The South African universal preschool year: a case study of policy development and implementation.

BACKGROUND: South Africa is the first sub-Saharan African country to legislate, fund and implement free preschool education. Human rights and restitution were at the forefront of the political struggle for democracy in South Africa. Levelling the playing fields by improving the school readiness of children disadvantaged by the racist policies of Apartheid is essential to the transformation of South African society. METHODS: A review of published and unpublished documents on Grade R was undertaken, and access and enrolment data come from the National Department of Basic Education's Education Management Information System (EMIS). RESULTS: A decade after initiation in 2005, 79% of 5-year-olds was enrolled in a preschool class; the vast majority of them in free public schools. Grade R is near universal and on track to becoming compulsory. It is part of the Foundation Phase (Grades 1-3) of schooling, falling under the Department of Basic Education, but also part of a broader national strategy to improve early child development under the direction of an Inter-Departmental Steering. Evaluations demonstrate wide access to Grade R and high uptake, especially in the poorest areas. However, the quality of Grade R provision in these areas is not up to standard because of low levels of funding; inadequate training, supervision, remuneration and retention of Grade R teachers; insufficient learner support materials; and inadequate monitoring and quality assurance. CONCLUSIONS: Lack of quality, amongst other factors, contributes to a widening school performance gap between children from more and less privileged areas. Quality of Grade R as well as earlier learning and subsequent years of schooling must be improved to achieve South Africa's aim to reduce poverty and inequality through, amongst others, parent and family involvement, learning in the home and preschool preparation.

Inhibition of platelet-derived growth factor- and epidermal growth factor-mediated mitogenesis and signaling in 3T3 cells expressing delta Raf-1:ER, an estradiol-regulated form of Raf-1.

We have recently described the properties of delta Raf-1:ER, a fusion protein consisting of an oncogenic form of human Raf-1 and the hormone binding domain of the human estrogen receptor. In this study, we demonstrate that activation of delta Raf-1:ER in quiescent 3T3 cells (C2 cells), while sufficient to promote morphological oncogenic transformation, was insufficient to promote the entry of cells into DNA synthesis. Indeed, activation of delta Raf-1:ER potently inhibited the mitogenic response of cells to platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) treatment. Addition of beta-estradiol to quiescent C2 cells led to rapid, sustained activation of delta Raf-1:ER and MEK but only two- to threefold activation of p42 mitogen-activating protein (MAP) kinase activity. Addition of PDGF or EGF to quiescent C2 cells in which delta Raf-1:ER was inactive led to rapid activation of Raf-1, MEK, and p42 MAP kinase activities, and entry of the cells into DNA synthesis. In contrast, when delta Raf-1:ER was activated in quiescent C2 cells prior to factor addition, there was a significant inhibition of certain aspects of the signaling response to subsequent treatment with PDGF or EGF. The expression and activation of PDGF receptors and the phosphorylation of p70S6K in response to PDGF treatment were unaffected by prior activation of delta Raf-1:ER. In contrast, PDGF-mediated activation of Raf-1 and p42 MAP kinases was significantly inhibited compared with that of controls. Interestingly, the mitogenic and signaling responses of quiescent C2 cells to stimulation with fetal bovine serum or phorbol myristate acetate were unaffected by prior activation of delta Raf-1:ER. It seems likely that at least two mechanisms contribute to the effects of delta Raf-1:ER in these cells. First, activation of delta Raf-1:ER appeared to uncouple the activation of Raf-1 from the activation of the PDGF receptor at the cell surface. This may be due to the fact that mSOS1 is constitutively phosphorylated as a consequence of the activation of delta Raf-1:ER. Second, quiescent C2 cells expressing activated delta Raf-1:ER appear to contain an inhibitor of the MAP kinase pathway that, because of its apparent sensitivity to sodium orthovanadate, may be a phosphotyrosine phosphatase. It is likely that the inhibitory effects of delta Raf-1:ER observed in these cells are a manifestation of the activation of some of the feedback inhibition pathways that normally modulate a cell's response to growth factors. 3T3 cells expressing delta Raf-1:ER will be a useful tool in unraveling the role of Raf-1 kinase activity in the regulation of such pathways.

Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human raf-1 protein kinase.

We report a strategy for regulating the activity of a cytoplasmic signaling molecule, the protein kinase encoded by raf-1. Retroviruses encoding a gene fusion between an oncogenic form of human p74raf-1 and the hormone-binding domain of the human estrogen receptor (hrafER) were constructed. The fusion protein was nontransforming in the absence of estradiol but could be reversibly activated by the addition or removal of estradiol from the growth media. Activation of hrafER was accompanied in C7 3T3 cells by the rapid, protein synthesis-independent activation of both mitogen-activated protein (MAP) kinase kinase and p42/p44 MAP kinase and by phosphorylation of the resident p74raf-1 protein as demonstrated by decreased electrophoretic mobility. The phosphorylation of p74raf-1 had no effect on the kinase activity of the protein, indicating that mobility shift is an unreliable indicator of p74raf-1 enzymatic activity. Removal of estradiol from the growth media led to a rapid inactivation of the MAP kinase cascade. These results demonstrate that Raf-1 can activate the MAP kinase cascade in vivo, independent of other "upstream" signaling components. Parallel experiments performed with rat1a cells conditionally transformed by hrafER demonstrated activation of MAP kinase kinase in response to estradiol but no subsequent activation of p42/p44 MAP kinases or phosphorylation of p74raf-1. This result suggests that in rat1a cells, p42/p44 MAP kinase activation is not required for Raf-1-mediated oncogenic transformation. Estradiol-dependent activation of p42/p44 MAP kinases and phosphorylation of p74raf-1 was, however, observed in rat1a cells expressing hrafER when the cells were pretreated with okadaic acid. This result suggests that the level of protein phosphatase activity may play a crucial role in the regulation of the MAP kinase cascade. Our results provide the first example of a cytosolic signal transducer being harnessed by fusion to the hormone-binding domain of the estrogen receptor. This conditional system not only will aid the elucidation of the function of Raf-1 but also may be more broadly useful for the construction of conditional forms of other kinases and signaling molecules.

Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells.

The protein kinase domains of mouse A-Raf and B-Raf were expressed as fusion proteins with the hormone binding domain of the human estrogen receptor in mammalian cells. In the absence of estradiol, 3T3 and rat1a cells expressing delta A-Raf:ER and delta B-Raf:ER were nontransformed, but upon the addition of estradiol the cells became oncogenically transformed. Morphological oncogenic transformation was more rapid and distinctive in cells expressing delta B-Raf:ER compared with cells expressing delta A-Raf:ER. Biochemical analysis of cells transformed by delta A-Raf:ER and delta B-Raf:ER revealed several interesting differences. The activation of delta B-Raf:ER consistently led to the rapid and robust activation of both MEK and p42/p44 MAP kinases. By contrast, the activation of delta A-Raf:ER led to a weak activation of MEK and the p42/p44 MAP kinases. The extent of activation of MEK in cells correlated with the ability of the different Raf kinases to phosphorylate and activate MEK1 in vitro. delta B-Raf:ER phosphorylated MEK1 approximately 10 times more efficiently than delta Raf-1:ER and at least 500 times more efficiently than delta A-Raf:ER under the conditions of the immune-complex kinase assays. These results were confirmed with epitope-tagged versions of the Raf kinase domains expressed in insect cells. The activation of all three delta Raf:ER proteins in 3T3 cells led to the hyperphosphorylation of the resident p74raf-1 and mSOS1 proteins, suggesting the possibility of "cross-talk" between the different Raf kinases and feedback regulation of intracellular signaling pathways. The activation of either delta B-Raf:ER or delta Raf-1:ER in quiescent 3T3 cells was insufficient to promote the entry of the cells into DNA synthesis. By contrast, the activation of delta A-Raf:ER in quiescent 3T3 cells was sufficient to promote the entry of the cells into S phase after prolonged exposure to beta-estradiol. The delta Raf:ER system has allowed us to reveal significant differences between the biological and biochemical properties of oncogenic forms of the Raf family of protein kinases. We anticipate that cells expressing these proteins and other estradiol-regulated protein kinases will be useful tools in future attempts to unravel the complex web of interactions involved in intracellular signal transduction pathways.

Improved survival with cyclic chemotherapy for nonseminomatous germ cell tumors of the testis.

Forty-eight patients with advanced nonseminomatous germ cell tumors of the testis received a combination of cyclophosphamide, doxorubicin, and cisplatin (CISCAII) and a modified combination of vinblastine and bleomycin (VBIV) cyclic chemotherapy. Forty-four (92%) have achieved a complete remission. No patient in complete remission has relapsed with a mean follow-up of 139.0 weeks (SEM 7.0 weeks). The patients were stratified according to the modified Samuels clinical staging criteria. Thirty-seven (77%) had advanced disease (stage III-B3 to III-B5), ten of whom had advanced visceral non-lung disease (stage III-B5). Chemotherapy was individualized by tumor volume and response to therapy. Two courses were delivered after complete remission or the development of a stable mass with negative serum biomarkers. Twenty-four patients (50%) were explored for a persistent and stable mass. No viable cancer was found; 15 (62%) had mature teratomas and nine (38%) had scar. No patients suffered from doxorubicin cardiotoxicity, clinical pulmonary bleomycin toxicity, or persistent cisplatin renal failure. Four patients died. One patient, an unrecognized drug abuser, died of toxicity. Three with far-advanced tumors died of progressive disease. CISCAII/VBIV cyclic chemotherapy is superior to chemotherapy with vinblastine, bleomycin, and cisplatin, resulting in a 92% complete remission rate and a significant reduction in long-term toxicity.

Successful treatment of pure endodermal sinus tumors in adult men.

Seven adult men with pure endodermal sinus tumors (EST) were treated with cyclical combination chemotherapy Cytoxan (cyclophosphamide; Bristol-Myers Company, Evansville, IL), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin/vinblastine and bleomycin (CISCAII/VBIV) and surgery at the University of Texas M.D. Anderson Hospital and Tumor Institute at Houston from 1978 through 1985. Six tumors were of extragonadal origin (four anterior mediastinum, one pelvic, one prostate), and one was of gonadal origin with retroperitoneal metastasis. All patients presented with advanced local disease and a relative absence of distant metastasis. Alpha-fetoprotein (AFP) levels were elevated in six patients (median, 4,400 ng/mL; range, 2,580 to 31,200 ng/mL). Six patients achieved a complete remission (CR): one with chemotherapy alone, one with initial surgery followed by chemotherapy, and four with chemotherapy followed by consolidative surgery. The remaining patient died of progressive disease. Of the six patients who achieved a CR, five are alive with no evidence of disease (+17, +23, +34, +43, +59 months); one patient developed recurrent disease at 6 months after completion of therapy and is currently undergoing salvage chemotherapy. Of the four patients who underwent postchemotherapy surgery, three were operated on for a marker-negative stable mass; in these patients, no viable tumor was found at pathologic review. The remaining patient underwent surgery for a stable mass with a persistent elevation in AFP levels. He was found to have 95% necrosis with 5% viable tumor and remains disease free without further therapy. The observed changes in AFP levels correlated with regression and progression of tumor; a normal AFP was consistent with a CR, and elevation was consistent with residual tumor. These seven patients demonstrate that when adult men with EST are treated aggressively with combination chemotherapy and surgery, high cure rates can be achieved.

Primary chemotherapy for clinical stage II nonseminomatous germ cell tumors of the testis: a follow-up of 50 patients.

Fifty patients with clinical stage II nonseminomatous germ cell tumor of the testis (NSGCTT) were treated with primary chemotherapy followed by a retroperitoneal lymph node dissection (RPLND) in selected patients. The study population included 34 patients with retroperitoneal masses and elevated levels of serum biomarkers (alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [BHCG] ), five with needle aspiration biopsy-proven retroperitoneal metastases but normal levels of biomarkers, and 11 in whom there were rising levels of serum biomarkers but no radiographic evidence of retroperitoneal metastases. Forty-eight patients (96%) achieved a complete response (CR), with a mean disease-free survival of 132 weeks (range, 55 to 273 weeks). Two patients developed recurrent disease. One died and one achieved a second CR with further therapy (48 + weeks). Postchemotherapy RPLND was required in 11 patients (22%). Patients with embryonal carcinoma had a lower frequency of RPLND (8%) than patients with teratomatous elements in their primary tumor [36%, P = .014]. To reduce the frequency of double therapy (surgery +/- chemotherapy), we propose individualized therapy. Patients presenting with clinical stage II embryonal carcinoma of the testis should receive primary chemotherapy. Patients with clinical stage II NSGCTT and teratomatous elements in their primary tumor continue to require an RPLND. Those patients with intermediate volume disease (greater than 2 cm less than or equal to 5 cm in maximum diameter) may be treated with an RPLND only. Patients with higher volume teratomatous elements (greater than 5 cm less than or equal to 10 cm in maximum diameter) are likely to require the combination of chemotherapy and surgery.

Chemotherapy of extragonadal germ cell tumors.

Forty-nine patients with histologically proven germ cell tumors arising in extragonadal sites were retrospectively reviewed. Included in the review were an additional seven patients with undifferentiated tumors with a pathologic appearance compatible with that of a germ cell tumor and elevated levels of serum biomarkers (beta subunit of human chorionic gonadotropin [beta-HCG] +/- alpha-fetoprotein [AFP]. Nineteen patients had a pure seminoma arising in an extragonadal site, whereas 30 patients had nonseminomatous germ cell tumors. Seven patients had primary undifferentiated tumors with elevated levels of serum biomarkers. Sixteen (84%) of the 19 patients with pure extragonadal seminomas with normal levels of serum AFP are alive and free of disease. Eighteen of these 19 patients received platinum-containing regimens and four had received prior chemotherapy that failed. Of the patients with nonseminomatous germ cell tumors, 12 (40%) of the 30 are alive and free of disease with vinblastine/bleomycin +/- cisplatin (13 patients) or CISCAII (cisplatin, cyclophosphamide, and doxorubicin) (nine patients) alternating CISCAII/VBIV (eight patients) chemotherapy. None of the seven patients with undifferentiated germ cell tumors are alive and free of disease. Three of the five patients with pure anterior mediastinal endodermal sinus tumors treated with chemotherapy remain alive and free of disease. Of the seven patients with choriocarcinomas arising in extragonadal sites, three are alive and free of disease. A classification for patients with extragonadal germ cell tumors incorporating site of origin, histology, and likelihood of being truly extragonadal is proposed. The implications of this classification are discussed.

Doxorubicin, mitomycin-C, and 5-fluorouracil (DMF) in the treatment of metastatic hormonal refractory adenocarcinoma of the prostate, with a note on the staging of metastatic prostate cancer.

Sixty-two patients with metastatic hormonal refractory adenocarcinoma of the prostate received a combination of doxorubicin, mitomycin-C, and 5-fluorouracil (DMF). Thirty (48%) of the patients achieved an objective response. Response criteria excluded disease "stabilization" as a manifestation of response. Four clinical prognostic categories were identified: osseous I (OI) had metastatic axial skeletal involvement (23 patients); osseous II (OII) had axial and extremity skeletaL involvement (18 patients); visceral I (VI) had pulmonary metastasis (9 patients); and visceral II (VII) had pulmonary metastasis and involvement of other viscera (12 patients). The 20 responding patients survived a median of 47.5 weeks, whereas the 32 nonresponding patients survived a median of 23.8 weeks (n = 0.002). Response rates were highest among patients with OI (52%) and VI (88%) disease; response rates were lower amont patients with OII (33%) and VII (33%) disease. Responding patients in each clinical category survived longer than nonresponding patients except for those patients with VII disease. The median duration of response for patients with OI disease was 11 months, for OII 9.5 months, for VI patients it was 6.5 months, and VII patients it was 5 months. DMF is an effective treatment of metastatic hormonal refractory prostate cancer, resulting in consistent objective responses. The staging system employed identifies four clinical categories of metastatic prostate cancer and allows for accurate comparison of diet and stratification of study populations.

Surgery in the management of stage III germinal cell tumors. Observations on the M.D. Anderson Hospital experience, 1971-1979.

Sixty patients with initial stage III germinal tumors treated with conventional vinblastine, bleomycin and cisplatin chemotherapy (VB + P) were surgically explored. Twenty-two patients not treated with an initial retroperitoneal node dissection were surgically explored to pathologically confirm a complete remission following chemotherapy. Thirty-eight patients had a persistent mass in the absence of elevated serum markers. Seventeen (28%) patients had viable carcinoma at surgery. Eight (47%) of the 17 patients with viable carcinoma at surgery died of recurrent tumor. All but three patients with persistent viable carcinoma at surgery were treated with surgery followed by chemotherapy. Fourteen patients were found to have mature teratoma and one (7%) developed recurrent carcinomatosis. Two (8%) of the 25 patients found to have scar died. One patient died of recurrent carcinomatosis and one of postoperative complications. Ten additional patients with a suboptimal response to chemotherapy were surgically explored for attempted salvage. All ten died of recurrent tumor, with a median postoperative survival of 7 months. We believe optimal individualized chemotherapy is required for the management of stage III testis cancer. Therapeutic benefit for surgery can be demonstrated only in unusual circumstances. Attempted surgical excision of a clinically active germinal tumor is futile; hence patients with elevated serum biomarkers should not be explored. Patients with non-seminomatous germinal tumors and a residual postchemotherapy mass must be explored. The excision of mature teratoma is mandatory, as is documentation of the absence of viable carcinoma prior to cessation of therapy.

Cyclic chemotherapy with cyclophosphamide, doxorubicin, and cisplatin plus vinblastine and bleomycin in advanced germinal tumors. Results with 100 patients.

One hundred patients with advanced mixed germ-cell tumors were treated with cisplatin, cyclophosphamide, and doxorubicin alternating with vinblastine and bleomycin (cyclic CISCAII/VBIV). The chemotherapy achieved an 89 percent continuous disease-free status (85 percent with chemotherapy, 4 percent with chemotherapy plus surgery). The mean follow-up duration for patients with continuous complete remission was 132 weeks (+/- 6.2), with a median of 126 weeks. Multivariate analysis using a stepwise logistic regression of prognostic variables revealed that a high serum level of the beta subunit of human chorionic gonadotropin (more than 50,000 mIU/ml) was of prognostic significance, followed by the Samuels staging criteria and extragonadal origin of disease. Thirty-two patients underwent exploratory surgery after they had had two courses of chemotherapy beyond the establishment of a stable mass and absent serum biomarkers. No viable cancer was found at exploration, and all patients remain alive and free of disease. The acute toxicity of the cyclic chemotherapy was formidable, but only one patient had a fatal complication. Thirty-six percent of the CISCAII courses and 44 percent of the VBIV courses were associated with leukopenic fever, and 5 percent of the CISCAII courses and 8 percent of the VBIV courses were associated with culture-positive infection. Long-term toxicity was unusual: bleomycin lung toxicity 1 percent, cardiac toxicity 1 percent. CISCAII/VBIV cyclic chemotherapy is superior to cisplatin, vinblastine, and bleomycin (PVB) chemotherapy; it results in a higher complete remission rate, a lower relapse rate, and a lower incidence of long-term complications. Patients with a high risk of failure of PVB chemotherapy (Samuels stage IIIB3 to IIIB5) or with extragonadal tumors should be treated with CISCAII/VBIV.

Cyclophosphamide, vincristine and sequential split-course radiotherapy in the treatment of small cell lung cancer.

Thirty-nine patients with small cell lung cancer were treated with large dose intravenous cyclophosphamide combined with vincristine. Sequential split-course radiotherapy was added when the gross disease was limited to one hemithorax and draining scalene nodes. Fifteen of 16 patients in the limited disease category showed objective response, eight of which were complete. Fourteen of 23 patients in the extensive disease category yielded an objective response, six of which were complete. The median survival for complete responders was 48 weeks, 38 weeks for partial responders and 14 weeks for non-responders. The difference between responders and non-responders was statistically significant. The major toxicity was myelosuppression with a median leukocyte nadir of 500/mm-3 noted on treatment day no. 15. Prompt recovery was the rule. Toxicity appeared to be cumulative for patients receiving radiotherapy. These results are superior to those evolving from treatment with cyclophosphamide as a solitary agent.

Serum lactate dehydrogenase isoenzyme 1 in patients with advanced testicular cancer.

Abnormal levels of serum lactic dehydrogenase-1 (LD-1) activity have been observed in 81% (34/42) of patients with stage III germ cell malignancy of the testis. The criteria for evaluation the electrophoretic isoenzyme patterns of these patients were, as follows: For criterion 1 elevations the LD-1 value in absolute units was greater than 52.0 U/I with the LD-1/Total LD ratio greater than 37.2%. Criterion 2 elevations had absolute values of LD-1 less than 52.0 U/I, but the LD-1/Total LD ratio was greater than 37.2%. For criterion 3 elevations of LD-1, the absolute value was greater than 52 U/I and the LD-1/Total LD ratio was less than 37.2% activity with the LD-5/LD-1 ratio less than 0.5; or when the LD-5/LD-1 ratio was greater than 0.5 but the LD-1 is equal to or greater than the LD-2. The frequency of LD-1 elevation correlated well with the extent of the disease (stage II-B-1 and 2, 50%; stage III-B-3, 86%; stage III-B-4, 91%; stage III-B-5, 93%). LD-1 elevation occurred in groups I, II, IV and V histopathologic cell types (Dixon and Moore Classification) and there did not appear to be any correlation between the histologic cell type and the frequency of elevation of LD-1. Interpretation of LD-1 activity only on the basis of its relative ratio to the total LD value (criterion 1 and 2) identified a total of 28 patients (67%). A criterion 3 elevation was demonstrated in 6 (14%) additional patients. All patients with persistent elevations or recurrent elevations of LD-1 have shown progressive or recurrent disease and patients with no clinical evidence of disease have demonstrated normal LD-1 values. In those patients with elevated LD-1 activity, serial measurements of serum. LD-1 isoenzyme reflect the response of the patient to therapy.

The correlation of vinblastine pharmacokinetics to toxicity in testicular cancer patients.

The clinical pharmacokinetics of vinblastine administered by continuous 5-day infusion (3 mg/m2/day) was studied in 12 patients with primary testicular cancer. Serum vinblastine concentrations were determined by radioimmunoassay on serum collected over a 10-day period. Steady-state vinblastine concentrations were achieved within 60 to 108 hours (median, 72 hours). Vinblastine pharmacokinetics were analyzed and correlated to hematologic and nonhematologic toxicity. Hematologic toxicity was severe (granulocytopenia of less than 500/microL) in all patients; however, no correlation of vinblastine pharmacokinetics to duration of granulocytopenia or nadir was noted. Nonhematologic toxicity, however, showed a direct correlation to steady-state vinblastine concentrations. Two distinct groups of patients were identified by a toxicity score evaluating nonhematologic toxicity: as low (group A) or high (group B). The toxicity score was calculated for each patient based on accumulated toxicity during the course of treatment. The mean toxicity score for all patients was 7.11 and for groups (A and B) it was 4.0 and 9.6, respectively (P = .02). Steady-state vinblastine concentration for each patient was compared with toxicity where the mean steady-state vinblastine concentration was 7.3 ng/mL for all patients, and 5.8 ng/mL and 8.5 ng/mL for groups A and B, respectively (P = .01). These steady-state vinblastine concentrations correlated directly with the mean toxicity scores revealing that patients with high steady-state vinblastine concentrations demonstrated more nonhematologic toxicity. Application of these data to pharmacokinetically directed studies are warranted to investigate this relationship and designate dosages of vinblastine to avoid excessive toxicity.

Chemotherapy of carcinoma of renal pelvis: preliminary report.

Seven patients with metastatic and/or recurrent transitional cell carcinoma of the renal pelvis treated with systemic chemotherapy are evaluated. The median age of the patients was fifty-five; 6 were men, 6 of the tumors were histologic grade III and Stage C at the time of nephroureterectomy. Most of the patients presented with a large recurrent mass at the original site of surgery in addition to bone and/or pulmonary metastases. Four patients were treated with CISCA combination chemotherapy (cis-platinum, cyclophosphamide, and doxorubicin), and responded with 1 partial remission, 1 less than partial remission, and 2 symptomatic improvement. Two patients were treated with FAM combination chemotherapy (5-fluorouracil, doxorubicin, and mitomycin C) and demonstrated an objective response. One patient had a less than partial remission (30 per cent) and the second patient a partial remission. The seventh patient was treated with alternating courses of CISCA and FAM and thus far has received 8 courses and is in complete remission. The median survival time of the 7 patients is seven months (range four to fourteen months). Transitional cell carcinoma of the renal pelvis is responsive to chemotherapy; therefore, trials are indicated.

Chemotherapy for adenocarcinomas of bladder and urachal origin: 5-fluorouracil, doxorubicin, and mitomycin-C.

Eight patients with unresectable adenocarcinoma of the bladder or urachus were treated with chemotherapy. Four had received cisplatin-based chemotherapy (CISCA), all 4 failed to respond. All 8 received intravenous and/or intra-arterial 5-fluorouracil, doxorubicin hydrochloride (Adriamycin), and mitomycin-C. Three of the 5 responding patients had short responses while 2 had achieved long-term control of disease. One is in complete remission for eleven plus months, and 1 patient had a partial remission of nineteen plus months. Five patients had serum CEA levels measured at presentation. In the 3 patients with an elevated CEA at presentation who responded to chemotherapy a corresponding drop in the initial level was seen. 5-Fluorouracil-based chemotherapy is effective in the management of adenocarcinoma of the bladder.

Alpha fetoprotein determinations in germ cell tumors of testis.

Alpha fetoprotein was demonstrated in 15 of 115 patients with histologically proved germinal testicular neoplasms. Alpha fetoprotein was detected in patients only with embryonal carcinoma and teratocarcinoma; determinations were negative in all cases of pure seminoma, teratoma, and choriocarcinoma. Of 15 patients having detectable alpha fetoprotein, 14 had Stage III disease and one had Stage II disease. When alpha fetoprotein is present, it usually heralds progression of the disease and therefore may serve as a valuable biologic marker to monitor response to therapy.

Metastases from testicular carcinoma. Study of 78 autopsied cases.

The necropsy records of 78 patients with histologically proved germ cell tumors of the testis, who died as a direct result of their malignant disease, were reviewed to determine the usual modes of spread, distribution of metastasis, the histologic characteristics of the metastatic foci as compared with the morphology of the primary tumor and the specific cause of death. The sites of metastases in order of decreasing frequency for all cases were lung, retroperitoneal lymph nodes, liver, mediastinal lymph nodes, brain, kidney, gastrointestinal tract, bones, adrenals, peritoneum and spleen. The absence of metastases solely in the anterior mediastinum without involvement of other mediastinal nodes (middle/posterior) strongly supports the premise for a primary extragonadal origin whenever the anterior mediastinum alone is involved with malignant disease having the histologic appearance of a primary germ cell tumor. The histologic features of the metastatic lesions were usually similar in nature to those of the primary tumor except for seminoma in which the metastatic lesions proved to be of a different histologic pattern in almost one third of the patients dying from the disease. It should be axiomatic that whenever a patient with seminoma fails to respond appropriately to radiotherapy that his treatment be immediately discontinued and that appropriate biopsies be obtained to substantiate the histologic pattern present.

Treatment of multiple superficial tumors of bladder with intravesical bleomycin.

Twenty-six patients with superficial Stage O or A transitional cell carcinoma of the urinary bladder, whose lesions were not amenable to transurethral resection, received bleomycin sulfate intravesically at weekly intervals for eight treatments. Five different drug regimens were tried, and the optimal concentration appeared to be 60 units dissolved in 30 cc. of sterile water. Serum determinations failed to reveal any significant absorption. There was a 27% complete response rate in patients with small tumor burdens. An additional 9% had partial responses which allowed the tumors to be readily managed transurethrally. However, no patients with extensive superficial tumor showed complete response to therapy. Although belomycin used intravesically is active against transitional cell carcinoma, the current cost of the drug precludes its routine use and restricts it to situations in which other agents are contraindicated.

Mixed mesodermal tumors of urinary bladder: prognosis and management.

Three cases of mixed mesodermal tumors of the urinary bladder characterized by the simultaneous occurrence of malignant epithelial and mesenchymal elements in the same tumor are reported. Integrated therapy consisting of preoperative radiotherapy followed by radical cystectomy is recommended. Chemotherapy is best withheld until the nature of any metastatic disease has been confirmed histologically in order that the appropriate drugs can be administered.