No association of the I1307K APC allele with ovarian cancer risk in Ashkenazi Jews.

Familial adenomatous polyposis is a dominantly inherited colon cancer syndrome associated with germ-line mutations in the APC tumor suppressor gene. An APC gene sequence alteration, the I1307K allele, occurs in 6% of the Ashkenazi Jewish population and is reported to double the risk for colorectal cancer. We screened a population of 190 Ashkenazi women who were diagnosed with epithelial ovarian carcinoma for the I1307K variant and measured the effect of this allele on the risk for cancer development in their first-degree relatives. We identified the I1307K allele in 7.9% (15 of 190) of our ovarian cancer cases. The average age of ovarian cancer diagnosis in carriers of the I1307K allele (57.5 years) was not statistically different than the age for noncarriers (56.4 years; P = 0.70). Among the 1087 first-degree relatives, there were 23 cases of colorectal cancer; 3 of 100 relatives of probands with the I1307K allele (3.0%) had a history of colorectal cancer versus 20 of 987 relatives of probands without the I1307K allele (2.1%; relative risk, 1.48; 95% confidence interval, 0.45-4.88; P = 0.462). Relatives of the I1307K carriers had a risk of 38.0% for developing any cancer to age 80, similar to the risk for relatives of noncarriers of the I1307K allele (42.1%; P = 0.86). The average age of diagnosis of cancer of any type was not different between relatives of carriers (59.0 years) and noncarriers (60.4 years). In the Ashkenazi Jewish population, the I1307K allele is unlikely to increase the risk of ovarian cancer or of cancer in general.

H19 expression and tumorigenicity of choriocarcinoma derived cell lines.

Certain embryonal tumors demonstrate a loss of heterozygosity at the parentally imprinted region of chromosome 11p15.5. It has been hypothesized that this implicates a tumor suppressor gene at this locus. The human H19 gene maps to 11p15.5, is expressed in fetal tissues including the placenta and is paternally imprinted. Here we show that the abundance of H19 transcripts in cells of two choriocarcinoma derived cell lines (JAr and JEG-3) differs greatly. While JAr cells express high levels of H19 RNA, the expression of H19 in JEG-3 cells is much lower than that of normal trophoblasts. Cells of these two cell lines were subcutaneously injected into nude mice with subsequent tumor formation. A fivefold increase in the H19 RNA level was measured in tumors derived from JEG-3 cell lines as compared to these cells before injection. However this increase in H19 RNA did not alter the clonogenicity in soft agar nor the growth rate of the cells derived from these tumors as compared to the original JEG-3 cells. Nevertheless, the cells retaining the elevated level of H19 transcripts were more tumorigenic than the original cells. We propose that there is a selection of cells expressing high levels of H19 from the total JEG-3 cell population during the microevolution of tumor formation. These observations, together with our previous publications on H19 expression in human cancers, do not support the notion of a tumor suppressor role for the H19 gene.

Serum amyloid A (SAA) variations in patients with cancer: correlation with disease activity, stage, primary site, and prognosis.

Serum amyloid A (SAA) was determined in 160 patients with cancer. Active disease was associated with high titre compared with the titre in non-active condition (31.8 v 5.8 micrograms/ml, respectively; p = 0.0002). SAA value showed a direct correlation with the stage of the disease: it was lowest at stages 1 and 2 and highest at the metastatic stage 4 (stage 1 v 4, p = 0.001; stage 2 v 3, p = 0.05). Cancers of the lung and unknown primary site were characterised by highly increased SAA concentration. Initial SAA value had prognostic significance: a value below 10 micrograms/ml correlated with survival advantage, whereas a higher initial value indicated a greater likelihood of a poor outcome (actuarial survival analysis p less than 0.001). When stage was accounted for, initial SAA value had significant prognostic bearing on survival of patients with advanced disease (stages 3 and 4) but not on that of patients with limited disease (stages 1 and 2). Serial testing showed good concordance between changes in SAA titre and clinical course.

Successful resolution of persistent trophoblastic disease after partial mole with the EMA-CO regimen.

A 29-year-old nullipara with partial hydatidiform mole at 8 weeks had pre-evacuation hCG levels of 275,000 mIU/ml. Free beta-hCG levels were measured as 3% (normal value below 4%). The patient developed persistent gestational trophoblastic disease, failed to respond to methotrexate and actinomycin D, but has responded to combination chemotherapy with EMA-CO. Such a response to EMA-CO was not reported previously.

Unsuspected uterine leiomyosarcoma discovered during treatment with a gonadotropin-releasing hormone analogue: a case report and literature review.

We report a case of a 37-year-old woman who had received five courses of gonadotropin-releasing hormone (GnRH) agonist (Decapeptyl) for presumed uterine leiomyomata associated with episodes of uterine bleeding. Submucous myoma (histologically proven) was partially removed on the first visit. After a period of significant reduction in the tumor size and cessation of uterine bleeding, the symptoms recurred along with rapid re-growth of the uterus. Total abdominal hysterectomy was performed and the pathologic evaluation revealed leiomyosarcoma with a high mitotic rate. This case and the literature review emphasize the problems encountered with the early diagnosis of uterine leiomyosarcoma during GnRH agonist therapy.

On the oncodevelopmental role of human imprinted genes.

Genome imprinting has an essential role in normal embryonal mammalian development. Starting early in differentiation, the transcripts of certain human genes, e.g. the paternally-H19 and the maternally-imprinted IGF2, are expressed in specific tissues and organs during fetal life. In several malignant disorders, imprinted genes are, again, unfolded. Characteristically, expression follows the same tissue presentation as during embryogenesis. Clinical paternal disomies, i.e. trophoblastic diseases, and their maternal counterpart, i.e. ovarian teratomas, are associated with apparent relaxation of imprinting once they turn malignant. Paediatric neoplasms, like Wilm's tumor (WT) and rhabdomyosarcoma, often express IGF2 and H19. Recently, we have found H19 expression in invasive urothelial cancer. Evidently, imprinted genes display an oncodevelopmental mode of expression, very much like the classical oncofetal proteins AFP and CEA. Based on available data, including tumor preferential paternal allele retention and chromosome 11 short arm physical linkage with oncogenes like H-ras, we hypothesize that imprinted genes not only accompany cancer but may play a causative role as well.

Hyperestrogenemia and presence of estrogen receptors associated with an epithelial ovarian tumor of low malignant potential.

An 80-year-old woman presented with breast congestion, tenderness and pain. Mammography was normal. Circulating estradiol was markedly elevated, while LH and FSH were low. Pelvic examination and imaging revealed an ovarian mass which was extirpated during total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathology revealed an ovarian mucinous cystadenocarcinoma of low malignant potential, stage 1. The tumor was positively stained for estrogen receptors. Estradiol levels returned to normal post-operatively, with a corresponding adjustment of LH/FSH. Possible autocrine steroid production is discussed.

Prognostic role of serum cytokeratin 19 fragments in advanced non-small-cell lung cancer: association of marker changes after two chemotherapy cycles with different measures of clinical response and survival.

Prognostic implication of serum cytokeratin 19 fragments (CYFRA 21-1) was explored in 60 advanced NSCLC patients, whereas in 45 patients assessable for serological response a >or=35% CYFRA 21-1 decline after two chemotherapy cycles was strongly associated with non-progression (NP), defined as a sum of objective response (OR)+stable disease (P<0.0001) and survival (P=0.0002). Association of OR with survival was not significant. In multivariate survival analysis, >or=35% marker decline and radiological NP status were found as major determinants of prolonged survival with RR: 0.37 (P=0.01) and 0.63 (P=0.01), respectively. In advanced NSCLC patients, NP reflects therapeutic efficacy better than traditional OR. CYFRA 21-1 >or=35% decline seems to be a reliable surrogate marker of treatment efficacy in terms of survival.

Circulating arginine-vasopressin, calcitonin, carcinoembryonic antigen, neuron-specific enolase, and beta-2 microglobulin fluctuations during combined modality induction therapy for small-cell bronchogenic carcinoma. Association of postchemotherapy AVP surge with high tumor response rate and durable remission.

While on combined modality induction therapy, 88 small-cell lung cancer (SCLC) patients were studied longitudinally for changes in circulating tumor-associated substances (TAS). Chemotherapy protocols were CAV (cyclophosphamide, doxorubicin, vincristine), PE (cisplatin, etoposide), sequential CAV greater than PE and alternate CAV/PE. Sixty patients were given prophylactic cranial irradiation (PCI) and 40 remitting patients were irradiated to the primary thoracic tumor. Of 73 evaluable patients, 43 had blood sampling adequate for analysis of treatment-related TAS fluctuations. Fourteen patients demonstrated 16 events of transient arginine-vasopressin surge following chemotherapy. In decreasing order of frequency, the surge occurred after the first (9), second (6) and third (1 event) course of chemotherapy. Three patients had a concomitant increase of one of the following markers: carcinoembryonic antigen (CEA), calcitonin and neuron-specific enolase. Another patient showed an exclusive CEA surge. This group of patients (10 with limited, 4 with extensive disease) had a 93% objective response rate (57% complete, 36% partial) with a median duration of 9 months and a survival of 15 months. Five other patients, 2 with limited and 3 with extensive disease, showed a TAS surge after PCI. Their response was complete in 1 (8 months' duration) and partial in 3 cases (2, 4 and 4 months' duration, respectively) with a median survival lasting only 8 months. This study suggests that a chemotherapy-related TAS surge may be an early indicator of a favorable tumor response in SCLC.

5-Fluorouracil, doxorubicin (adriamycin) and mitomycin-C (FAM) in advanced gastric cancer: observations on response, patient characteristics, myelosuppression and delivered dosage.

Forty-four patients with advanced gastric adenocarcinoma were treated with the fluorouracil, adriamycin and mitomycin-C (FAM) regimen. One was excluded from response evaluation. Partial (PR) and minor (MR) response rates were 7 and 9% respectively. These patients enjoyed remission for a median of 7.0 months. Stabilization (S) occurred in 25% and lasted a median of 6.0 months. No response (NR) was associated with a median survival of 3 months (p less than 0.001). The predominant pretreatment factors to affect survival were diagnosis to treatment interval and initial CEA serum level. Performance status influenced survival less markedly. Toxicity was mainly myelosuppression, which resulted in death of one patient. 'Responders' had marrow suppression more frequently than NR. Comparison of PR + MR, PR + MR + S and NR patient groups showed median minimum WBC counts of 1.4 x 10(3), 2.6 x 10(3) and 4.3 x 10(3) per mm3 respectively. Leukopenia (less than 3,000/mm3) was associated with a median survival advantage of 9.5 versus 3.5 months (p less than 0.05) and did not depend significantly on given FAM dosage. The median dosage of FAM agents delivered to nonresponders was reduced. A trend of dose-response (including dose-survival) relationship was found but was inconclusive statistically.

Receptor sites for complement and for immune complexes on human nonhemopoietic tumor cells.

Tumor cells in primary cultures derived from 11 untreated nonhemopoietic cancer patients were reacted with specifically coated sheep erythrocytes. Rosette formation between tumor and indicator cells was assessed, Eight of the primary cultures reacted positively with both IgG-coated (EAIgG) and with IgM-human complement coated (EAIgMC or EAIgMC 4,3) sheep erythrocytes. EAIgG rosette formation in positive cultures ranged from 25 to 85%, and for EAIgMC/EAIgMC 4,3 reactivity ranged between 22--95%. Rosette formation with E (uncoated) and EAIgM was negligible. These findings suggest that human nonhemopoietic tumor cells may carry on their surface receptor sites for an IgG component of immune complexes and for human complement. These receptor sites may be important in the host-tumor relationship.

Exposure of cryptantigens on erythrocytes in patients with breast cancer.

One hundred thirty-two patients with breast cancer were examined for exposure of cryptantigens on their erythrocytes (RBC) using a lectin panel consisting of Arachis hypogaea and Glycine soja. Eight had exposed cryptantigens; of the eight, five were classified with additional lectins as T-polyagglutination type and three as Th-polyagglutination. A control group of 300 healthy blood donors had no exposed cryptantigens on their RBC. These findings could not be correlated with the staging of the tumor, extension of metastases, or positive estrogen or progesterone receptors of malignant tumor cells. Only one study has been found that describes the incidence of agglutination of erythrocytes from cancer patients using a monoclonal antibody, which detected an epitope on the RBC from cancer patients and was considered to be distinct from the antigen bound by naturally occurring anti-T. Studies have been made describing polyagglutinable sites on breast cancer tumor cells, where there was a much higher incidence. This discrepancy can be explained either by a difference in the methods used to search for cryptantigen exposure on the various types of cells, or by the existence of a different mechanism, which causes the exposure of cryptantigens on RBC as opposed to malignant breast tumor cells.

Plasma platinum elimination in a hemodialysis patient treated with cisplatin.

The pharmacokinetics of intravenously administrated cisplatin (CDDP) were studied in a patient with meduloblastoma receiving regular hemodialysis for chronic renal failure. The patient received four CDDP infusions of 25 mg/m2 in two courses and underwent hemodialysis before each treatment and in intervals of 48 h thereafter with blood sampling at the beginning and the end of each hemodialysis. The data obtained were compared with the pharmacokinetic data from follow-up studies of 19 CDDP treatments in 15 patients suffering from various malignancies with no renal failure where a biexponential pharmacokinetic curve was recorded. The data of platinum (Pt) elimination of the patient receiving hemodialysis resembled the curve of those who had not, but following the second CDDP treatment in each course the peak Pt level in plasma was doubled, with a somewhat slower rate of elimination.

Selective right ventricular dysfunction following doxorubicin therapy.

Cardiotoxicity is one of the major side effects of doxorubicin therapy. The side effect presents in an acute and chronic form. It has been observed mainly when the cumulative dosage exceeds 450 mg/m2 of body surface. The cardiotoxicity presents with a low left ventricular ejection fraction. We report three patients who developed selective right ventricular dysfunction, expressed by low right ventricular ejection fraction as measured by radionuclide angiography. This complication was observed with rather low cumulative dosages of the drug (105 to 318 mg/m2). Two of the patients received concurrent mitomycin-C chemotherapy and the third patient underwent prior mediastinal irradiation. The possible mechanism for this selective cardiotoxicity is discussed. Monitoring of right ventricular performance by radionuclide angiography during doxorubicin therapy is recommended so that therapy can be discontinued before the left ventricle is damaged.

Human imprinted genes as oncodevelopmental markers.

Imprinted genes mediate unique maternal or paternal genetic roles and their function is essential in prenatal development. The reciprocally imprinted human insulin-like growth factor 2 (IGF2) and H19 genes are expressed during embryonal life, also in the placenta, and are downregulated postnatally. They reexpress in pediatric tumors (e.g. Wilms' tumor) and in inborn developmental syndromes predisposing to such tumors (e.g., Beckwith-Wiedemann syndrome). H19 (RNA transcripts) and IGF2 are manifested in Wilms' tumor, rhabdomyosarcoma, immature ovarian teratoma and gestational trophoblastic diseases. We have found that in the placenta and in urothelial carcinoma, H19 expression reflects the degree of invasiveness. These genes, displaying a tissue-specific oncofetal pattern of expression, are, therefore, tumor markers.

Pneumothorax following induction chemotherapy in patients with lung metastases: a case report and literature review.

A 29-year-old patient presented with bilateral pulmonary lesions following surgery for recurrent placental site trophoblastic tumor (PSTT). On day seven after institution of the 'EMA' regimen (etoposide, medium dose methotrexate with folinic acid rescue and actinomycin-D), complete pneumothorax occurred. Closed-system air drainage brought only transient lung expansion and subsequent talc pleurodesis was needed. During follow-up, complete regression of lung metastases was observed. A literature survey of post-chemotherapy pneumothorax in patients with lung metastases disclosed fourteen hitherto reported cases. Including the present PSTT case, non-epithelial gynecologic malignancy (3 patients) ranks second to osteogenic sarcoma (6 cases) with regard to the primary tumor involved.

The radiographic diagnosis and treatment of paraneoplastic central nervous system disease.

Paraneoplastic nervous system syndromes are being identified with increasing frequency because of greater physician awareness and the availability of serodiagnostic tests for some syndromes. Frequently, paraneoplastic syndromes develop in the setting of an indolent, limited stage, or otherwise occult malignancy. As a result, the paraneoplastic disorder often becomes the most disabling part of a patient's disease. Effective treatment appears to require early identification. For these reasons, the ability to diagnose a paraneoplastic syndrome, follow its course, and treat it successfully are important. The authors describe four patients with neurologic paraneoplastic syndromes and identical magnetic resonance imaging abnormalities. Three patients responded to immunosuppressive or immunomodulatory therapy, and in one, corresponding radiographic improvement was documented. Strategies for early diagnosis and options for treatment of paraneoplastic nervous system disorders are discussed.