Background
In recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, ...different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown that patients with serous adenocarcinoma of the ovary in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A02* genotype. We aimed to study the relationship between HLA-A02* genotype in these patients and the subsequent HLA class I HC protein product defects in the tumour tissue.
Materials and methods
One hundred and sixty-two paraffin-embedded tumour lesions obtained from Swedish women with epithelial ovarian cancer were stained with HLA class I heavy chain (HC) and β
2
-microglobulin (β
2
-m)-specific monoclonal antibodies (mAb). Healthy ovary and tonsil tissue served as a control. The HLA genotype of these patients was determined by PCR/sequence-specific primer method. The probability of survival was calculated using the Kaplan–Meier method, and the hazard ratio (HR) was estimated using proportional hazard regression.
Results
Immunohistochemical staining of ovarian cancer lesions with mAb showed a significantly higher frequency of HLA class I HC and β
2
-m down-regulation in patients with worse prognosis (WP) than in those with better prognosis. In univariate analysis, both HLA class I HC down-regulation in ovarian cancer lesions and WP were associated with poor survival. In multivariate Cox-analysis, the WP group (all with an HLA-A02* genotype) had a significant higher HR to HLA class I HC down-regulation.
Conclusions
HLA-A02* is a valuable prognostic biomarker in epithelial ovarian cancer. HLA class I HC loss and/or down-regulation was significantly more frequent in tumour tissues from HLA-A02* positive patients with serous adenocarcinoma surgical stage III–IV. In multivariate analysis, we show that the prognostic impact is reasonably correlated to the HLA genetic rather than to the expression of its protein products.
The increasing number of negative trials for ovarian cancer treatment has prompted an evaluation of new biologic agents, which in combination with chemotherapy may improve survival. The aim of this ...study was to investigate the response rate in platinum-resistant, KRAS wild-type ovarian cancer patients treated with pegylated liposomal doxorubicin (PLD) supplemented with panitumumab.
Major eligibility criteria were relapsed ovarian/fallopian/peritoneal cancer patients with platinum-resistant disease, measurable disease by GCIG CA125 criteria and KRAS wild-type. Patients were treated with panitumumab 6 mg/kg day 1 and day 15 and with PLD 40 mg/m2 day 1, every 4 weeks.
Forty-six patients were enrolled by 6 study sites in this multi-institutional phase II trial. The response rate in the intention-to-treat population (n = 43) was 18.6%. Progression-free and overall survival in the intention-to-treat population was 2.7 months (2.5-3.2 months, 95% confidence interval) and 8.1 months (5.6-11.7 months, 95% confidence interval), respectively. The most common treatment-related grade 3 toxicities included skin toxicity (42%), fatigue (19%), and vomiting (12%).
The combination of PLD and panitumumab demonstrates efficacy in platinum refractory/resistant patients but the skin toxicity was considerable.
New data show a continuously increased five-year survival for almost all analyzed cancer diagnoses since 1990. It has to be emphasized that the figures are uncertain due to the limited number of ...patients. The variation is huge and the greatest improvements are seen not least among the three major tumor diseases (breast, colorectal and prostate cancer), where the society, industry and research bodies made the biggest investments over the years. The causes of improved survival can be sought in several areas, such as earlier detection and better treatments. In addition to survival estimates, it is also always of importance to consider aspects around patient related outcome, such as quality of life.
Background: We have quantified the site-specific risk of second malignant neoplasms among nearly 29 000 survivors (⩾1 year) of testicular cancer, taking into account the histologic type of initial ...cancer and the primary therapy used to treat it. Methods: The study cohort consisted of 28 843 men identified within 16 population-based tumor registries in North America and Europe; over 3300 men had survived more than 20 years. New invasive cancers were identified through a search of registry files. Results: Second cancers were reported in 1406 men (observed-to-expected ratio O/E = 1.43; 95% confidence interval = 1.36–1.51), with statistically significant excesses noted for acute lymphoblastic leukemia (O/E = 5.20), acute nonlymphocytic leukemia (O/E = 3.07), melanoma (O/E = 1.69), non-Hodgkin's lymphoma (O/E = 1.88), and cancers of the stomach (O/E = 1.95), colon (O/E = 1.27), rectum (O/E = 1.41), pancreas (O/E = 2.21), prostate (O/E = 1.26), kidney (O/E = 1.50), bladder (O/E = 2.02), thyroid (O/E = 2.92), and connective tissue (O/E = 3.16). Overall risk was similar after seminomas (O/E = 1.42) or nonseminomatous tumors (O/E = 1.50). Risk of solid tumors increased with time since the diagnosis of testicular cancer, yielding an O/E = 1.54 (O = 369) among 20- year survivors (two-sided P for trend = .00002). Secondary leukemia was associated with both radiotherapy and chemotherapy, whereas excess cancers of the stomach, bladder, and, possibly, pancreas were associated mainly with radiotherapy. Conclusions: Men with testicular cancer continue to be at significantly elevated risk of second malignant neoplasms for more than two decades following initial diagnosis. Patterns of excess second cancers suggest that many factors may be involved, although the precise roles of treatment, natural history, diagnostic surveillance, and other influences are yet to be clarified.
Background: Men with testicular cancer are at an increased risk of leukemia, but the relationship to prior treatments is not well characterized. The purpose of our study was to describe the risk of ...leukemia following radiotherapy and chemotherapy for testicular cancer. Methods: Within a population-based cohort of 18 567 patients diagnosed with testicular cancer (from 1970 through 1993), a case–control study of leukemia was undertaken. Radiation dose to active bone marrow and type and cumulative amount of cytotoxic drugs were compared between 36 men who developed leukemia and 106 matched control patients without leukemia. Conditional logistic regression was used to estimate the relative risk of leukemia associated with specific treatments. All P values are two-sided. Results: Radiotherapy (mean dose to active bone marrow, 12.6 Gy) without chemotherapy was associated with a threefold elevated risk of leukemia. Risk increased with increasing dose of radiation to active bone marrow (P for trend = .02), with patients receiving radiotherapy to the chest as well as to the abdominal/pelvic fields accounting for much of the risk at higher doses. Radiation dose to active bone marrow and the cumulative dose of cisplatin (P for trend = .001) were both predictive of excess leukemia risk in a model adjusted for all treatment variables. The estimated relative risk of leukemia at a cumulative dose of 650 mg cisplatin, which is commonly administered in current testicular cancer treatment regimens, was 3.2 (95% confidence interval = 1.5–8.4); larger doses (1000 mg) were linked with statistically significant sixfold increased risks. Conclusions: Past treatments for testicular cancer are associated with an increased risk of leukemia, with evidence for dose–response relationships for both radiotherapy and cisplatin-based chemotherapy. Statistically nonsignificant excesses are estimated for current radiotherapy regimens limited to the abdomen and pelvis: Among 10 000 patients given a treatment dose of 25 Gy and followed for 15 years, an excess of nine leukemias is predicted; cisplatin-based chemotherapy (dose, 650 mg) might result in 16 cases of leukemia. The survival advantage provided by current radiotherapy and chemotherapy regimens for testicular cancer far exceeds the small absolute risk of leukemia.
Platinum-based chemotherapy is the cornerstone of modern treatment for ovarian, testicular, and other cancers, but few investigations have quantified the late sequelae of such treatment.
We conducted ...a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups.
Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0 (95 percent confidence interval, 1.4 to 11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 (95 percent confidence interval, 1.2 to 36.6) and 3.3 (95 percent confidence interval, 1.1 to 9.4), respectively. We found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (P for trend <0.001). Radiotherapy without chemotherapy (median dose, 18.4 Gy) did not increase the risk of leukemia.
Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.
Ovarian cancer is the most common cause of death from a gynecologic cancer. Every year around 700 women contracts ovarian cancer in Sweden. The overall survival is among the highest in Europe, but ...still long term relative survival is only 46%. It is a long-held myth that ovarian cancer is a disease without symptoms. Almost 90% of women have symptoms, even in the early stages. Symptoms that should arise suspicion of ovarian cancer and initiate diagnostic work-up are continuous abdominal extension, early feeling of satiety, pelvic or abdominal pain, urinary urge and postmenopausal bleeding. Women's awareness of symptoms and willingness to seek medical advice and the organization of the health care system are important factors determining cancer survival. Ovarian cancer is a heterogeneous group of diseases with different tumor traits and prognosis. Personalized medicine and preventive measures recognizing recent knowledge about tumor biology will positively affect survival.
Major histocompatibility complex antigens are mandatory for the immune response, and a genetic imbalance may be linked to tumor escape. We have previously characterized a cluster of ovarian cancer ...patients with high incidence of HLA-A2. To find a prognostic relevance, the presence of HLA-A2 was correlated to defined clinical parameters.
A population-based set of 97 patients with confirmed epithelial ovarian cancer were recorded in a database by age, histology, stage, surgery and treatment. At the time the study was initiated, the majority of the patients were not alive and HLA-A2 expression was therefore determined by PCR/sequence-specific oligonucleotide hybridization using DNA extracted from paraffin-imbedded tissue specimens.
88 patients with a median age of 65 years (36–87) could be evaluated. 44% were serous adenocarcinomas, 28% endometrioid, 6% mucinous, 13% clear cell carcinomas, 7% undifferentiated and 2% other epithelial tumors. Stages I–II comprised 33% and stages III–IV 67%. In stages III–IV and serous histology, 73% were HLA-A2 positive. Cox analysis, in this group, showed high univariate (HR7.16; CI 2.04–25.03;
P = 0.002) and multivariate (HR 6.8; CI 2.10–22.4;
P = 0.001) Hazard Ratios. None of the HLA-A2 positive patients survived 5 years, compared to more than 50% of the HLA-A2 negative patients.
HLA-A2 is a negative factor for survival in women with serous adenocarcinomas of the ovary in stages III–IV. This finding has implications for clinical patient management. Association with known oncogenes needs further analysis.
Patients with breast cancer who have mutations in the high penetrance genes BRCA1 and BRCA2, have an increased risk of ovarian cancer. Because these mutations are rare, easily obtained information ...such as age and family history of breast or ovarian cancer might be preferable for assessment of ovarian cancer risk in clinical practice.
We linked data from the Swedish Cancer Register to the Swedish Generation Register and generated a cohort of 30 552 breast-cancer patients born after 1931, with information on breast and ovarian cancer diagnosis from 146 117 first-degree relatives. Standardised incidence ratios (SIRs) with 95% CIs were calculated with nationwide rates of ovarian cancer, adjusted for age and calendar year.
During a mean follow-up of 6 years, 122 incident ovarian cancers were identified in the cohort, yielding an overall SIR of 2·0 (95% Cl 1·6–2·4). The risk was higher in breast-cancer patients diagnosed before the age of 40 years, with a family history of breast cancer (5·6; 1·8–13·1) or ovarian cancer (17·0; 3·5–50·0). A consistently increased risk was noted in patients with a relative who was diagnosed before the age of 50 years, with either breast or ovarian cancer. Women with a family history of ovarian cancer have an almost 10% risk of developing ovarian cancer before the age of 70.
In young women with breast cancer, the risk of ovarian cancer is greatly raised when a family history of breast or ovarian cancer is present. Close medical surveillance, and perhaps even prophylactic oophorectomy, might be justified in high-risk groups.
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