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Biomedical subjects

M A Dimopoulos

Publications and source records attributed to M A Dimopoulos.

At least 19 recordsLinked to original sources

Analysis of p53 protein expression levels on ovarian cancer tissue microarray using automated quantitative analysis elucidates prognostic patient subsets.

BACKGROUND: p53 protein is regarded as a valuable prognostic marker in cancer with a potential use as a molecular target. Here, we sought to determine the prognostic value of p53 in ovarian cancer using a novel method of compartmentalized in situ protein analysis. PATIENTS AND METHODS: A tissue array composed of 141 advanced stage ovarian cancers uniformly treated was constructed. For evaluation of p53 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). RESULTS: High nuclear p53 expression levels were associated with better outcome for overall survival (OS) (P = 0.0023) and disease-free survival (P = 0.0338) at 5-years. High cytoplasmic p53 expression levels were associated with better outcome for OS (P = 0.0002). In multivariable analysis, high nuclear and high cytoplasmic p53 level with International Federation of Gynecology and Obstetrics (FIGO) stage were the most significant predictor variables for OS and high nuclear p53 level with FIGO stage were the significant predictor variables for disease-free survival. CONCLUSIONS: Assessment of the prognostic value of p53 protein levels using conventional immunohistochemistry is limited by the nonquantitative nature of the method. AQUA provides precise estimation of p53 protein levels and was able to elucidate the association of p53 protein levels and ovarian cancer prognosis.

Adult↗

The impact of age in the outcome of patients with advanced or recurrent cervical cancer after platinum-based chemotherapy.

OBJECTIVES: Cervical cancer is a disease of middle-aged and elderly but still there are young women diagnosed with advanced disease that is incurable with local treatment and is treated with platinum-based combination chemotherapy. It is unknown whether these young patients have a poorer outcome compared to older patients or whether elderly patients have inferior outcome than younger patients when treated with combination chemotherapy. METHODS: We compared the outcome between young (<35), elderly (>70) and middle-aged (35-70) women who were treated with platinum-based combination chemotherapy for advanced, recurrent or persistent disease. RESULTS: Two hundred and eighteen patients were included in our database. The baseline clinical and disease characteristics were not different between age groups but anemia and thrombocytosis were more frequent in younger patients. Median survival for all patients was 13.4 (95%CI 11-15.8) months while survival of patients<35 years of age was 9 months (95% CI 5.8-12), of patients older than 70 was 10 months (95% CI 6.9-13) of patients 35 to 70 years of age was 14.5 months (95% CI 11-18) (p=0.004). Multiple factors were significant for survival in univariate analysis but only weight loss, pain score and relapse inside an irradiated filed were significant predictors of outcome in multivariate analysis. CONCLUSIONS: Very young (<35) and elderly (>70) patients have a worse prognosis after treatment with combination chemotherapy for advanced or recurrent cervical cancer. Nevertheless, this difference is not significant when adjusted for other prognostic factors.

Adult↗

Automated quantitative analysis of DCC tumor suppressor protein in ovarian cancer tissue microarray shows association with beta-catenin levels and outcome in patients with epithelial ovarian cancer.

BACKGROUND: The deleted in colorectal cancer (DCC) protein, the product of DCC tumor suppressor gene, is frequently altered in cancer. Preclinical data demonstrate that DCC regulates beta-catenin levels. Here, we sought to determine the association of DCC with beta-catenin protein levels, clinicopathological parameters and patient outcome in ovarian cancer using a method of in situ compartmentalized protein analysis. METHODS: A tissue array composed of 150 advanced-stage ovarian cancers, treated with surgical debulking and platinum-paclitaxel (Taxol) combination chemotherapy, was constructed. For evaluation of protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). RESULTS: One hundred and twelve patients (74%) had sufficient tissue for AQUA. The median follow-up time for the entire cohort was 33 months. Patients with low nuclear DCC expression had a 3-year progression-free survival (PFS) rate of 0% compared with 33% of those with high DCC expression (P = 0.0067). In multivariate analysis, low nuclear DCC expression level retained its prognostic significance for PFS. Between DCC and beta-catenin, a significant relationship was found, where tumors with low DCC had low beta-catenin and vice versa (P = 0.003). CONCLUSIONS: Low nuclear DCC levels predict for poor patient outcome in epithelial ovarian cancer. DCC may exert its antitumor function, in part, through regulation of beta-catenin levels.

Automation↗

Intramedullary spinal cord and leptomeningeal metastases in a patient with carcinoma of the uterine cervix.

BACKGROUND: : Neoplastic meningitis in patients with carcinoma of the uterine cervix is unusual in the course of their diseases. Even more unusual are intramedullary spinal metastases. CASE: We report the case of a 64-year-old woman who presented with leptomeningeal and intramedullary spinal cord metastases from a grade 2 squamous cell cancer of the uterine cervix. This is just the second case of intramedullary metastases from cervical carcinoma. CONCLUSION: Neoplastic meningitis or intramedullary metastases are extremely rare in the course of uterine cervix carcinoma. Nevertheless, when indicated by symptoms, patients should undergo MRI of the brain and/or spine and have a lumbar puncture performed, for the diagnosis of this devastating complication. Treatment is mainly palliative but may offer symptom relief.

Female↗

Systemic chemotherapy in inoperable or metastatic bladder cancer.

Urothelial cancer is a common malignancy. The management of patients with recurrent disease after cystectomy or initially metastatic or unresectable disease represents a therapeutic challenge. Systemic chemotherapy prolongs survival but long-term survival remains infrequent. During recent years there has been improvement due to the use of novel chemotherapeutic agents, mainly gemcitabine and the taxanes. The long-considered-standard MVAC has been challenged by combinations showing more favourable toxicity profiles and equal (gemcitabine-cisplatin) or even improved (dose-dense, G-CSF-supported MVAC) efficacy. Specific interest has also been generated in specific groups of patients (elderly patients, patients with renal function impairment or comorbidities), who are not fit for the standard cisplatin-based chemotherapy but can derive significant benefit from carboplatin- or taxane-based treatment. Retrospective analyses have enabled the identification of groups of patients with different prognoses, who possibly require different therapeutic approaches. Modern chemotherapy offers a chance of long-term survival in patients without visceral metastases, possibly in combination with definitive local treatment. Finally, the progress of targeted therapies in other neoplasms seems to be reflected in advanced bladder cancer by recent studies indicating that biological agents can be combined with modern chemotherapy. The true role of such therapies is currently being evaluated.

Antineoplastic Agents↗

Pulmonary toxicity from novel antineoplastic agents.

BACKGROUND: The pulmonary side-effects induced by novel antineoplastic agents have not been well characterized. METHODS: To further investigate this topic, relevant English and non-English language studies were identified through Medline. For our search we used the generic names of novel cytotoxic or non-cytotoxic antineoplastic agents and the key phrases pulmonary/lung toxicity, dyspnea, pneumonitis, acute lung injury, acute respiratory distress syndrome and alveolar damage. The references from the articles identified were reviewed for additional sources. Abstracts from International Meetings were also included. Furthermore, information was obtained from the Pneumotox website, which provides updated knowledge on drug-induced respiratory disease as well as from pharmaceutical websites. RESULTS: Most novel antineoplastic drugs may induce pulmonary toxicity, which involves mainly the parenchyma, and less frequently the airways, pleura or the pulmonary circulation. Furthermore, a subset of these agents impairs pulmonary function tests. The exact incidence of lung toxicity remains unclear. The most common patterns consist of dyspnea without further details and infiltrative lung disease (ILD), denoting changes in the interstitium or alveoli. The diagnosis is one of exclusion. ILD is usually benign and responds to appropriate treatment; however, fatalities have been reported. CONCLUSIONS: Clinicians should be aware of the potential of most novel antineoplastic agents to cause lung toxicity. A high index of suspicion is required if these are combined with other cytotoxic drugs or radiation.

Antineoplastic Agents↗

Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma.

BACKGROUND: Magnetic resonance imaging (MRI) has been a useful technique for the assessment of patients with multiple myeloma (MM). We evaluated the prognostic significance of different MRI patterns in symptomatic patients with MM. PATIENTS AND METHODS: A total of 142 symptomatic MM patients underwent MRI before treatment. MRI patterns of involvement were correlated with known prognostic variables, including the International Staging System (ISS), response to treatment and survival. RESULTS: Focal marrow lesions were identified in 50% of patients, diffuse marrow replacement in 28%, a variegated pattern in 14% and normal pattern in 8%. When patients with the diffuse pattern were compared with patients with the other MRI patterns, they had features of more advanced disease such as higher ISS, anemia, hypercalcemia, elevated lactate dehydrogenase and extensive marrow plasmacytosis. Response rate was similar among patients with different MRI patterns. Median survival was 24 months for patients with the diffuse pattern, 51 months for those with the focal pattern, 52 months for those with the variegated pattern and 56 months for patients with the normal pattern (P = 0.001). The presence or absence of a diffuse MRI pattern separated patients with ISS stages I and II into two subgroups with significantly different survival times of 28 months and 61 months, respectively (P = 0.01). Furthermore, a diffuse MRI pattern predicted inferior outcome regardless of whether or not patients had received high-dose therapy with autologous stem cell transplantation. CONCLUSION: Diffuse marrow replacement on MRI adds to the evaluation of patients with multiple myeloma and their management.

Aged↗

The outcome of advanced or recurrent non-squamous carcinoma of the uterine cervix after platinum-based combination chemotherapy.

BACKGROUND: Data about the outcome and prognostic factors in the group of patients with non-squamous cell advanced or recurrent carcinomas of the uterine cervix are limited. We compared the outcome of patients with non-squamous with that of squamous cell carcinomas after platinum-based combination chemotherapy as first line therapy for stage IV or recurrent cervical carcinoma. PATIENTS AND METHODS: A total of 200 patients with stage IV or recurrent carcinomas of the cervix received platinum-based combination chemotherapy and were included in our analysis. RESULTS: There were 58 patients with non-squamous and 142 patients with squamous cell carcinomas. Response to chemotherapy was 53.5% in non-squamous vs. 43.5% in squamous carcinomas. Histology was not an independent predictor of tumor response (P = 0.797). Response rates were lower in patients with relapse only in a previously irradiated area in both squamous (26.9% vs. 53.5%, P = 0.005) and non-squamous carcinomas (47.1% vs. 65%, P = 0.270). Weight loss was the only significant predictor of survival in non-squamous histology patients (P < 0.0001). There was no significant difference in median survival between squamous (11.57 months [95% CI 9.35-13.79]) and non-squamous carcinomas (19.05 months [95% CI 13.63-24.47]) (P = 0.064). After adjustment for independent prognostic factors (ECOG performance status and weight loss), differences in survival remained not significant. CONCLUSION: Our study showed a similar outcome for both squamous and non-squamous stage IV or recurrent cervical carcinomas treated with platinum-based combination chemotherapy.

Adenocarcinoma↗

Phase I study of etoposide, cisplatin and irinotecan triplet in patients with advanced-stage small-cell lung cancer.

AIM: The irinotecan-cisplatin combination has emerged as a new standard for the treatment of advanced-stage small-cell lung cancer (AS-SCLC). To move forward we developed a 3-day regimen of cisplatin, etoposide and irinotecan. METHODS: Successive cohorts of AS-SCLC patients were treated with irinotecan administered as a single 1-h infusion in combination with fixed doses of cisplatin (20 mg/m(2)) and etoposide (75 mg/m(2)), both given for three consecutive days (ECI regimen). Irinotecan dose was escalated from 60 mg/m(2) by 40-mg/m(2) increments. At mid-step between the maximum tolerated dose (MTD) and the previous dose level, patients were randomized for the day of administration of irinotecan (day 1 vs day 3). RESULTS: A total of 36 AS-SCLC patients received 166 courses of treatment at four dose levels. The MTD of irinotecan was 140 mg/m(2) (three dose-limiting toxicities, DLTs), and the recommended optimal dose (ROD) 120 mg/m(2) (two DLTs). DLTs were febrile neutropenia and grade 3 diarrhea. Other toxicities were mild. No difference in toxicity was seen between the two time schedules. A 77% (95% CI 63.25-90.75%) response rate was recorded among 31 evaluable patients and the median survival was 12 months. CONCLUSIONS: The ECI regimen was well tolerated and showed considerable activity in patients with AS-SCLC. Phase II/III evaluation is ongoing.

Aged↗

Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study.

BACKGROUND: We compared the combination plus Carboplatin plus paclitaxel, which is considered the treatment of choice for initial chemotherapy of advanced ovarian cancer (AOC) with a regimen combining alternating carboplatin and cisplatin plus paclitaxel. The two platinum derivatives have been previously combined as they are not totally cross-resistant and as they share no overlapping toxicities. PATIENTS AND METHODS: Patients with AOC, after the initial cytoreductive surgery were randomized to either 6 courses of paclitaxel at 175 mg/m2 as 3 h infusion plus Carboplatin at 7 AUC (Arm A) or Paclitaxel at the same dose plus Carboplatin again at 7 AUC for cycles 1,3,5, while for cycles 2,4,6 Cisplatin at 75 mg/m2 substituted for Carboplatin (Arm B). RESULTS: 247 patients are analyzed. Significant differences were not found, both in terms of PFS (38 vs 39 months, p=0.95) and overall survival (40.6 vs 38.6 months, p=0.79). There was not also difference in 5-year survival rate (35% vs 39%) or 5-year PFS rate (23% vs 28%). Age >60, PS 2, stage IV disease and presence of residual disease were adversely related to the overall survival. CONCLUSION: Both regimens are well tolerated and effective. Alternating cisplatin with carboplatin does not improve the results compared with the standard combination.

Antineoplastic Combined Chemotherapy Protocols↗

Combination of docetaxel, estramustine phosphate, and zoledronic acid in androgen-independent metastatic prostate cancer: efficacy, safety, and clinical benefit assessment.

OBJECTIVES: Docetaxel is an effective agent for the treatment of androgen-independent prostate cancer (AIPC). Its combination with estramustine phosphate (EMP) has shown promising results in AIPC but the toxicity remains considerable. In an effort to minimize toxicity, we designed an every-2-week docetaxel administration regimen with a 3-day low-dose EMP regimen. Patients with bone metastases also received zoledronic acid. METHODS: A total of 54 patients with AIPC received docetaxel at 45 mg/m2 and EMP (140 mg orally every 8 hours for nine doses) every 2 weeks. Zoledronic acid was administered at 4 mg every 28 days. RESULTS: Of the 49 assessable patients, 22 (45%, 95% confidence interval [CI] 31% to 60%) had a prostate-specific antigen response. Of 24 patients with measurable disease, 9 (38%, 95% CI 19% to 59%) had a response to therapy (one complete response and eight partial responses). The median time to progression was 4.4 months (95% CI 2.7 to 6), and overall survival was 13.3 months (95% CI 9 to 17.6). Toxicity was mild, with only 5 cases of grade 3 or 4 toxicity. The pain score improved by 1 point in 21 (54%) of 39 symptomatic patients, and 14 (40%) of 38 patients who used analgesics discontinued analgesic consumption by the end of treatment. CONCLUSIONS: The combination of an every-2-week regimen of docetaxel, EMP, and zoledronic acid is an effective, well-tolerated regimen that results in symptomatic improvement in a significant proportion of patients with AIPC.

Adenocarcinoma↗

The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio.

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.

Adult↗

The outcome of elderly patients with advanced urothelial carcinoma after platinum-based combination chemotherapy.

BACKGROUND: The majority of patients with advanced urothelial cancer are elderly, but data regarding this specific age group are limited. We compared the tolerability and efficacy of first-line platinum (cisplatin or carboplatin)-based chemotherapy in elderly patients (> or =70 years) with those in younger patients. PATIENTS AND METHODS: A total of 381 patients with advanced urothelial carcinoma received CIMV (cisplatin, ifosphamide, methotrexate, vinblastine) (n=32), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) (n=105), DC (docetaxel, cisplatin) (n=174), CaG (carboplatin, gemcitabine) (n=64) or other regimes (n=6) and were included in this analysis. RESULTS: A total of 116 patients were > or =70 years. Elderly patients experienced more frequent neutropenia grade 3/4 (55% versus 37%, P=0.087) and renal toxicity (28% versus 10%, P=0.033) among patients treated with CIMV/MVAC, and neutropenic infections (4% versus 0%, P=0.019) among patients treated with DC. Median survival did not differ significantly between elderly and younger patients (9.3 versus 10.5 months, P=0.16). Eastern Cooperative Oncology Group performance status (PS) and haemoglobin were independently associated with prognosis. Patients with PS <2 and haemoglobin > or =10 g/dl had a median survival of 14 months as opposed to 5 months for patients with PS > or =2 or haemoglobin <10 g/dl (P <0.001). CONCLUSION: Elderly patients with advanced urothelial cancer tolerate platinum-based chemotherapy well and derive the same benefit as their younger counterparts.

Adult↗

Age-related thymic activity in adults following chemotherapy-induced lymphopenia.

BACKGROUND: The potential role of the adult thymus in T-cell homeostasis subsequent to lymphopenia remains the subject of debate. We examined whether thymic activity contributes to reconstitution of the peripheral T-cell pool, a critical process for patients recovering from antineoplastic therapy. METHODS: In selected patients with various neoplastic diseases we assessed peripheral blood lymphocyte subsets by flow-cytometry, including thymus-derived, CD4+ T cells expressing the CD45RA molecule, and thymic size rebound by CT scan before, and 3, 6 and 12 months after completion of cytotoxic therapy. RESULTS: Adult patients (n = 21, mean age of 30 years, range 18-49) had higher baseline numbers of B and lower numbers of NK cells than elderly patients (n = 15, mean age of 79 years, range 70-91), while total T-cell numbers did not differ. Despite the reduction of lymphocyte counts being comparable in the adult (mean of 45%) and elderly (mean of 49%) groups, occurring at, or near, completion of treatment, an enlargement of the previously atrophic thymus was evident in 63% of the adult, but in none of the elderly, subjects. In 22 patients who remained active disease-free during the following year, B cells and NK cells recovered to pretreatment levels as soon as at 3 months, whereas overall T-cell recovery occurred at 6 months post-treatment. Thymic rebound, observed in 11 of 22 patients who were of younger age, correlated significantly with a faster and more complete recovery of CD45RA+ CD4+ (mainly helper-naïve) T cells. CONCLUSION: The adult thymus appears capable of regeneration, at least up to middle age, contributing significantly to the reconstitution of the peripheral T-cell pool following chemotherapy-induced lymphopenia. In advanced age, however, although peripheral homeostatic pathways appear intact, regeneration of the naïve repertoire is incomplete.

Adolescent↗

Non-Hodgkin's lymphomas in Greece according to the WHO classification of lymphoid neoplasms. A retrospective analysis of 810 cases.

The purpose of this retrospective study, the largest unselected series in our country, was to illustrate the clinicopathological features of non-Hodgkin's lymphoma (NHL) classified according to the World Health Organization (WHO) classification of lymphoid neoplasms. A retrospective analysis was conducted and clinical features of histological subtypes were established in 810 patients (age > or = 15 years) with NHL who were treated at 8 major centers representative of Greece. There were 435 males and 375 females 95% of them aged >30 years. B symptoms were present in 34% of the patients, while 45.3% had stages I-II and 54.6% had stages III-IV. LDH was increased in 37% of the patients. B cell lymphomas formed 88% of the cases whereas T cell lymphomas formed 12% of the total. Indolent lymphomas accounted for 31.1%, aggressive ones for 66.7% and very aggressive ones for 2.4% of all NHLs. Among indolent lymphomas extranodal ones (MALT B cell lymphoma) were the most common subset while follicular lymphoma grade I and II and small lymphocytic ones presented with equal frequency. Among the aggressive lymphomas diffuse large cell lymphoma (DLCL) was the most common subtype; this entity along with large-cell immunoblastic lymphomas accounted for 45.2% of all B cell lymphomas. Among the T cell lymphomas, peripheral T cell lymphomas and anaplastic large cell lymphomas of the T/null-cell type were the most common subtypes. The most common extranodal presentation was the gastrointestinal tract (GI). Next in frequency were primary extranodal NHL of the head and neck region. MALT B cell lymphomas were found in almost half of the patients with GI tract NHL, whereas in all other extranodal places DLCL was the predominant histological subtype. The median survival for indolent and aggressive NHL was 123.5 and 55.5 months, respectively. This is the first report of a large series of malignant lymphomas in Greece using the WHO classification. It appears that there are no significant differences between NHL in Greece and other large series as far as clinical and extranodal presentation is concerned. The frequency of follicular lymphoma in the current study is comparable to that reported from Asian countries and mainland Europe, but lower than that of US and Northern European series. There were no important differences in the incidence of the remaining histological subtypes between Greece and other European countries.

Adolescent↗

Carboplatin hypersensitivity reactions: a single institution experience.

Carboplatin-related hypersensitivity reactions, frequently encountered in the heavily pretreated subpopulation of patients with gynecologic malignancies, can be severe and even potentially lethal-precluding these patients from an effective salvage treatment. We describe our experience in the management of such reactions and the application of a pretreatment protocol with corticosteroids, antihistamines and a slow infusion rate in order to safely re-administer carboplatin to the above patients. From 1998 to 2004, twenty patients developed an allergic reaction to carboplatin. Sixteen of them (80%) suffered from ovarian cancer. Upon resolution of the acute reaction, thirteen patients were pretreated according to our protocol and were re-exposed to carboplatin. Fifteen patients experienced the reaction during second-line carboplatin-based treatment and 5 patients after 3 or more regimens. Fifteen of the reactions (75%) were severe. Thirteen patients were re-treated with carboplatin after the application of our protocol, all of them successfully, even though 10 patients (77%) experienced minor symptoms during subsequent courses. On the contrary, only one of the 6 patients who were re-treated without the application of the protocol was able to receive further platinum-based treatment. In conclusion, pretreatment with corticosteroids, antihistamines and a slower infusion rate may make re-treatment possible in patients having experienced hypersensitivity to carboplatin.

Adult↗

Late relapse of epithelial ovarian cancer: a single institution experience.

PURPOSE OF INVESTIGATION: Late relapses are infrequent in ovarian cancer. We present the characteristics and outcome of patients who relapsed at least five years after first-line chemotherapy. METHODS: Six cases were retrieved from 203 patients treated from 1994 to 1998. RESULTS: Time to recurrence ranged from five to nine years. The initial stage was I or II in all cases, while histology was: endometrioid (4 cases), clear cell (1 case) and unspecified adenocarcinoma (1 case). Only two of five assessable patients responded to chemotherapy. Compared to earlier relapses, late relapses were characterized by earlier stages (p < 0.001), non serous histology (p = 0.010) and absence of symptoms (0% vs 46.5%, p = 0.025) at baseline. Five of 16 relapses (31%) among patients with Stage I or II were late relapses. CONCLUSION: Late relapses of ovarian cancer occur in early stages, where they are relatively frequent, while the chemosensitivity of the disease may be less than expected.

Adenocarcinoma↗