IV ovarian cancer. Surgical debulking may play a significant role in the treatment of these patients.

Improved ways to diagnose acute respiratory viral infections could decrease inappropriate antibacterial use and serve as a vital triage mechanism in the event of a potential viral pandemic. Measurement of the host response to infection is an alternative to pathogen-based diagnostic testing and may improve diagnostic accuracy. We have developed a host-based assay with a reverse transcription polymerase chain reaction (RT-PCR) TaqMan low-density array (TLDA) platform for classifying respiratory viral infection. We developed the assay using two cohorts experimentally infected with influenza A H3N2/Wisconsin or influenza A H1N1/Brisbane, and validated the assay in a sample of adults presenting to the emergency department with fever (n = 102) and in healthy volunteers (n = 41). Peripheral blood RNA samples were obtained from individuals who underwent experimental viral challenge or who presented to the emergency department and had microbiologically proven viral respiratory infection or systemic bacterial infection. The selected gene set on the RT-PCR TLDA assay classified participants with experimentally induced influenza H3N2 and H1N1 infection with 100 and 87% accuracy, respectively. We validated this host gene expression signature in a cohort of 102 individuals arriving at the emergency department. The sensitivity of the RT-PCR test was 89% [95% confidence interval (CI), 72 to 98%], and the specificity was 94% (95% CI, 86 to 99%). These results show that RT-PCR-based detection of a host gene expression signature can classify individuals with respiratory viral infection and sets the stage for prospective evaluation of this diagnostic approach in a clinical setting.

The approaches outlined in this report, coupled with a spirit of internal and external collaboration, enable complete translation of the MD Anderson multidisciplinary care model as well as extension of our organizational research mission. Quality management with the ability to benchmark quality metrics against our main Houston campus remains a cornerstone of our overarching strategy to maintain consistent high-quality care throughout our national network.

The health care industry, including consumers, providers, and payers of health care, recognize the importance of developing meaningful, patient-centered measures. This article describes our experience using an existing electronic medical record largely based on free text formats without structured documentation, in conjunction with tumor registry abstraction techniques, to obtain and analyze data for use in clinical improvement and public reporting.We performed a retrospective analysis of 2467 previously untreated patients treated with curative intent who presented with laryngeal, pharyngeal, or oral cavity cancer in order to develop a system to monitor and report meaningful outcome metrics of head and neck cancer treatment. Patients treated between 1995 and 2006 were analyzed for the primary outcomes of survival at 1 and 2 years, the ability to speak at 1 year posttreatment, and the ability to swallow at 1 year posttreatment.We encountered significant limitations in clinical documentation because of the lack of standardization of meaningful measures, as well limitations with data abstraction using a retrospective approach to reporting measures. Almost 5000 person-hours were required for data abstraction, quality review, and reporting, at a cost of approximately $134,000. Our multidisciplinary teams document extensive patient information; however, data is not stored in easily accessible formats for measurement, comparison, and reporting.We recommend identifying measures meaningful to patients, providers, and payers to be documented throughout the patients' entire treatment cycle, and significant investment in the improvements to electronic medical records and tumor registry reporting in order to provide meaningful quality measures for the future.

60 years of survival outcomes at the University of Texas M.D. Anderson Cancer Center / , 60 years of survival outcomes at the University of Texas M.D. Anderson Cancer Center / , کتابخانه دیجیتال جندی شاپور اهواز

BACKGROUND Although the technique for gracilis myocutaneous vaginal reconstruction was first described in the mid-1970s and has been used in conjunction with pelvic exenteration since that time, there is little available information regarding sexual adjustment after such a procedure. The purpose of this study was to assess the sexual adjustment of women who underwent pelvic exenteration and gracilis myocutaneous vaginal reconstruction at the study institution. METHODS In a prospective study design, 95 patients were identified who underwent pelvic exenteration and gracilis myocutaneous vaginal reconstruction at the study institution from 1977 through 1989 and a convenience sample was selected of 44 patients who completed a modified version of the Sexual Adjustment Questionnaire (SAQ) when they returned to the gynecologic oncology outpatient clinic for routine follow-up care. A vaginal assessment was also performed by the attending physician. RESULTS Twenty-one of 40 patients (52.5%) completing the questionnaire reported not resuming sexual activity after surgery; 19 patients reported resuming sexual activity between 1.5 months to 12 years postoperatively. Of the patients who resumed sexual activity, 84% did so within 1 year of surgery. The most common problems noted by patients in adjusting to sexual activity after surgery were self-consciousness about the urostomy or colostomy and being seen in the nude by their partner, vaginal dryness, and vaginal discharge. The mean rank of preexenteration SAQ scores was 66.4, and the mean rank of postexenteration scores was 48.7 (P < 0.0001), demonstrating that sexual adjustment after exenteration was significantly poorer than before the surgery. On the basis of data gathered from a vaginal assessment form, 31 of 44 patients (70.4%) were judged to have a potentially functional neovagina. CONCLUSIONS Based on the findings of this questionnaire study, sexual adjustment is often significantly impaired in women after pelvic exenteration and gracilis myocutaneous vaginal reconstruction. Future modifications in surgical technique, more realistic patient counseling, and aggressive postoperative support will hopefully minimize such problems. Cancer 1996;78:2229-35.

Objective: To describe and analyze the outcome of urinary conduits utilizing the transverse colon over an 11-year period. Materials and Methods: All patients undergoing a urinary conduit on the gynecologic oncology service from 1983 to 1993 were identified and a retrospective review was conducted. Results: Transverse colon urinary conduits (TCC) were performed in 86 patients. The majority of patients had a history of cervical cancer (81%), and all but one patient had prior pelvic radiotherapy. TCC was performed in conjunction with pelvic exenteration in 47 patients (55%) and alone as palliation for the effects of progressive malignancy in 10 patients (12%). Other indications for conduit construction included urinary fistulas (19%), ureteral or urethral obstruction (7%), conduit revision (5%), overflow incontinence (2%), or intraoperative ureteral injury (1%). Abnormal preoperative renal morphology was common (48%). A total of 165 ureterocolic anastomoses were performed. Ureteral stents and intestinal staplers were used routinely. The perioperative mortality rate was 3%. Loss of renal function occurred in 10 of 165 renal units (6%). Nineteen (22%) patients had partial ureteral obstruction managed by percutaneous nephrostomy or indwelling stents. Conduit reconstruction was undertaken in 7 patients (8%). Renal calculi were noted in 3 patients. Overall median survival was 30 months. Conclusion: The complications of TCC are similar to those experienced in other urinary diversions. No distinct advantage to using the transverse colon was observed. Management of progressive ureteral obstruction by conservative methods, such as percutaneous nephrostomy or ureteral stents, was frequent and provided a reasonable alternative to reoperation in the poor operative candidate.

Objective: To determine the feasibility of intraperitoneal lymphatic mapping of the uterine fundus as a means of identifying target sites for lymph node biopsy during staging laparotomy and to develop preliminary experience with the technique. Methods: Fifteen women with high-risk endometrial tumors were entered on this Institutional Review Board-approved pilot study. At laparotomy, isosulfan blue dye (1.0 ml) was injected into the subserosal myometrium at three sites: the superior midpoint of the fundus, 2 cm inferiorly on the anterior wall, and 2 cm inferiorly on the posterior wall. Dye uptake into lymphatic channels was observed for 10 min. The retroperitoneal spaces were opened. Blue lymphatic channels and nodes within the pelvic and paraaortic regions were identified. Nodes demonstrating dye uptake were biopsied as separate specimens: the locations of these nodes were carefully recorded. Hysterectomy and selective lymphadenectomy were then performed as usual. Results: Lymphatic channels coursing into the broad ligament and along the ovarian vessels were identified from all uteri injected. Deposition of dye into grossly identifiable lymph nodes was seen in 10 of 15 cases (67%). A total of 31 nodes demonstrated dye uptake. The locations of these nodes included paraaortic sites in 12, common iliac in 6, and pelvic in 13. No dye-containing paraaortic nodes were seen below the origin of the inferior mesenteric artery. Lymphatic channels coursing above the renal vessels were seen routinely. Microscopic nodal metastases to sentinel nodes were identified in 2 of 4 women with proven lymphatic spread. Conclusions: Lymphatic mapping of the uterine fundus is feasible and can identify targets for selective nodal biopsy in some women. Preliminary observations confirm that the lymphatic network draining the uterus is complex and involves both pelvic and paraaortic nodes. Lymphatic channels that parallel the ovarian vessels were not observed to enter nodes until reaching the level of the midabdomen. Further experience and refinement of techniques may lead to the development of a selective lymphadenectomy based upon direct visualization of the lymphatic drainage of the uterus rather than the current random sampling.

Objective: To survey the surgical practice of gynecologic oncologists regarding the extent of groin dissection for early vulvar cancer. Methods: A 14-item questionnaire was developed and presented to the Annual Meeting of the Felix Rutledge Society. Gynecologic oncologists were asked to describe in descriptive, categorical, and visual terms the groin procedure that they perform as part of management of early vulvar cancers. Three ink-line drawings were created by a medical illustrator for the purpose. Fifty returned surveys were evaluable. Results: The most commonly performed procedures were removal of the lymph nodes above the cribriform fascia and those medial to the femoral vein (40%), removal of lymph nodes above the cribriform fascia (34%), and removal of all nodes above and below the cribriform fascia (22%). Respondents performing the first procedure termed it "superficial inguinal lymphadenectomy" (40%), "inguinal femoral lymphadenectomy" (25%), and a variety of other names (35%). Respondents performing the second two procedures were much more consistent in the figure and name that they matched with their description of the nodes removed. When respondents were asked to match the figures with categorical definitions based on their understanding of the literature, the figure depicting Scarpa's triangle following removal of the superficial inguinal and medial femoral nodes was named superficial inguinal lymphadenectomy by 24% despite the fact that the femoral vein was clearly visible and labeled. Conclusions: We conclude that (1) among this group of gynecologic oncologists superficial inguinal and medial femoral lymphadenectomy is the most commonly performed procedure for women with early vulvar cancer and that the procedure is frequently called superficial inguinal lymphadenectomy; (2) publications and protocols on this topic must provide complete descriptions of procedures performed, and investigators must assure that individual surgeons are performing the same procedure; and (3) treatment results with superficial inguinal and medial femoral lymphadenectomy are poorly described and a fertile area for further study.

Objective: We describe early results of and potentially important anatomic findings with intraoperative lymphatic mapping in patients with vulvar cancer. Methods: Isosulfan blue was injected into the dermis at the leading edge of the vulvar lesion in 21 patients. One to five minutes later a standard groin incision was made and carried to the superficial fascia. After gentle dissection, the afferent lymphatic channel and/or sentinel lymph node was identified by its bright blue color. The sentinel node was removed and then the superficial inguinal lymphadenectomy was completed. Results: The 21 patients, ranging in age from 23 to 85 years (median, 52 years), underwent intraoperative lymphatic mapping. The clinical stages were as follows: T1in 9, T2in 10, T3in 1, and unknown in 1 patient with a prior wide local excision. Two patients had palpably suspicious nodes. Ten patients had lateral lesions, and 11 had midline tumors. Eight of the 11 patients had bilateral groin dissections, making a total of 29 groins dissected. The sentinel node was identified in 18 patients (86%) and in 19 groins (66%). Five patients had unilateral node metastases, and one patient had bilateral node metastases. A sentinel node was found in five of these seven groins. A total of 238 nodes were removed (median, 8.2 nodes per groin). In no case was a nonsentinel node positive if the sentinel node was negative. In one patient the only metastasis was microscopic tumor in the sentinel lymph node. In one case, the sentinel node was found below the cribriform fascia. The sentinel node could not be identified in either groin in one patient with a clitoral primary; however, dye was seen in lymphatic channels passing under the symphysis pubis. The sentinel node was identified in various sites within the superficial compartment including lateral to the femoral artery and at the extreme medial border of the dissection. No complication related to the injection of isosulfan blue was seen. Conclusion: Intraoperative lymphatic mapping is safe and simple to perform and may help identify the sentinel node, define the extent of superficial inguinal lymphadenectomy, and identify uncommon anatomic variations.

Twelve patients ages 37-85 years (mean, 59 years) with locoregionally advanced vulvar carcinoma were treated with a combination of irradiation and chemotherapy using prolonged continuous infusions of 5-fluorouracil (5-FU) and cisplatin. Eleven patients had advanced vulvar disease with tumors 5-18 cm in maximum diameter (mean, 8.7 cm), eight had palpable inguinal nodes with biopsy-proven metastatic carcinoma, and five had fixed nodes. Patients received weekly 96-hr infusions of cisplatin (4 mg/m2/day) and 5-FU (250 mg/m2/day) for a total of 64 mg/m2 of cisplatin and 4 g/m2 of 5-FU in 4 weeks. Concurrent radiation therapy was delivered to the lower pelvis, vulva, and inguinal nodes to a total dose of 40-50 Gy at 2 Gy per fraction in 11 patients. One patient who had been previously treated for cervical cancer received radiation only to the vulva with an appositional electron beam field. Chemoradiation was well tolerated with virtually no hematologic toxicity and no unscheduled breaks in treatment. Eleven of 12 patients had at least a partial clinical response; one patient had a minimal response of unresectable vulvar disease. Of eight patients who underwent vulvar resection 6 weeks after chemoradiation, four had no residual disease in the resected vulvar specimen and remain disease-free 17, 20, 25, and 37 months, respectively, after surgery. Another patient is disease-free 28 months after a complete clinical response without vulvar resection. However, of four patients who had residual disease in the vulvar surgical specimen, disease has recurred within the irradiation field in three. Overall, 6 of 12 patients treated with this chemoradiation regimen remain disease-free 17-30 months after treatment. This is a well-tolerated outpatient regimen that yields a high response rate in patients with massive vulvar carcinomas.

The untunneling of the ureters and the transsection of the parametria are two well-characterized steps of radical hysterectomy. Two sets of instruments were developed to facilitate the mobilization (untunneling) of the ureters and the dissection of the paravaginal and parametrial tissues during radical hysterectomy.Instrument set one consists of a modified Uchida spoon, two ureteral tunnel clamps, and a pair of tunnel scissors. Set two contains a long and a short sharply angled parametrial clamp with matching parametrial scissors.This technique permits one-step exposure of the ureter, protected from injury by the spoon. The instruments for parametrial transsection facilitate controlled transsection of the paravaginal and parametrial tissues while conserving surgical margins. They can also be conveniently used for transsection of the uterosacral ligaments.The authors believe that the instruments contribute to an enhanced safety and accuracy of radical hysterectomy with improved efficiency by shortened operating time.

Twenty-one patients who underwent pelvic exenteration for primary ( n = 8) or recurrent ( n = 13) vulvar malignancy at the M. D. Anderson Cancer Center between 1956 and 1989 were evaluated. A posterior exenteration was performed in 12 patients, anterior exenteration was performed in 6, and total exenteration was performed in 3. In patients with primary tumors, radical vulvectomy and inguinal lymphadenectomy were also performed. The median patient age was 57 years. The mean tumor diameters were 5 cm (primary) and 4 cm (recurrent). Infections were the most frequent postoperative complications ( n = 15), followed by pulmonary ( n = 4) and cardiac problems ( n = 3). There were no treatment-related deaths. Five patients required further surgery to correct late postoperative sequelae. Four of eight patients experienced recurrence after treatment of their primary tumor; the recurrences were local only ( n = 1), in the inguinal area ( n = 2), or local and in the pelvis ( n = 1). Nine of the 13 patients treated for recurrent tumors developed a second recurrence; the second recurrences were all within the pelvis, although two also had a distant component. The 5-year survival rates were 70% for patients treated for primary disease and 38% for patients treated for recurrent disease, Pelvic exenteration is indicated for selected patients with advanced vulvar malignancy.

Background. Paclitaxel is a diterpenic plant product that has significant activity in several solid tumors, including epithelial ovarian cancer. After promising results in Phase I and II studies, its use has increased dramatically. With this increased use, isolated reports of local tissue reactions to paclitaxel have been described. The purpose of this study was to characterize further the presentation and clinical course of this toxic effect. Methods. Nine hundred fifty-five courses of paclitaxel were administered to patients with gynecologic malignancies at M.D. Anderson Cancer Center during a 13-month period. Nineteen (2%) local infusion-site injuries in 17 patients were observed. Results. The primary disease site was the ovary in 13 patients, the peritoneum in 2, and the endometrium in 2. Pacitaxel was administered as initial therapy in 6 patients and as salvage therapy in 11. Clinical evidence of infiltration was decumented during infusion in 8 of 19 (42%) reported episodes. Immediate reactions consisting of mild discomfort, erythema, and edema were observed in six patients, three of whom had complete resolution of the lesion within 1 month. The remaining patients noted initial development of injury between 3 and 13 days after paclitaxel infusion. The typical injury was a discolored, raised, rounded, and indurated lesion that was moderately painful. Two patients (11%) had Grade 1 lesions, 13 (68%) had Grade 2 lesions, and four (21%) had Grade 3 lesions with central ulceration. Cellulitis requiring intravenous antibiotic therapy was associated with two lesions. At last follow-up, 13 injuries had persistent discoloration and induration; one patient had persistent ulceration present at the timt of her death 6 months after presentation and one patient underwent excision of a persistent lesion at 12 months. Conclusion. Given the incidence of Grade 2 and Grade 3 local reactions, it appears that paclitaxel should be considered a vesicant.

Uterine papillary serous adenocarcinoma (UPSC) is one of the most aggressive endometrial tumors. UPSC has been associated with an increased propensity for extrauterine spread. Survival rates of not more than 50% are commonly reported even for tumors which appear to be confined to the uterus. Small areas of UPSC can be found in otherwise well-differentiated endometrial lesions and yet still determine the overall prognosis. In the present study we evaluated histologic criteria that might be helpful in diagnosing small-volume UPSC, including silver-stained nucleolar organizer regions (AgNOR) which have prognostic importance in a variety of tumors, and nuclear size which has been used for prognostication in endometrial cancer. We examined 25 UPSC specimens and compared them to grade III (GIII, n = 10) and grade I (GI, n = 10) typical endometrial adenocarcinoma using the following parameters: mean AgNOR count per cell was UPSC 6, GIII 6.0, and GI 4.3; mean AgNOR area was UPSC 1.28 microns2, GIII 1.35 microns2, and GI 0.86 microns2; total AgNOR area per cell was UPSC 7.5 microns2, GIII 8.13 microns2, GI 4.47 microns2; and nuclear size was UPSC 66.9 microns2, GIII 60.3 microns2, GI 34.8 microns2. All differences between UPSC or GIII tumors and GI lesions were statistically significant. Overexpression of p53, as determined histochemically, was seen in 64% of the UPSC specimens. UPSC is characterized by high AgNOR count and area per cell, large nuclear size, and a high rate of p53 overexpression. Evaluation of these parameters in biopsy material may aid in selecting high-risk patients for adjuvant therapy trials.

To investigate the structure and regulation of the genes encoding components of the basal RNA polymerase II transcriptional machinery, the Drosophila melanogaster genes encoding transcription factor IIB (TFIIB) and the TATA-box-binding protein (TBP) were isolated and characterized. In the TBP gene, a single intron bisects the sequences that encode the two repeated DNA-binding domains of TBP, which supports the notion that TBP evolved from an earlier form that possessed only a single domain. The transcription start points (tsp) were determined, and there was a good correlation between the tsp that were used in vivo and transcription reactions in vitro. The TFIIB and TBP genes have several similar features, which include high A+T content (68 to 74%) upstream from the tsp, multiple copies of an ATTATTATT sequence motif in the proximal promoter region, the absence of a consensus TATA-box element, and small introns (55 to 64 nucleotides). These genes should be useful in the combined genetic and biochemical analysis of TFIIB and TBP in D. melanogaster.

Objective To prospectively evaluate tumor control, survival, and toxic effects in patients with International Federation of Gynecology and Obstetrics (1988) stage I–IIIA papillary serous carcinoma of the endometrium treated with concurrent chemoradiation and adjuvant chemotherapy. Methods Thirty-two patients were enrolled from October 2001 through July 2009. Patients underwent full surgical disease staging and postoperative concurrent weekly paclitaxel (50mg/m 2 ) and pelvic RT to 45Gy plus a vaginal cuff boost followed by 4cycles of adjuvant paclitaxel (135mg/m 2 ). Results Thirty patients (94%) were evaluable (3 with stage IA disease, 11 IB, 3 IC, 1 IIB, and 12 IIIA). Eighteen patients (60%) received all 5 planned courses of concurrent chemotherapy, 10 (33%) received 4 courses, and 2 (7%) received 3 courses. All 30 patients received RT; 27 (90%) received the full dose, 2 received 43.2Gy, and 1 received 39.6Gy owing to toxic effects. Twenty-three patients (77%) completed all 4cycles of adjuvant paclitaxel, 3 (10%) completed 3cycles, 2 (7%) completed 2cycles, and 2 received no adjuvant therapy. Overall survival (OS), progression-free survival (PFS), and local control rates for all patients were 93%, 87%, and 87%, respectively, at 2years and 85%, 83%, and 87%, respectively, at 5years. Six patients developed (20%) grade 3/4 toxicities from the treatment. Four patients (13%) had grade 3 or more severe bowel complications and two patients developed symptomatic pelvic fractures. Conclusions Treatment with concurrent paclitaxel and pelvic RT followed by 4 courses of systemic paclitaxel produced favorable results in patients with surgically staged I–III UPSC.

PURPOSE To investigate and define better the role of salvage surgery for patients with chemorefractory gestational trophoblastic disease (GTD). PATIENTS AND METHODS A retrospective review of medical records at The University of Texas M.D. Anderson Cancer Center identified 33 patients with chemorefractory GTD who underwent salvage surgery between 1962 and 1991. The end points selected for analysis were serologic response and survival. RESULTS Initial salvage procedures consisted of 29 hysterectomies, four thoracotomies, and one nephrectomy (in conjunction with a hysterectomy). Fourteen patients (42%) had a serologic complete response (CR) to surgery (normalization of human chorionic gonadotropin [hCG]), 10 (30%) had a partial response (> 50% decrease in hCG level), and nine had no response (< or = 50% decrease in hCG level). Of 19 patients who received further chemotherapy, eight (42%) attained a CR. Four patients underwent a second salvage surgery: two thoracotomies, one craniotomy, and one partial hepatectomy. All achieved a CR. The probability of achieving a CR was influenced by the time from diagnosis to surgery, number of preoperative disease sites, preoperative World Health Organization (WHO) score, and histologic type. Survival was influenced by the type of antecedent pregnancy, number of preoperative regimens, number of preoperative disease sites, time from diagnosis to surgery, and preoperative WHO score. CONCLUSION Based on the findings of this study, it appears that a select subset of patients with chemorefractory GTD who have a limited number of clinically detectable tumor foci may benefit from salvage surgery.

Our purpose was to study the incidence, severity, timing, clinical management, and outcome for patients who developed hemorrhagic cystitis following pelvic radiotherapy for stage Ib cancer of the cervix. A total of 1784 patients with stage Ib cancer of the cervix were treated with pelvic radiotherapy at the University of Texas M. D. Anderson Cancer Center between 1960 and 1989. The majority received a combination of external-beam and intracavitary treatments. Patients with hemorrhagic cystitis were identified through retrospective review of their medical records, and a grade was assigned to each occurrence. A total of 116 (6.5%) patients with hemorrhagic cystitis were identified. The initial occurrence was grade 1 (minor occurrence) in 59%, grade 2 (repeated minor bleeding) in 23%, and grade 3 (hospitalization for medical management) in 18%. The median interval from the beginning of radiotherapy to the onset of hematuria was 35.5 months (mean 58 months). The median time to initial grade 3 occurrences was 37.5 months (mean 84 months). Actuarial life table analysis revealed that the risk of hematuria is 5.8% at 5 years, 7.4% at 10 years, and 9.6% at 20 years. The risk for a grade 3, 4 (requiring surgical intervention), or 5 (death) complication is 1.0, 1.4 and 2.3% at 5, 10, and 20 years, respectively. Approximately one-third of the patients with a grade 3 occurrence were rehospitalized for management of bladder complications a median of 3.5 months following the first grade 3 occurrence, although some of these readmissions occurred many years later. Associated urinary-tract infection was common. In no case did a cystoscopic bladder biopsy reveal recurrent tumor or a second primary tumor when visual inspection revealed typical radiation changes. The incidence of severe hemorrhagic cystitis following radiation for stage Ib cancer of the cervix is low and can occur many years following treatment. Minor episodes of hematuria are managed by empiric antibiotic therapy until the results of urine cultures are available. Cystoscopy is reserved for patients with persistent bleeding to rule out clot retention or the slight possibility of a second primary tumor or recurrent disease. Biopsy should be avoided if obvious radiation changes are present. Clot evacuation and continuous bladder irrigation remain the standard treatment for patients with heavy bleeding.

This study was undertaken to determine whether secondary surgical debulking is beneficial for patients with malignant ovarian germ cell tumors (OGCT). Twenty patients with OGCT treated at our institution between 1975 and 1992 were retrospectively identified and analyzed. Survival was analyzed using the life-table methods of Kaplan and Meier and the statistical significance of various perioperative factors was tested by both the log-rank and the Wilcoxon tests. Histologic tumor type included 8 immature teratomas, 6 mixed tumors, 5 endodermal sinus tumors, and 1 dysgerminoma. After primary surgery, all patients received chemotherapy--non-platinum-based in 12 patients, platinum-based in 5, and both types in 3 patients. Treatment failure was classified as progression in 14 patients, persistence in 3, and recurrence in 3. Salvage surgery consisted of exploratory laparotomy and tumor debulking in 18 patients, inguinal lymphadenectomy in 1, and thoracotomy and wedge resection in 1. Sixteen patients subsequently received salvage chemotherapy. At the time of analysis, 11 patients were alive disease-free, 1 was alive with tumor, 6 had died of tumor progression, and 2 had died of treatment-related complications. Survival of patients with immature teratoma who underwent salvage surgery was significantly better than survival of those with other tumor cell types (P = 0.006). In conclusion, although the role of secondary debulking in chemorefractory OGCT remains undetermined, it may have some benefit for a select group of patients, particularly those with immature teratoma.

We retrospectively reviewed 80 cases of endometrioid carcinoma of the ovary: 68 pure endometrioid tumors and 12 predominantly endometrioid carcinomas (> 50%) mixed with either papillary serous or undifferentiated carcinoma. Each group had 11 cases of stage III or IV tumors, which were studied to determine whether the overall prognosis was affected by grade, histology, number of mitoses, residual tumor after surgery, and patient's age. Prognosis was significantly affected only by a mixed histologic pattern. The 5- and 10-year survival rates and the median survival time for pure endometrioid carcinomas were much better than those for mixed endometrioid carcinomas (63% and 45% and > 86 months versus 8% and 0% and 18 months, respectively). Recurrent tumors in cases of mixed endometrioid carcinoma were pure serous or undifferentiated carcinomas, whereas those in cases of pure endometrioid carcinoma were either endometrioid or high-grade carcinoma. Our results show that the presence of even a small component of serous or undifferentiated carcinoma in an otherwise predominantly endometrioid carcinoma significantly affects the prognosis. Thus pathologists should thoroughly sample all endometrioid carcinomas, especially high-stage tumors, to ensure that no serous or undifferentiated component is present.

Between March 1990 and July 1992, 42 women with squamous carcinoma of the uterine cervix were prospectively treated with carboplatin (260 mg/m 2 ) on Day 1 and cisplatin (50 mg/m 2 ) on Day 2 every 28 days. Patients had either stage IVb (FIGO) cancer (5 patients) or recurrent cancer (37 patients) and a Zubrod score ⩽2. Forty-one patients had received either radiation or surgery as primary therapy; 179 cycles of chemotherapy were delivered. The mean number of cycles administered to each patient was 4 (range, 2-8 cycles). Dose escalation was possible in 32 cycles (23.4%) and dose reduction was required in 10 cycles (7.3%). The dose-limiting toxic effect was myelosuppression, with grade 3-4 thrombocytopenia in 39 cycles (22%) and neutropenia in 19 cycles (11%). Neurotoxic effects were observed in 3 patients. Forty-two patients were evaluable for response: 1 had a complete response and 11 had a partial response (response rate 28.6%, 95% confidence interval, 14.9-42.3%). For all patients and for responders, median progression-free interval was 4.4 and 9.5 months, respectively, and median length of survival was 8.9 and 9.5 months, respectively. This regimen was well tolerated and had significant activity in the treatment of cervical cancer. Comparison to other platinum-based regimens in a Phase III trial should be considered.

Uterine papillary serous carcinoma (UPSC), an aggressive histologic variant of endometrial cancer, is particularly resistant to cytotoxic chemotherapy. In reviewing a group of patients treated with cisplatin, doxorubicin, and cyclophosphamide, we were surprised to find that 90% of specimens tested by biochemical analysis were positive for estrogen receptor (ER), progesterone receptor (PR), or both. To further study receptor content and localization, we performed immunocytochemical analysis (ICA) on 29 archival UPSC specimens. In ER studies, three specimens were unevaluable because of inadequate internal controls; of the remaining 26, only two were ER positive, showing weak, focal staining. In PR studies, 18 samples had adequate controls, and all tumor specimens were receptor negative. Corresponding biochemical ER data were available for 11 cases, of which 10 were ER positive. ICA, however, showed all 10 to be negative. Biochemical PR data were available for seven samples: Six were positive. All six biochemically positive PR specimens were PR negative when analyzed by ICA. Biochemical assays for ER and PR may overestimate positivity as a result of contamination with normal tissue or the presence of receptor-positive typical endometrial adenocarcinoma in tumors of mixed histology. ICA may eliminate this problem, but it has technical limitations, especially when used for archival tissue analysis. Because urinary papillary serous carcinoma appears to be a receptor-negative tumor, further evaluation of hormonal therapy is not likely to be beneficial.

SUMMARY Secondary cytoreduction to optimal levels can be successfully accomplished in a substantial number of ovarian cancer patients and in a variety of clinical settings. Although frequently complex, secondary operations can be performed with acceptable morbidity. All operations should be undertaken by experienced oncologic surgeons. Prospective randomized clinical trials to evaluate the survival benefits of secondary cytoreduction will probably never be conducted. Consequently, estimates of survival benefit must be derived from the evaluation of outcome in clinically homogeneous subsets. There is good evidence that a survival advantage can be obtained in patients whose gross disease is completely resected at second-look laparotomy and in patients whose disease recurs after a complete response to primary cytoreduction and cisplatin-based chemotherapy. Patients who fail to respond to primary treatment are probably not appropriate candidates for a secondary resection. Because most patients are left with at least microscopic residual disease, the lack of effective second-line chemotherapy limits the survival impact of secondary cytoreduction.

The long-term survival of women with stage I cervical cancers is excellent. Microinvasive tumors can be acceptably treated with low morbidity by simple extrafascial hysterectomy. Tumors beyond the microscopic stage require more aggressive therapy with either radical hysterectomy or radiotherapy. Within stage I, tumor volume is the major predictor of complete response and cure. Most often, this is estimated by the clinical measurement of cervical diameter. Lymph node spread is also correlated with risk of treatment failure and death from disease. Patients with tumor diameters of 4 cm or less can usually be offered either therapy option. Although different complications are associated with each modality, the overall incidence of severe problems is small for both. We favor radical hysterectomy for premenopausal women who wish to retain natural hormonal function and who have no major contraindications to surgery. Postmenopausal patients, those with larger tumors, and, perhaps, those with high-grade tumors may be better treated by irradiation. Women with very large tumors and those with lymph node metastases represent significant treatment challenges and should be considered for experimental protocols.

Responding to growing concerns regarding the safety, quality, and efficacy of cancer care in the United States, the Institute of Medicine (IOM) of the National Academy of Sciences commissioned a comprehensive review of cancer care delivery in the US health care system in the late 1990s. The National Cancer Policy Board (NCPB), a 20-member board with broad representation, performed this review. In its review, the NCPB focused on the state of cancer care delivery at that time, its shortcomings, and ways to measure and improve the quality of cancer care. The NCPB described an ideal cancer care system in which patients would have equitable access to coordinated, guideline-based care and novel therapies throughout the course of their disease. In 1999, the IOM published the results of this review in its influential report, Ensuring Quality Cancer Care. The report outlined 10 recommendations, which, when implemented, would: 1) improve the quality of cancer care, 2) increase the current understanding of quality cancer care, and 3) reduce or eliminate access barriers to quality cancer care. Despite the fervor generated by this report, there are lingering doubts regarding the safety and quality of cancer care in the United States today. Increased awareness of medical errors and barriers to quality care, coupled with escalating health care costs, has prompted national efforts to reform the health care system. These efforts by health care providers and policymakers should bridge the gap between the ideal state described in Ensuring Quality Cancer Care and the current state of cancer care in the United States. Cancer 2011;. © 2011 American Cancer Society.

Preparation for pelvic exenteration is a traumatic experience for every patient, especially so when the procedure has to be aborted because of advanced disease. This occurred in 111 of 394 patients who underwent exploration for possible pelvic exenteration for recurrent cervical cancer at the University of Texas M. D. Anderson Cancer Center between 1970 and 1990. We reviewed these cases to better delineate preoperative factors predictive of unresectability. Distributions of initial stages and pathological diagnoses were similar to those for all cases of primary cervical cancer. The median time from primary therapy to recurrence was 12 months. The reasons for aborting the procedure included the presence of peritoneal disease in 49 patients (44%), for which the only preoperative finding with significant correlation was the presence of a pelvic mass (P = 0.03). Other reasons for aborting the procedure included nodal disease in 45 patients (40%), related to a short interval from primary therapy (P = 0.008) and the notation of fibrosis on preoperative exam (P = 0.01), parametrial fixation in 15 patients (13%), and hepatic lesions or bowel involvement in 5 patients (4.5%). Peritoneal cytology was negative in 61 of 79 patients (77.2%) and was of predictive value only in patients with adenocarcinoma. In conclusion, disseminated disease can seldom be detected during preoperative work-up. Evaluation of nodal status with computed tomography, lymphangiogram and directed fine-needle aspiration, and examination of peritoneal cytology in cases with adenocarcinoma, are the best available means of reducing the number of aborted procedures.