Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer.

PURPOSE: We compared response, survival and side effects of regiments with intravenous cyclophosphamide followed by intraperitoneal cisplatin versus intravenous cyclophosphamide followed by intraperitoneal carboplatin as second line treatment in one center retrospective study. MATERIAL AND METHODS: Inclusion criteria were: relapse or recurrence of the disease after surgery and first line treatment; stage III histologicaly documented serous epithelial ovarian cancer after one or more prior regiments of chemotherapy. Recurrence were confirmed throughout restaging laparotomy or second look laparotomy. Patients from one of the groups received 90 mg/m(2) cisplatin on the first day and 750 mg/m(2) cyclophosphamide intravenously, while the second group members AUC 6 carboplatin intraperitoneally and 750 mg/m(2) cyclophosphamide intravenously. Four courses were administrated for each patient. RESULTS: Of the 49 patients in the cisplatin group the response rates were 21 (43%), 10 (20%) and 18 (37%) in the groups of pathologic complete response, pathologic partial response and progressive disease, respectively. The median survival from the initiation of intraperitoneal chemotherapy was 59 months. Of the 25 patients in the carboplatin group the response rates were 10 (40%), 4 (16%) and 11 (44%) respectively. The median survival -51 months. The differences between the groups were not statistically significant p>0.05 either in response or in toxicity. CONCLUSIONS: The results of our research including relatively long survival from intraperotoneal chemotherapy initiation confirm that carboplatin treatment is as good as cisplatin in second line intraperitoneal chemotherapy for ovarian cancer.

Loss of heterozygosity at BRCA1/2 loci in hereditary and sporadic ovarian cancers.

Loss of heterozygosity at BRCA1/2 loci in breast and ovarian tumors is a suggested risk factor for germline BRCA1/2 mutation status. We evaluated the presence of losses of selected microsatellite markers localized on chromosomes 17 and 13q in hereditary and sporadic ovarian tumors. 151 consecutive primary ovarian tumors (including 21 with BRCA1/2 mutations and 130 without the mutations) were screened for loss of heterozygosity at loci on chromosomes 17 and 13q. Losses of heterozygosity of at least one microsatellite marker localized on chromosomes 17 and 13q were revealed in 123 (81.5%) and 104 (68.9%) tumors, respectively. Losses of all informative markers on chromosomes 17 and 13 occurred in 30 (19.9%) and 31 (20.5%) tumors, respectively. There was no difference in the frequency of losses at BRCA1 intragenic markers (D17S855 and D17S1323) between BRCA1-positive and BRCA1-negative patients. The frequency of losses on chromosome 17 was higher in high-grade than in low-grade carcinomas. Loss of heterozygosity on chromosomes 17 and 13q is a frequent phenomenon in both hereditary and sporadic ovarian cancers. The frequency of losses at BRCA1 intragenic markers in the ovarian tumor tissue is not strongly related to the presence of BRCA1 germline mutations.

Analysis of the results and long-term follow-up of second-look laparotomy in advanced ovarian cancer.

OBJECTIVE: The goal of the study was to analyze results of 171 second-look laparotomy and compare survival of patients with advanced ovarian cancer depending on SLL results. RESULTS: We obtained the following results: complete pathologic response (CPR)--56.2% (96 patients), microscopic disease (R(micro))--12.8% (22 patients), macroscopic disease (R(marco))--31% (53 patients). In patients with negative SLL results disease recurrence was diagnosed in 38.5%. We compared survival in separate groups of patients depending on SLL results: no difference between the CPR group and R(micro) group. Significantly longer survival of patients in the R(micro) group was found compared to patients with recurrence after negative SLL. There were no differences between the group with recurrence after negative SLL and the R(macro) group. CONCLUSIONS: An important observation is that the survival rate in patients with recurrence after negative SLL was significantly lower compared to patients with microscopic disease. The probable explanation for favorable prognosis in the group with microscopic disease was early administration of chemotherapy after SLL.

Microsatellite instability and HPV genotype in Polish women with cervical cancer.

INTRODUCTION: Human papillomaviruses (HPVs) are associated with anogenital cancer. Little is known about the prevalence of microsatellite instability (MSI) in cervical cancer. The aim of this study was to investigate the incidence of microsatellite instability in cervical cancer and to see whether there is a relation between MSI, HPV and clinicopathological characteristics in the study population. RESULTS: Using three assays (pU1M/2R, GP5+/6+ and E6-nested multiplex PCR) HPV was detected in 110 out of 113 patients with histologically confirmed cervical cancer. The presence of MSI was investigated in 95 of the 113 cases using seven microsatellite loci. In total, 12 out of the 95 patients (12.6%) showed MSI. None of clinicopathological parameters showed a significant difference between microsatellite stable and MSI cases. CONCLUSION: In this population of Polish cervical cancer patients, 12.6% showed microsatellite instability. There was no correlation between MSI positivity and clinicopathological parameters and/or survival.

Significance of hypoxia in uterine cervical cancer. Multicentre study.

PURPOSE: The aim of the study was to evaluate hypoxia markers (VEGF, GLUT-1, and HIF-1alpha) in cervical cancer tissue depending on staging (FIGO) and grading. We also analyzed the adverse effects of radiotherapy according to expression levels of hypoxic markers in the studied tissue. MATERIAL AND METHODS: Expression of hypoxia-inducible factor-1alpha (HIF-1alpha), glucose transporter 1 (GLUT-1) and vascular endothelial growth factor (VEGF, also known as proangiogenic factor) were estimated in biopsy or surgical specimens from 106 patients diagnosed with uterine cervical cancer. Immunohistochemical methods with EbVision+ complex using monoclonal antibodies anti-VEGF and anti-HIF-1alpha and polyclonal antibody anti-GLUT-1 were applied. RESULTS AND CONCLUSIONS: Hypoxia features measured by percentage of cells undergoing reaction with antibodies anti-HIF-1alpha, anti-GLUT-1 and anti-VEGF were similar in all clinical stages; however the biggest hypoxia features were shown in low differentiated cancers G2 and G3. The 5-year survival for FIGO Stage III patients was shorter in cases with a high expression of hypoxic markers. We observed adverse effects in 45.3% of patients, which occurred more often in patients with higher expression of the studied factors. The presence of hypoxic cells is established as one of the most important factors affecting resistance against tumor radiotherapy and patient prognosis.

Combination of intraperitoneal hyperthermic perfusion chemotherapy (IHPC) with intraperitoneal chemotherapy as a treatment modality for persistent ovarian cancer.

Persistent minimal residual disease diagnosed after the first line of chemotherapy during second-look surgery can be an indication for intraperitoneal chemotherapy. Another treatment option is intraperitoneal hyperthermic perfusion chemotherapy (IHPC) where the drug is administrated into the peritoneal cavity with the use of extracorporeal closed circuit perfusate circulation at a temperature of 41-42 degrees C. We have started to perform, as a second-line treatment, a combination of one IHPC procedure and four cycles of standard intraperitoneal chemotherapy. In a patient who had previously undergone three different chemotherapy regimens, stabilization of the disease was achieved. In our opinion combining the IHPC procedure with intraperitoneal chemotherapy can be valuable in patients with small volume residual tumor.

Mannan-binding lectin (MBL) in women with tumours of the reproductive system.

Mannan-binding lectin (MBL) is an important factor of innate immunity contributing to the clearance of microorganisms. Recently, an antitumourigenic role of MBL has been suggested. We investigated mbl2 genotypes, MBL concentrations, and MBL-MASP-2 complex activity in patients with ovarian cancer. The expression of both mbl2 and masp-2 genes were investigated in ovarian tissue sections. Additionally, samples from patients with other malignant and benign tumours of the reproductive tract were tested. A significantly higher incidence of MBL deficiency/insufficiency-associated genotypes was found among patients with malignant disease compared to age-matched controls. Unexpectedly, no differences in median MBL level or MBL-MASP-2 complex activity were found between the groups. This was partly a reflection of higher MBL concentrations and MBL-MASP-2 activity in cancer patients compared with healthy women carrying corresponding genotypes. MBL-specific mRNA expression was detected in several normal and malignant ovarian tissues, as well as in ovarian epithelial cell lines. Intracellular staining with MBL-specific antibodies demonstrated the presence of MBL in ovarian cell lines, and in normal as well as malignant ovarian tissue sections. In contrast, MASP-2-specific mRNA expression was detected only in the ovary tissues of patients with malignant disease. No significant changes in MBL concentration during 3 months of chemotherapy were noticed. MBL was detected in ascites and in the fluid of benign ovarian cysts. Our findings may reflect anti-tumourigenic activity of MBL protein which might suggest potential therapeutic application. However, it cannot be excluded that mbl-2 mutant alleles may be in linkage disequilibrium with an unidentified tumour susceptibility gene(s).

The problem of accurate initial diagnosis of Bartholin's gland carcinoma resulting in delayed treatment and aggressive course of the disease.

Carcinoma of the Bartholin's gland is a rare lesion accounting for only 5% of all vulvar cancers. Initial diagnosis of Bartholin's gland cancer (BGC) and recurrence after primary radical surgery and adjuvant radiotherapy poses a challenge in the treatment of BGC. This case report presents a particularly aggressive course of BGC. Spontaneous rupture of the femoral artery in the postoperative period was observed. The length of the survival period from the moment of diagnosis amounted to less than 16 months. Aspects of initial diagnosis problem and treatment options in groin recurrence of vulvar carcinoma and vascular complications are discussed.

Sentinel node identification in cervical cancer patients undergoing transperitoneal radical hysterectomy: a study of 100 cases.

We investigated the feasibility of sentinel lymph node (SN) identification using radioisotopic lymphatic mapping with technetium-99m-labeled nanocolloid and blue-dye injection in 100 patients with early cervical cancer (FIGO stage IB1 in 58, IB2 in 18, and IIA in 24) undergoing radical hysterectomy with pelvic lymphadenectomy. At least one SN was found in 84% on one side and in 66% on both sides. The sentinel detection rates according to the stages were as follows: 96.6% in IB1, 66.7% in IB2, and 62.5% in IIA with at least one SN on one side, and 86.2% in IB1, 38.9% in IB2, and 37.5% in IIA with at least one SN on both sides. Successful identification of at least one SN was less likely in patients with tumors >2 cm (54% of SN) compared with those with tumors

The role of pelvic exenteration for treatment of pelvic malignancy--a nine-year experience.

Pelvic exenteration offers the last chance for some women with gynecological and rectal malignancy. A series of 23 patients who underwent pelvic exenteration for local advanced gynecological and rectal malignancies between 1996 and 2004 were retrospectively reviewed. The exenteration was performed because of vulvar cancer in 14 patients and other pelvic malignancies in nine cases: rectal cancer in four cases, in three cases cervical cancer, in one case ovarian cancer and in one case uterine sarcoma. Nine patients developed major complications of the operative field involving the urinary tract or the wound. Early complications included massive bleeding from the sacral plexus in two cases (one patient died during surgery), acute respiratory distress syndrome (ARDS) in one case and thrombophlebitis in one case. Urinary incontinence was observed in two women as a late complication. Only one patient had a complication connected with the gastrointestinal tract. Twenty-two patients were followed-up. In the group of patients with vulvar cancer five women died after 4-29 months because of recurrence of disease. The nine surviving patients are still being followed-up and are without disease; survival time ranges from 6-74 months. In the group of patients with other malignancies four women died.

Management of massive presacral pelvic bleeding in patients with gynecological malignances: review of the literature.

Hemorrhage has always been a significant potential complication in the field of gynecological oncology. Throughout the years, a variety of medical and surgical modalities aimed at controlling pelvic hemorrhage have been developed. Most recently, these have focused on attempting to decrease the morbidity associated with pelvic bleeding. The effectiveness of and the complications involved in controlling massive hemorrhage by the preemptive method of vascular clamping of the aorta, intraoperative methods, such as the local application of procoagulants and of prolonged compression (pelvic gauze packing, plastic wrapped gauze packing, autograft tissue compression and balloon compression) have all been reviewed. Surgeons are able to acquaint themselves with the choice of methods that can be employed during massive pelvic bleeding resulting from procedures on gynecological malignancies.

TP53 status determines clinical significance of ERBB2 expression in ovarian cancer.

ERBB2 expression has been found in 19 to 44% of ovarian carcinomas; however, its predictive value has not been demonstrated, and trastuzumab has not found clinical application in ovarian cancer patients. We evaluated clinical significance of ERBB2 expression in relation to TP53 accumulation in ovarian carcinoma patients treated with platinum-based regimens. Immunohistochemical analysis with CB11 and a novel NCL-CBE356 antibody (against the internal and external domains of ERBB2, respectively) was performed on 233 tumours (FIGO stage IIB-IV); the US Food and Drug Administration-approved grading system with 0 to 3+ scale was used for evaluation, and the results were analysed by the Cox and logistic regression models. In all, 42% of the tumours expressed (category 1+, 2+ or 3+) either CB11 or CBE356 or both (CB11/CBE356 parameter). Associations between ERBB2 expression and clinical factors were observed only if tumours with staining category 1+ were grouped together with tumours showing staining categories 2+ and 3+. CB11/CBE356 parameter had a better predictive value than CB11 alone. CB11/CBE356 expression was negatively associated with platinum sensitivity (PS) in the TP53(-) group (P=0.022) and with disease-free survival (DFS) in the TP53(+) group (P=0.009). Our results may suggest that trastuzumab should be given postoperatively to patients with TP53(-)/ERBB2(+) ovarian carcinomas to enhance PS, and after completion of chemotherapy to patients with complete remission and TP53(+)/ERBB2(+) carcinomas to extend DFS time (in total to 30.4% of all patients analysed). Thus, novel criteria for ovarian cancer patient inclusion for clinical trials with trastuzumab should be considered and tested.

Surgical pelvic packing as a means of controlling massive intraoperative bleeding during pelvic posterior exenteration--a case report and review of the literature.

This is a report of a case of gynecological hemorrhage after a posterior pelvic exenteration in patients with vulvar cancer treated by temporary pelvic packing at the Department of Gynecology of the Medical University in Gdansk. The packing was successful and the sponges were removed after 24 h. Twenty-eight days after the operation, the patient was transferred to the Department of Radiotherapy for supplementary treatment. In patients with severe intraoperative hemorrhage, intra-abdominal packing has been successful as a mode of treatment.

Acute renal failure after anterior pelvic exenteration: a case report and review of the literature.

This is a report of a case of advanced cervical carcinoma in a 34-year-old woman treated with anterior pelvic exenteration at the Department of Gynecology of the Medical University in Gdansk. Despite annual gynecological check-ups, the patient presented with profuse bleeding from the genital tract. IVa cervical carcinoma according to the International Federation of Gynecology and Obstetrics (FIGO) staging was diagnosed. A vesicovaginal fistula was confirmed. In the postoperative period acute renal failure occurred. Twenty-four days after the operation when normal renal parameters had been restored, the patient was transferred to the Department of Radiotherapy for supplementary treatment. Pelvic exenteration offers the last chance for some women with gynecological malignancy and can provide a good chance of long-term survival in carefully selected patients with gynecological cancer.

HPV and histological status of pelvic lymph node metastases in cervical cancer: a prospective study.

AIMS: The purpose of this prospective study was to describe the incidence and distribution pattern of human papillomavirus (HPV) DNA in intraoperative dissected lymph nodes and to relate this to the pathological confirmation of metastasis. METHODS: Samples of primary cervical cancer lesions and dissected lymph nodes were obtained from women undergoing surgical treatment. The presence of HPV DNA was detected by the polymerase chain reaction. RESULTS: Tissue from 79 tumours and 365 lymph nodes was analysed. Metastasis to the lymph nodes was found in 19 cases. Metastasis correlated with the volume of the primary lesion, the depth of cervical and vaginal invasion, and with invasion of the corpus. HPV DNA was found in 60 of the primary lesions and 31 of the lymph nodes. The presence of HPV DNA in the lymph nodes correlated with the volume of the primary lesion and vaginal invasion. CONCLUSIONS: The incidence of HPV DNA in lymph nodes is twice as high as that of histopathologically confirmed metastases. The risk of the presence of HPV DNA and histopathologically confirmed metastases in lymph nodes is related to certain features of the primary tumour.

Intraperitoneal cisplatin versus no further treatment: 8-year results of EORTC 55875, a randomized phase III study in ovarian cancer patients with a pathologically complete remission after platinum-based intravenous chemotherapy.

First-line intravenous chemotherapy (CT) following debulking surgery is associated with prolonged survival, in particular in patients who achieve a pathological complete remission (pCR) at second-look surgery but in whom a high rate of relapses still occurs. Between 1988 and 1997, 153 patients in pCR following platinum-based intravenous CT were randomized between four courses of intraperitoneal cisplatin (P) (90 mg/m2 every 3 weeks) or observation. Overall survival (OS) was the primary endpoint, while progression-free survival (PFS) was a secondary endpoint. This intent-to-treat analysis includes 16 patients who were not eligible and 17 patients who had protocol violations. The two groups were well balanced in terms of age (median = 55 years), performance status (78% P.S. O), FIGO stage (96% stage III), histology (serous in 66%), grade (2 or 3 in 80%), and residuum before intravenous CT (>1 cm in 40%). Intraperitoneal CT was delivered mainly through intraperitoneal catheters (Port-a-Cath 61% and Tenckhoff 25%). Side effects of intraperitoneal cisplatin included vomiting [> or =grade 2 (82%)], rise in serum creatinine [> or =grade 2 (14%)], abdominal pain [grade 1-2 (38%)], and neurotoxicity [grade 2-3 (15%)]. After a median follow-up of 8 years, 80 patients (52%) have progressed with no difference in the pattern of relapse between the two groups and 75 patients (49%) have died; the respective hazard ratios for PFS and OS with 95% CI are 0.89 (0.59-1.33) and 0.82 (0.52-1.29). These results are suggestive of a treatment benefit but do not support a change in clinical practice. Other randomized clinical trials of intraperitoneal CT are reviewed and briefly discussed.

P21WAF1, P27KIP1, TP53 and C-MYC analysis in 204 ovarian carcinomas treated with platinum-based regimens.

BACKGROUND: The prognostic and predictive value of cell cycle regulatory proteins in ovarian cancer has not been established. We evaluated the clinical and biological significance of P21(WAF1), P27(KIP1), C-MYC, TP53 and Ki67 expressions in ovarian cancer patients. MATERIALS AND METHODS: Immunohistochemical analysis was performed on 204 ovarian carcinomas of International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV treated with platinum-based chemotherapy. Multivariate analysis with Cox and logistic regression models was performed in the whole group, and in the TP53-negative and TP53-positive subgroups. RESULTS: High P21(WAF1) labeling index (LI) was an independent positive predictor of platinum-sensitive response (P = 0.02). Overall survival was positively influenced by P21(WAF1) LI (P = 0.02) or by P21(WAF1) plus P27(KIP1) LI (P = 0.004) in the TP53-negative group only. Ki67 LI showed borderline association with disease-free survival (P = 0.05). Growth fraction was negatively associated with P21(WAF1) and P27(KIP1) indices in the TP53-negative group (P = 0.023 and 0.008, respectively), and these associations were borderline or lost in the TP53-positive group. Endometrioid and clear cell carcinomas differed from other carcinomas by having a low incidence of TP53 accumulation, a high incidence of C-MYC overexpression (70%) and a low median Ki67 LI (all with P <0.001). CONCLUSIONS: We have shown an independent predictive value of P21(WAF1) LI in ovarian carcinoma patients. The prognostic value of P21(WAF1) and P21(WAF1) plus P27(KIP1) LI was determined by TP53 status. A high frequency of C-MYC overexpression in endometrioid and clear cell carcinomas may suggest its role in the development of these tumor types.

Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen.

In cell line studies, BCL-2, BAX, as well as novel MEK1 protein levels have strong influence on ovarian cancer response to cisplatin-based chemotherapy. However, such associations have not been demonstrated clinically. We evaluated prognostic/predictive significance of these proteins with regard to TP53 status. Immunohistochemical analysis was performed on 229 ovarian carcinomas FIGO stage IIB-IV treated with platinum-based chemotherapy; the results were analysed by the Cox and logistic regression models. Clinical parameters (residual tumour size, patient age, FIGO stage) were the only indicators of overall survival (OS) and the strongest predictors of complete remission (CR). On the other hand, BAX expression was the strongest (P=0.005) or the only (in FIGO IIIC, P=0.02) prognostic indicator of disease-free survival (DFS) in the TP53(+) group. TP53(+) and TP53(-) ovarian carcinomas differed in clinical and molecular prognostic and predictive factors. Another novel finding is that CR was negatively influenced by high BAX expression in all patients group (P=0.047) and by BCL2 expression in the TP53(-) group (P=0.05). High MEK1 expression was associated with endometrioid and clear cell carcinomas (P=0.049); its loss was found with advancing FIGO stage (P=0.002). Our results suggest that binomial TP53 status divides ovarian carcinomas into two biologically distinct groups. BAX expression is an important factor of DFS in the TP53(+) group. BCL-2 and BAX, but not MEK1 expressions have predictive value in ovarian cancer patients treated with platinum-based chemotherapy.

[Endometrial carcinoma in patients with family history of neoplasms]. / Rak blony sluzowej trzonu macicy u chorych z obciazonym nowotworowo wywiadem rodzinnym.

OBJECTIVES: The aim of the study was multifactorial clinical analysis of patients with neoplasmatic family history operated because of endometrial carcinoma in 2nd Dept. of Obstetrics and Gynecology Medical University of Gdansk between 1983-1997. MATERIAL AND METHODS: The group of 117 women who answered inquiry forms was analysed. The other data was obtained from case histories. The subgroup of patients with neoplasmatic family history was selected. RESULTS: The subgroup of patients with neoplasmatic family history was 41.9% of all treated women (49 women). The median age was 58.8; most of them were para- and postmenopausal women. In the group of patients with adenocarcinoma of endometrium the neoplasmatic family history was obtained twice more often then in group with adenosquamous carcinoma. The neoplasmatic disease was found in different members of family (parents, sisters, brothers, grandparents, uncles, aunties and other). In 1/3 cases a neoplasmatic disease was found in few members of the family. CONCLUSION: Women with neoplasmatic family history have to be controlled more strictly because of "coexisted" genetic, internal and economic factors.

[Evaluation of risk factors after intraperitoneal chemotherapy in patients with ovarian cancer]. / Ocena czynników rokowniczych w leczeniu dootrzewnowym chorych na raka jajnika.

DESIGN: The authors sought to evaluate risk factors of patients with ovarian cancer treated with intraperitoneal cisplatin based chemotherapy (IPC). MATERIAL AND METHODS: From January 1996 to December 1998, 24 patients with recurrent or persistent ovarian cancer were treated. We divide them in two groups first beneath 65 year old (19 patients), second above 65 year (5 patients), and in three groups with residual microscopic diseases, residual below 0.5 cm, and between 0.5 and 2 cm in the time of the beginning of treatment with IPC. We also estimate stage (FIGO) as a risk factor. RESULTS: In the first group the study showed (CRP) among 9 patients (SD) among 2 patients PD in among patients. In the second group CRP were observed among 2 patients PD among 2 patients, and SD 1 patient. CONCLUSION: IPC is the valuable method of second line chemotherapy for ovarian cancer. Age is not a risk factor in IPC. IPC prolongs survival in ovarian cancer patients, progression free survival, and gives only slightly adverse effects.