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2.
Gynecol Oncol Rep ; 31: 100532, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31934607

ABSTRACT

PURPOSE: NRG Oncology conducted a phase II trial to assess the antitumor activity and tolerability of copanlisib, a selective inhibitor of PIK3CA, in persistent or recurrent endometrial carcinoma harboring hotspot PIK3CA mutations. PATIENTS AND METHODS: Eligible patients had endometrial cancer with endometrioid, serous or mixed histology, a somatic PIK3CA gene mutation, measurable disease, and GOG performance status ≤2. Treatment consisted of IV copanlisib (60 mg weekly, day 1, 8 and 15 of 28-day cycle) until disease progression or prohibitive toxicity. The primary endpoints of the study were objective tumor response as assessed by RECIST 1.1 and to determine the nature and degree of toxicity of copanlisib as assessed by CTCAE version 4. The study used a 2-stage group sequential design. RESULTS: Eleven patients were enrolled onto stage I of the treatment trial. Five patients had endometrioid, four serous and two had a tumor of mixed histology. The most common PIK3CA mutation was Q546X (n = 3) in exon 9. The most common grade 3 or 4 AE was hyperglycemia. No grade 5 adverse events were reported. No clinical responses were detected. Six patients had a best overall response of stable disease. Of 11 who initiated treatment, 10 progressed on treatment. One patient with stable disease on copanlisib withdrew from treatment secondary to relocation. The median progression-free survival (PFS) was 2.8 months; at 6 months 27% were alive, progression-free. The median overall survival (OS) was 15.2 months. Due to the lack of CR/PR continuation of accrual to the second stage of accrual was not warranted. CONCLUSION: Copanlisib is well tolerated but has limited activity as a single agent in this population.

3.
Cancer ; 123(7): 1144-1155, 2017 04 01.
Article in English | MEDLINE | ID: mdl-27926776

ABSTRACT

BACKGROUND: Synuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023). METHODS: High-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage. RESULTS: The overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels. CONCLUSIONS: This largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.


Subject(s)
Biomarkers, Tumor , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/mortality , Uterine Neoplasms/metabolism , Uterine Neoplasms/mortality , gamma-Synuclein/metabolism , Aged , Aged, 80 and over , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/therapy , Female , Gene Expression , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Prognosis , Uterine Neoplasms/pathology , Uterine Neoplasms/therapy , gamma-Synuclein/genetics
4.
Mod Pathol ; 25(12): 1644-53, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22790015

ABSTRACT

BRCA1/BRCA2 mutations are common and the hallmarks of high-grade serous ovarian carcinoma. We found that MIR182, a negative BRCA1 regulator, is significantly overexpressed in high-grade serous ovarian carcinoma. To examine whether overexpression of MIR182 and its target genes, including BRCA1, HMGA2 (high-mobility group A2), FOXO3 and MTSS1, are associated with high-grade serous ovarian carcinoma tumor types and clinical outcome, we studied MIR182 by in situ hybridization and its target gene expression by immunohistochemistry in 117 cases of advanced ovarian cancer. We found that high-grade serous ovarian carcinoma had significantly higher MIR182 (P=0.0003) and HMGA2 (P=0.04) expression, and significantly lower BRCA1 (P<0.0001) and FOXO3 (P<0.001) expression than normal controls. MIR182 is significantly correlated with MTSS1 expression (r=0.31; P<0.001), whereas other target genes did not show a significant correlation with MIR182, indicating a complicated regulatory mechanisms of these genes in high-grade serous ovarian carcinoma. Among the examined MIR182 target genes, only HMGA2 was significantly associated with serous type carcinomas (P<0.01), ascites (P<0.01) and high death rate (P=0.02). FOXO3 expression was associated with lower-stage disease (P=0.04) and solid growth pattern (P=0.03). MIR182 expression is significantly higher in high-grade serous ovarian carcinoma than in fallopian tubes.


Subject(s)
Cystadenocarcinoma, Serous/genetics , Gene Expression Regulation, Neoplastic/physiology , MicroRNAs/genetics , Ovarian Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/mortality , Cystadenocarcinoma, Serous/secondary , DNA, Neoplasm/analysis , Female , HMGA2 Protein/genetics , Humans , Illinois/epidemiology , Immunohistochemistry , In Situ Hybridization , Lymph Nodes/pathology , MicroRNAs/metabolism , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Survival Rate
5.
Gynecol Oncol ; 114(2): 293-8, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19476987

ABSTRACT

OBJECTIVES: SNCG in breast cancer is a marker for advanced and aggressive disease thereby correlating with a poor prognosis in patients. We set out to determine if SNCG expression in UPSC correlates with aggressive cellular properties, poor prognosis, and chemoresistance, and if silencing SNCG can reverse these attributes in vitro. METHODS: A focused, real time PCR array was performed comparing a papillary serous (SPEC2) and an endometrioid (Ishikawa) endometrial cancer cell line. SNCG was the most differentially expressed gene. SNCG expression was confirmed by real time PCR, Western blot, and immunohistochemistry (IHC) and correlated with outcomes in a pilot set of 20 UPSC patients. A stably transfected SPEC2 cell line was created using shSNCG oligonucleotides. The effect of SNCG knockdown in SPEC2 cells on cell proliferation and sensitivity to paclitaxel-induced apoptosis was measured using a cell viability assay, BrdU incorporation assay, as well as cleaved PARP analyses. RESULTS: SNCG mRNA as well as protein was highly expressed in SPEC2 cells while minimally to undetectable in several endometrioid endometrial cancer and normal endometrial cell lines. IHC also confirmed unique SNCG expression in UPSC tumors compared to low grade endometrial cancers. In UPSC patients, SNCG expression by IHC correlated with advanced stage and decreased progression-free survival. Knockdown of SNCG in SPEC2 cells caused a significant decrease in cell proliferation and increased sensitivity to paclitaxel-induced apoptosis. CONCLUSIONS: SNCG is a novel biomarker for aggressive disease and chemoresistance in UPSC and merits further investigation both as a prognostic tool and as a therapeutic target.


Subject(s)
Biomarkers, Tumor/biosynthesis , Carcinoma, Papillary/metabolism , Cystadenocarcinoma, Serous/metabolism , Neoplasm Proteins/biosynthesis , Uterine Neoplasms/metabolism , gamma-Synuclein/biosynthesis , Apoptosis/drug effects , Apoptosis/physiology , Biomarkers, Tumor/genetics , Carcinoma, Papillary/drug therapy , Carcinoma, Papillary/genetics , Cell Growth Processes/physiology , Cell Line, Tumor , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/genetics , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Paclitaxel/pharmacology , RNA, Small Interfering/genetics , Transfection , Uterine Neoplasms/drug therapy , Uterine Neoplasms/genetics , gamma-Synuclein/antagonists & inhibitors , gamma-Synuclein/genetics
6.
Int J Med Robot ; 5(4): 392-7, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19455550

ABSTRACT

BACKGROUND: Evaluation of the impact of a new robotic surgery programme on perioperative outcomes for endometrial cancer METHODS: A prospective database of all patients undergoing staging for endometrial cancer during July 2007-July 2008 was collected and analysed. Demographic data and perioperative outcomes were compared between cases performed via laparotomy, laparoscopy and robotics. RESULTS: Sixty-five patients underwent staging during the time of data collection (LAP-26, LSC-7, ROB-32). No difference in surgical volume in the year before vs. after robotics was identified. Median operative time for robotics and laparotomy was significantly less than for laparoscopy (p = 0.023). There was no significant difference in lymph node yields between the three groups (p = 0.92). Robotics was associated with significantly less blood loss (p < 0.0001). Complication rates were significantly lower in the robotic group compared to the laparotomy group (p = 0.05). Median hospital stay was 1 day for the minimally invasive groups. Total number of perioperative inpatient days decreased from 331 to 150 in one year. Practice management of endometrial cancer transitioned from a predominantly open approach (5.6% LSC) to robotics (11% LSC, 49% ROB) within 12 months. CONCLUSIONS: Robotic surgery dramatically altered our management of endometrial cancer and was associated with a significant improvement in several perioperative outcomes when compared to laparotomy and laparoscopy.


Subject(s)
Endometrial Ablation Techniques/statistics & numerical data , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/surgery , Practice Patterns, Physicians'/statistics & numerical data , Robotics/statistics & numerical data , Surgery, Computer-Assisted/statistics & numerical data , Workload/statistics & numerical data , Chicago/epidemiology , Female , Humans , Middle Aged , Outcome Assessment, Health Care , Prevalence , Treatment Outcome
7.
Gynecol Oncol ; 114(2): 168-72, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19446869

ABSTRACT

OBJECTIVES: To report the impact of a new robotic surgery program on the surgical training of gynecologic oncology fellows over a 12 month period of time. METHODS: A robotic surgery program was introduced into the gynecologic oncology fellowship program at Northwestern University Feinberg School of Medicine in June 2007. A database of patients undergoing surgical management of endometrial and cervical cancer between July 2007 and July 2008 was collected and analyzed. Changes in fellow surgical training were measured and analyzed. RESULTS: Fellow surgical training for endometrial and cervical cancer underwent a dramatic transition in 12 months. The proportion of patients undergoing minimally invasive surgery increased from 3.3% (4/110 patients) to 43.5% (47/108 patients). Fellow training transitioned from primarily an open approach (94.4%) to a minimally invasive approach (11% laparoscopic, 49% robotic, 40% open) for endometrial cancer stagings, and from an open approach (100%) to an open (50%) and robotic (50%) approach for radical hysterectomies. Fellow participation in robotic procedures increased from 45% in the first 3 months to 72% within 6 months, and 92% by 12 months. The role of the fellow in robotic cases transitioned from bedside assistant to console operator within 3 months. CONCLUSIONS: Fellow surgical training underwent a dramatic change with the introduction of a robotic surgery program. The management of endometrial and cervical cancer was impacted the most by robotics. Robotic surgery broadened fellowship surgical training, but balanced surgical training and standardized fellow training modules remain challenges for fellowship programs.


Subject(s)
Endometrial Neoplasms/surgery , Gynecologic Surgical Procedures/education , Medical Oncology/education , Robotics/education , Uterine Cervical Neoplasms/surgery , Education, Medical, Graduate , Fellowships and Scholarships , Female , Gynecologic Surgical Procedures/methods , Humans , Hysterectomy/education , Hysterectomy/methods , Laparoscopy/methods , Robotics/methods
8.
Gynecol Oncol ; 113(1): 63-7, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19201457

ABSTRACT

OBJECTIVES: To assess the feasibility, associated toxicities, and reasons for early cessation of an outpatient intraperitoneal (IP) chemotherapy regimen for treatment of advanced ovarian cancer following optimal cytoreductive surgery. METHODS: Between January 2006 and December 2007, 42 patients with stages IIC-IV epithelial ovarian, tubal, or primary peritoneal cancer who had residual disease <1 cm after cytoreductive surgery were treated with an outpatient IP chemotherapy protocol. Patients received intravenous (IV) docetaxel 75 mg/m(2) and IP cisplatin 75-100 mg/m(2) on day 1, followed by IP paclitaxel 60 mg/m(2) on day 8, with the intent to treat patients every 21 days for 6 cycles of chemotherapy. Charts were abstracted for demographic, chemotherapy, and toxicity-related data. RESULTS: The median age of the 42 patients was 59 years (range 33-70) and the majority of patients had epithelial ovarian cancer (80%), FIGO stage IIIC (83%), and papillary serous histology (74%). Of an intended 252 IP chemotherapy cycles, 172 (68%) were administered. Twenty-nine patients (69%) completed >or=4 cycles and 12 (29%) received all 6 IP cycles. Common grade 3/4 toxicities by patient included neutropenia (43%), infection (21.5%), and gastrointestinal effects (14%). There was one treatment-related death. Reasons for discontinuation were largely chemotherapy (43%) or port (37%) related. CONCLUSIONS: With supportive measures, such as scheduled hydration and granulocyte colony-stimulating factors, outpatient administration of IP chemotherapy was feasible. This regimen resulted in few hospitalizations or treatment delays and demonstrated less toxicity than previously reported IP chemotherapy regimens. Port-related complications were a leading cause of IP chemotherapy discontinuation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Ovarian Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adult , Aged , Amifostine/administration & dosage , Cisplatin/administration & dosage , Combined Modality Therapy , Fallopian Tube Neoplasms/drug therapy , Fallopian Tube Neoplasms/pathology , Fallopian Tube Neoplasms/surgery , Female , Humans , Infusions, Parenteral , Middle Aged , Neoplasm Staging , Outpatients , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , Paclitaxel/administration & dosage , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/pathology , Peritoneal Neoplasms/surgery , Pilot Projects , Retrospective Studies
9.
J Robot Surg ; 3(1): 19, 2009 Mar.
Article in English | MEDLINE | ID: mdl-27628448

ABSTRACT

A robotics surgery program was introduced into the division of gynecologic oncology at Northwestern University Feinberg School of Medicine in June 2007. A prospective database of all patients undergoing a type III radical hysterectomy for stage IB1 cervical cancer between July 2007 and June 2008 was collected and analyzed. Demographic data and perioperative outcomes were analyzed between a traditional and robot-assisted approach. A total of 14 patients were identified who underwent a type III radical hysterectomy for stage IB1 cervical cancer. Seven patients underwent robotic surgery and seven patients underwent traditional surgery. There were no significant differences in median age or body mass index between the two groups. A significant difference in blood loss between robotic (75 cc) and traditional (700 cc) surgery was detected (P = 0.002). A significant difference in hospital stay between robotic (1 day) and traditional (5 days) surgery was observed (P = 0.0007). No significant difference in operative time (260 vs. 264 min) or lymph node yield (19 and 14) was identified between the robotic and traditional approaches. No major operative complications occurred with robotic radical hysterectomy. Robot-assisted radical hysterectomy was associated with a significant reduction in blood loss and hospital stay. Improved nodal yields, fewer operative complications, and less pain was observed with the robotic approach. Robot-assisted radical hysterectomy appears safe and feasible and further investigation is warranted in a prospective fashion.

11.
Gynecol Oncol ; 108(3): 609-18, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18234299

ABSTRACT

OBJECTIVE: Endometrial cancer is the most common type of gynecologic cancer in the United States. In this study, we propose that inhibition of the AKT pathway sensitizes cells to chemotherapeutic agents by increasing FOXO1 expression. METHODS: Ishikawa and RL95 cells were treated with the AKT inhibitor (API-59CJ-OMe) alone and in combination with carboplatin or paclitaxel. Cells were counted using a hemocytometer and cell cycle analysis done with flow cytometry. Apoptosis was measured with TUNEL and Annexin V/DAPI staining. FOXO1 protein expression and localization was done using immunofluorescent staining of cells. Finally, the adenovirus containing triple mutant FOXO1 was used to overexpress the constitutively active FOXO1 in Ishikawa cells and its effects on cell viability were studied. RESULTS: Treatment with 6 microM API-59CJ-OME resulted in preferential cell death in Ishikawa and RL95 cells compared to another endometrial cancer cell line, ECC1 after 48 h of treatment. API-59CJ-OME treatment of Ishikawa cells resulted in cell cycle arrest in the G2/M phase. The addition of API-59CJ-OME to carboplatin resulted in a synergistic increase in cell death by apoptosis compared to the responses to each agent separately. Treatment with API-59CJ-OME, carboplatin, paclitaxel or the combinations for 24 h increased nuclear expression of FOXO1 in Ishikawa cells. Overexpression of FOXO1 caused 37% of the cells to die within 24 h. Addition of carboplatin to the AD-FOXO1 expressing cells further increased cell death to 71%. CONCLUSIONS: Inhibition of AKT signaling potentiates cell death in Ishikawa and RL95 cells when combined with carboplatin through mechanisms involving FOXO1 activation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Ellipticines/pharmacology , Endometrial Neoplasms/drug therapy , Forkhead Transcription Factors/metabolism , Proto-Oncogene Proteins c-akt , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Apoptosis/drug effects , Carboplatin/administration & dosage , Carboplatin/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor/drug effects , Cell Line, Tumor/metabolism , Ellipticines/administration & dosage , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Female , Flow Cytometry , Forkhead Box Protein O1 , Humans , Paclitaxel/administration & dosage , Paclitaxel/pharmacology , Signal Transduction/drug effects
12.
Gynecol Oncol ; 111(3): 546-8, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18191185

ABSTRACT

BACKGROUND: Thalidomide is an oral immunomodulatory agent with antiangiogenic properties and activity in ovarian cancer. Pulmonary toxicity unrelated to venous thromboembolism is rare and its etiology is poorly understood. CASE: We present the first reported case of reversible drug-induced interstitial lung disease in a patient with recurrent ovarian cancer treated with weekly topotecan and thalidomide. The patient's symptoms and radiographic findings completely resolved upon discontinuing thalidomide while continuing on topotecan. CONCLUSION: Due to its antiangiogenic properties and good tolerance, thalidomide is an attractive agent for the treatment of recurrent ovarian cancer. Gynecologic oncologists and pulmonologists should be aware that acute interstitial lung disease is a possible side effect that appears easily reversible when the drug is stopped.


Subject(s)
Angiogenesis Inhibitors/adverse effects , Lung Diseases, Interstitial/chemically induced , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Thalidomide/adverse effects , Angiogenesis Inhibitors/therapeutic use , Female , Humans , Middle Aged , Thalidomide/therapeutic use
13.
Endocrinology ; 149(4): 1942-50, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18096667

ABSTRACT

In many type I endometrial cancers, the PTEN gene is inactivated, which ultimately leads to constitutively active Akt and the inhibition of Forkhead box O1 (FOXO1), a member of the FOXO subfamily of Forkhead/winged helix family of transcription factors. The expression, regulation, and function of FOXO1 in endometrial cancer were investigated in this study. Immunohistochemical analysis of 49 endometrial tumor tissues revealed a decrease of FOXO1 expression in 95.9% of the cases compared with the expression in normal endometrium. In four different endometrial cancer cell lines (ECC1, Hec1B, Ishikawa, and RL95), FOXO1 mRNA was expressed at similar levels; however, protein levels were low or undetectable in Ecc1, Ishikawa, and RL95 cells. Using small interfering RNA technology, we demonstrated that the low levels of FOXO1 protein were due to the involvement of Skp2, an oncogenic subunit of the Skp1/Cul1/F-box protein ubiquitin complex, given that silencing Skp2 increased FOXO1 protein expression in Ishikawa cells. Inhibition of Akt in Ishikawa cells also increased nuclear FOXO1 protein levels. Additionally, progestins increased FOXO1 protein levels, specifically through progesterone receptor B (PRB) as determined by using stably transfected PRA-specific and PRB-specific Ishikawa cell lines. Finally, overexpression of triple mutant (Tm) FOXO1 in the PR-specific Ishikawa cell lines caused cell cycle arrest and significantly decreased proliferation in the presence and absence of the progestin, R5020. Furthermore, TmFOXO1 overexpression induced apoptosis in PRB-specific cells in the presence and absence of ligand. Taken together, these data provide insight into the phosphoinositide-3-kinase/Akt/FOXO pathway for the determination of progestin responsiveness and the development of alternate therapies for endometrial cancer.


Subject(s)
Endometrial Neoplasms/metabolism , Forkhead Transcription Factors/physiology , Receptors, Progesterone/physiology , Cell Line , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/pathology , Endometrium/chemistry , Female , Forkhead Box Protein O1 , Forkhead Transcription Factors/analysis , Humans , Phosphatidylinositol 3-Kinases/physiology , Phosphorylation , Protein Processing, Post-Translational , Proto-Oncogene Proteins c-akt/physiology , Receptors, Progesterone/analysis , S-Phase Kinase-Associated Proteins/physiology
14.
Cancer Res ; 67(15): 7113-23, 2007 Aug 01.
Article in English | MEDLINE | ID: mdl-17671178

ABSTRACT

This study is the first comprehensive, integrated approach to examine grade-specific changes in gene expression along the entire neoplastic spectrum of cervical intraepithelial neoplasia (CIN) in the process of cervical carcinogenesis. This was accomplished by identifying gene expression signatures of disease progression using cDNA microarrays to analyze RNA from laser-captured microdissected epithelium and underlying stroma from normal cervix, graded CINs, cancer, and patient-matched normal cervical tissues. A separate set of samples were subsequently validated using a linear mixed model that is ideal to control for interpatient gene expression profile variation, such as age and race. These validated genes were ultimately used to propose a genomically based model of the early events in cervical neoplastic transformation. In this model, the CIN 1 transition coincides with a proproliferative/immunosuppression gene signature in the epithelium that probably represents the epithelial response to human papillomavirus infection. The CIN 2 transition coincides with a proangiogenic signature, suggesting a cooperative signaling interaction between stroma and tumor cells. Finally, the CIN 3 and squamous cell carcinoma antigen transition coincide with a proinvasive gene signature that may be a response to epithelial tumor cell overcrowding. This work strongly suggests that premalignant cells experience a series of microenvironmental stresses at the epithelium/stroma cell interface that must be overcome to progress into a transformed phenotype and identifies the order of these events in vivo and their association with specific CIN transitions.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/genetics , Uterine Cervical Dysplasia/genetics , Uterine Cervical Neoplasms/genetics , Carcinoma, Squamous Cell/pathology , Epithelium/metabolism , Epithelium/pathology , Female , Humans , Lasers , Microdissection , Neoplasm Invasiveness/pathology , Oligonucleotide Array Sequence Analysis , RNA, Neoplasm/analysis , Reverse Transcriptase Polymerase Chain Reaction , Stromal Cells/metabolism , Stromal Cells/pathology , Transcriptional Activation , Uterine Cervical Neoplasms/pathology , Uterine Cervical Dysplasia/pathology
15.
Gynecol Oncol ; 99(2): 261-6, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16140364

ABSTRACT

OBJECTIVE: End-of-life (EOL) medical care consumes 10-12% of national health care expenditures and 27% of Medicare dollars annually. Studies suggest that hospice services decrease EOL expenditures by 25-40%. The goal of this study was to compare the total cost of hospital-based resources utilized in ovarian cancer patients during their last 60 days of life for those enrolled in hospice versus those not on hospice. METHODS: Study eligibility included patients who expired from ovarian cancer from 1999 to 2003. Medical records were reviewed for demographic data as well as treatment, response and recurrence rates, histologic type, grade and stage. Billing records were analyzed for costs of inpatient and outpatients visits, including radiologic, laboratory and pharmacy charges. Total cost of hospital resources was compared between patients managed on hospice for >10 days (hospice group) versus <10 days (non-hospice group) using the following methods: Mann-Whitney U, Kruskal-Wallis and Student's t tests. Overall survival was compared using Kaplan-Meier statistics. RESULTS: Of the 84 patients analyzed, 67 (79.8%) were in the non-hospice group and 17 (20.2%) were in the hospice group. Demographic, histologic and staging characteristics as well as platinum sensitivity were similar between the two groups before the last 60 days of life. Mean number of chemotherapy cycles before the study period was also similar (20.4 and 21.0, respectively). However, during the study period, the mean total cost per patient in the non-hospice group was dollar 59,319 versus dollar 15,164 in the hospice group (P = 0.0001). A significant difference in cost was noted for mean inpatient days (dollar 6584 vs. dollar 1629, P = 0.0007), radiology (dollar 6063 vs. dollar 2343, P = 0.003), laboratory (dollar 12,281 vs. dollar 2026, P = 0.0004) and pharmacy charges (dollar 13,650 vs. dollar 4465, P = 0.0017) as well as for treating physician per patient (dollar 112,707 vs. dollar 34,677, P = 0.04). Overall survival for the two groups was the same. CONCLUSIONS: Our findings demonstrate that there is a significant cost difference with no appreciable improvement in survival between ovarian cancer patients treated aggressively versus those enrolled in hospice at the EOL. These data suggest that earlier hospice enrollment is beneficial. Furthermore, cost variations between physicians and patients imply that education may be an important variable.


Subject(s)
Ovarian Neoplasms/economics , Ovarian Neoplasms/therapy , Terminal Care/economics , Adult , Aged , Aged, 80 and over , Female , Health Services/economics , Health Services/statistics & numerical data , Hospice Care/economics , Hospitalization/economics , Humans , Medical Futility , Middle Aged , Palliative Care/economics , Retrospective Studies , Terminal Care/methods
16.
Obstet Gynecol ; 105(1): 35-41, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15625139

ABSTRACT

OBJECTIVE: Guidelines for referring women with pelvic masses suspicious for ovarian cancers to gynecologic oncologists have been published jointly by Society of Gynecologic Oncologists (SGO) and the American College of Obstetricians and Gynecologists (ACOG). They are based on patient age, CA 125 level, physical findings, imaging study results, and family history. Although the guidelines are evidence-based, their predictive value in distinguishing cancers from benign masses is unknown. METHODS: Chart review for factors included in the guidelines of surgically evaluated women with pelvic masses at 7 tertiary care centers during a 12-month interval was performed. This information was used to estimate the predictive values of the SGO and ACOG guidelines in identifying patients with malignant pelvic masses. RESULTS: A total of 1,035 patients were identified, including 318 (30.7%) with primary malignancies of the ovary, fallopian tube, or peritoneum. Seventy-seven were younger than 50 years old (premenopausal group), and 240 were 50 years old or older (postmenopausal group). Fifty additional patients (4.8%) had cancers metastatic to the ovaries, and the remaining 667 (64.4%) had benign masses. The referral guidelines captured 70% of the ovarian cancers in the premenopausal group and 94% of the ovarian cancers in the postmenopausal group. The positive predictive value was 33.8% for the premenopausal group and 59.5% for the postmenopausal group, whereas the negative predictive values were more than 90% for both groups. Elevated CA 125 level was the single best predictor of malignancy in both groups. CONCLUSION: The SGO and ACOG referral guidelines effectively separate women with pelvic masses into 2 risk categories for malignancy. This distinction permits a rational approach for referring high-risk patients to a gynecologic oncologist for management.


Subject(s)
Pelvic Neoplasms/surgery , Referral and Consultation/standards , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , CA-125 Antigen/analysis , Female , Gynecology , Humans , Medical Oncology , Middle Aged , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/surgery , Pelvic Neoplasms/diagnosis , Postmenopause , Practice Guidelines as Topic , Premenopause
17.
Am J Hum Genet ; 74(6): 1262-9, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15098177

ABSTRACT

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by inherited mutations in DNA mismatch-repair genes, most commonly MLH1 or MSH2. The role MSH6 plays in inherited cancer susceptibility is less well defined. The aim of this study was to investigate the penetrance and expressivity of MSH6 mutations in kindreds ascertained through endometrial cancer probands unselected for family history. Detailed pedigrees were constructed for six MSH6 mutation carriers. All reported cancers and precancers were confirmed, and tissues were obtained when available. Tumors were analyzed for microsatellite instability (MSI) and for expression of MSH2, MLH1, and MSH6. MSH6 mutation status was determined for 59 family members. Of these 59 individuals, 19 (32%) had confirmed cancers and precancers. There was an excess of mutation carriers among the 19 affected family members (11 [58%] of 19) compared with those among the 40 unaffecteds (8 [20%] of 40, P=.0065, odds ratio = 5.5, 95% CI = 1.66-18.19). In four of the seven tumors analyzed from mutation carriers other than the probands, MSI and/or MMR protein expression was consistent with the involvement of MSH6. Overall estimated penetrance of the MHS6 mutations was 57.7%. Of the tumors in mutation carriers, 78% were part of the extended HNPCC spectrum. This study demonstrates that MSH6 germline mutations are, indeed, associated with increased cancer risk and that the penetrance of mutations may be higher than appreciated elsewhere. A combination of MSI and immunohistochemistry analyses may be helpful in screening for MSH6 mutation carriers.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA-Binding Proteins/genetics , Endometrial Neoplasms/genetics , Germ-Line Mutation/genetics , Heterozygote , Adaptor Proteins, Signal Transducing , Adult , Aged , Aged, 80 and over , Carrier Proteins , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , DNA Repair , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/pathology , Female , Genomic Instability , Humans , Male , Microsatellite Repeats , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein , Neoplasm Proteins/genetics , Nuclear Proteins , Pedigree , Penetrance , Proto-Oncogene Proteins/genetics
18.
Clin Cancer Res ; 10(2): 481-90, 2004 Jan 15.
Article in English | MEDLINE | ID: mdl-14760069

ABSTRACT

PURPOSE: The aim of this study was to evaluate number and types of synchronous and metachronous malignancies in patients with endometrial carcinoma with and without microsatellite instability (MSI). EXPERIMENTAL DESIGN: From a series of 413 endometrial cancer patients, we identified 94 patients with MSI-positive (MSI+) cancers and grouped them by tumor MLH1 promoter methylation status. These 94 patients were matched by year of surgery to 94 patients with MSI-negative (MSI-) endometrial cancers from the same series. Medical records were reviewed for clinicopathologic information including rates and types of synchronous and metachronous malignancies. Hereditary nonpolyposis colorectal cancer (HNPCC)-associated second and third cancers were analyzed for MSI and MSH2, MSH6, and MLH1 expression for comparison with the corresponding endometrial cancers. RESULTS: The MSI+ and MSI- cohorts were similar with regard to age, race, grade, and histology. Twenty-eight MSI+ endometrial cancers (29.8%) were MLH1 unmethylated. Rates of synchronous and metachronous cancers were also similar in the MSI+ and MSI- groups at 20 and 23%, respectively. However, patients with MSI+ MLH1 unmethylated endometrial cancers had an excess of HNPCC-associated second and third cancers compared with those with MSI+ MLH1 methylated and MSI- endometrial cancers (18% versus 4.5%, P = 0.034, and 2.1%, P = 0.002). Six of seven second tumors from 5 patients with MSI+ MLH1 unmethylated endometrial cancers showed concordant MSI and mismatch repair protein expression status. CONCLUSIONS: Our observation that patients with MSI-positive MLH1 unmethylated endometrial carcinoma are at increased risk for HNPCC-associated synchronous and metachronous malignancies suggests inherited cancer susceptibility. These patients and their families may warrant more intense cancer surveillance.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Methylation , Endometrial Neoplasms/genetics , Microsatellite Repeats , Neoplasms, Second Primary/genetics , Promoter Regions, Genetic , Age of Onset , Aged , Cohort Studies , DNA/metabolism , Endometrial Neoplasms/complications , Female , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Middle Aged , Models, Biological , Risk , Tamoxifen/therapeutic use
19.
Proc Natl Acad Sci U S A ; 100(10): 5908-13, 2003 May 13.
Article in English | MEDLINE | ID: mdl-12732731

ABSTRACT

Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC patients have inherited defects in DNA mismatch repair and the microsatellite instability (MSI) tumor phenotype. Sporadic endometrial cancers also exhibit MSI, usually associated with methylation of the MLH1 promoter. Germ-line MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma. We reasoned that MSH6 mutation might account for loss of mismatch repair in MSI-positive endometrial cancers in which the cause of MSI is unknown. We therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. MSI and MLH1 promoter methylation status were associated with age of onset and tumor histology. One hundred cases (23% of the entire series) were evaluated for MSH6 defects. Inactivating germ-line MSH6 mutations were identified in seven women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. The MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 versus 64.6, P = 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. Our data suggest that inherited defects in MSH6 in women with endometrial cancer are relatively common. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer is 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer.


Subject(s)
Base Pair Mismatch/genetics , DNA-Binding Proteins/genetics , Endometrial Neoplasms/genetics , Mutation , Age Factors , Amino Acid Sequence , Codon/genetics , Codon, Terminator/genetics , DNA Methylation , DNA Transposable Elements/genetics , Endometrium/metabolism , Exons/genetics , Female , Frameshift Mutation , Genetic Variation , Humans , Middle Aged , Molecular Sequence Data , Mutagenesis, Insertional , Polymorphism, Single-Stranded Conformational , Reference Values , Sequence Deletion
20.
Obstet Gynecol ; 99(1): 11-7, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11777503

ABSTRACT

OBJECTIVE: To identify prognostic factors that may be used to predict an aggressive disease course and poor outcome in patients with epithelial ovarian tumors of low malignant potential (borderline tumors). METHODS: Data on 126 patients with ovarian borderline tumors were analyzed with regard to demographic characteristics, staging, presence of microinvasion, duration of follow-up, recurrence rate, rate of recurrence as invasive disease, mortality rate, preoperative and postoperative CA-125, and treatment. Chi-square and Fisher exact tests were used to evaluate proportions for statistical significance. Disease-free and overall survival was calculated by using the Kaplan-Meier method and log-rank test. RESULTS: Patients were followed for a median of 39.0 months (mean 47.8 months). Seven patients (5.6%) had recurrent disease. Advanced stage disease and microinvasion were associated with significantly higher recurrence and mortality rates than were stage I/II disease and borderline tumors without microinvasion, respectively. Two of 13 (15%, 95% CI 8.7, 21.3) patients with microinvasion died of recurrent invasive cancer, whereas only 1 out of 113 patients without microinvasion died of recurrent borderline tumor (OR 20.4, 95% CI 1.2, 239). All 3 patients with an aggressive disease course and poor outcome had increasing CA 125 levels at the time of recurrence. CONCLUSION: Certain patients with microinvasion may be at higher risk for recurrence as invasive disease and may require different treatment strategies. CA 125 monitoring may have a role in early detection of recurrence in patients with aggressive disease.


Subject(s)
Carcinoma/mortality , Carcinoma/pathology , Neoplasm Invasiveness/pathology , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Biopsy, Needle , Carcinoma/therapy , Disease-Free Survival , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/therapy , Probability , Registries , Risk Factors , Statistics, Nonparametric , Survival Rate , Time Factors
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