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The current trial was designed to assess whether the addition of prednisone or prednisone + tamoxifen would enhance the therapeutic effectiveness of 1 year of adjuvant CMF therapy. Premenopausal women with ipsilateral axillary node-positive breast carcinoma and known estrogen receptor (ER) status were randomized to receive 1 year of postoperative treatment with 12 28-day cycles of cyclophosphamide, methotrexate, 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus tamoxifen (CMFPT). There were 553 analyzed cases with 188 receiving CMF, 183 CMFP, and 182 CMFPT. The overall time to relapse (TTR) and survival comparisons between the regimens are not statistically different at a median follow-up time of 7.7 years. The major subgroups currently with a suggestive TTR difference are greater than 3N+ (CMFPT greater than CMF, P = 0.07) and estrogen receptor-negative (ER-) greater than 3N+ (CMFPT greater than CMF, P = 0.03). Patients receiving CMFPT appeared to have a superior survival to CMF in the ER- greater than 3N+ cohort (P = 0.02). The following patient characteristics were associated with a significantly longer TTR: decreasing nodal involvement or tumor size, positive ER status, age greater than or equal to 40 years, and decreasing obesity. The favorable effects of decreasing nodal involvement, positive ER status, age 40 years or greater, and decreasing obesity carried over to survival. Development of amenorrhea was also significantly associated with improved survival (P = 0.001). Toxicity was increased by the addition of prednisone to CMF and by the addition of tamoxifen to CMFP. Overall relapse patterns were similar among the three regimens. The results of the current trial do not currently suggest an overall therapeutic benefit for adding prednisone or only 1 year of tamoxifen to CMF adjuvant treatment.

There have been repeated claims in the literature that hearing thresholds can be estimated by means of acoustic reflex threshold (ART) measurements. We have evaluated this thesis in depth by examining the statistical relationships between conventional puretone thresholds and ARTs for tonal and broadband stimuli in a large sample (1207) of adult patients with sensorineural hearing loss; they were compensation claimants for noise-induced loss. All relevant data were stored in a computer database, and analysed using the Statistical Package for the Social Sciences (SPSS). The relationships were examined from two distinct standpoints; dependency of ART's upon puretone thresholds, and prediction of audiogram features using ARTs. The average tonal ART is constant up to 70 dB average loss, and thereafter increases rapidly. The broadband noise ART increases steadily for average losses of 10 to 85 dB. The convergence principle is therefore valid up to 70 dB in this population. The predictor suggested by Niemeyer & Sesterhenn does not fit the data. The single ART which best predicts average loss is that for white noise, but a multiple regression prediction using the white noise and 500 Hz ARTs is preferable. Predictive accuracy is dependent upon audiogram slope, but the latter cannot be predicted usefully from the ART measures used. None of the predictors studied is adequate for medico-legal assessment and the method is probably not sufficiently accurate for clinical use in adults.

A group of 19 patients with advanced (Stage D) prostate cancer were treated with one of three dose levels of the anti-estrogen tamoxifen, 10 mg (3 patients), 20 mg (8 patients), or 30 mg (8 patients) daily. Five patients had received no prior systemic therapy. The treatment was tolerated well, but no objective responses occurred.

The primary emphasis in rehabilitating the hearing impaired has involved fitting a hearing aid. There are patients however, who can be helped by communication aids in addition to, or in place of hearing aids. Communication aids include any device, other than a conventional hearing aid, which assists the hearing impaired in maintaining contact wiht the normally hearing. In Scandinavian countries a sophisticated system for rehabilitating the hearing impaired has evolved and communication aids are recommended extensively. Similar aids exist in North America, but clinicians have not yet developed a full awareness of how these devices can benefit their patients. This paper represents the results of a two year survey undertaken to identify and evaluate various devices available in Toronto. The contribution these aids can offer in rehabilitating patients is discussed.

A total of 202 patients with advanced breast cancer were entered into two prospectively randomized Phase II trials conducted by the Eastern Cooperative Oncology Group, in an effort to identify promising agents and combinations for previously treated cases. Patients in Study 1 received bleomycin, CCNU, or streptozotocin and those in Study 2 received tilorone, Baker's antifol, or a combination of 5-fluorodeoxyuridine plus arabinosyl cytosine. Partial responses were seen only with bleomycin, Baker's antifol, and 5-fluorodeoxyuridine plus arabinosyl cytosine. The median times to treatment failure ranged from 3.6 weeks to 5.7 weeks, and the median survival times, from 8 weeks to 25 weeks for tilorone and bleomycin, respectively. Toxic reactions was primarily hematologic and gastrointestinal, but skin, neurologic, respiratory, and renal abnormalities were noted in some treatment arms. The treatment schedules outlined and the toxic effects noted provide background information that might prove useful in designing complex new chemotherapeutic programs, since there is pharmacological rationale for incorporating some of the agents tested into present standard combination chemotherapy regimens.

The occurrence of diffuse hyperpigmentation secondary to a xenografted human malignant melanoma was observed in nude mice. The patient from whom this cell line was established developed cutaneous hyperpigmentation after his disease became disseminated. Light and electron microscopy studies were performed on skin and organ biopsy specimens from the hyperpigmented mice. These studies indicated that this melanoma-associated melanosis was secondary to the release of pigment granules from the xenografted tumors and to the uptake of these granules by macrophages throughout the body, including those located in the dermis.

We examined the relationship between age and extent of disease at initial diagnosis as part of a population-based, prospective study documenting the patterns of care received by over 1500 newly diagnosed lung, breast, and colorectal cancer patients identified in nine Rhode Island hospitals. For each cancer site examined, no age by extent of disease relationship was observed; however, analysis by sex among lung cancer patients indicated an inverse age relationship for men. The absence of an age effect for breast cancer patients is in contrast to earlier research findings that identify a positive association between extent of disease and age at diagnosis. Past results may reflect age-related differences in patient and physician screening behavior characteristic of earlier time periods.

The Eastern Cooperative Oncology Group conducted a study of pentostatin (2'-deoxycoformycin) in 37 patients with hairy-cell leukemia. Among the 27 patients who met all the study's entry criteria, the response rate was 96 percent, with 16 patients (59 percent) entering complete remission and 10 patients (37 percent) partial remission. In one patient no response was observed. These results were not significantly changed by the inclusion of nine additional patients who were found retrospectively not to have fulfilled the entry criteria. When complete remission was attained, maintenance therapy was not given. Despite this, no patient has had a relapse, and the duration of complete remission ranges from 1 to 375 days. Pentostatin appears to be equally effective in untreated patients and in those who have progressive disease after splenectomy or after both splenectomy and treatment with interferon. Whether pentostatin is superior to splenectomy or interferon as therapy for hairy-cell leukemia will have to be assessed by direct comparison in randomized studies. Lengthy follow-up will be required to determine a median duration for the responses of hairy-cell leukemia to pentostatin.

Clinical, pharmacologic, and immunologic effects of 2'-deoxycoformycin (dCF) were evaluated in 15 patients with advanced malignancies. Toxicity was less severe with a low dose (4 mg/m2) of dCF, but this dose still resulted in suppression of cellular adenosine deaminase activity, skin test reactivity, and lymphocyte responses to mitogens. Improvement in cutaneous T cell lymphoma plaques was seen after dCF. Further investigations of antitumor efficacy with the use of this low dosage schedule should continue in patients with hematologic neoplasms, and additional preliminary studies of the combination of an adenosine deaminase inhibitor with an adenosine analog should also be considered.

One hundred seventy elderly women with stage II breast cancer, stratified on the basis of the number of positive axillary nodes and estrogen receptor status, were randomly assigned to receive tamoxifen or placebo for 24 months in a prospective, double-blind, adjuvant trial. The median age was 71 years with a range from 65 to 84 years. The overall percentage of patients disease-free at 4 years was 76% for those given tamoxifen and 52% for those given placebo (p = 0.0004). Benefit was seen in all subgroups of patients treated with tamoxifen. Two years of tamoxifen therapy represents an effective postoperative adjuvant treatment for elderly women with stage II breast cancer, resulting in improved time to relapse, statistically fewer distant first recurrences, and minimal toxicity. No improvement in overall survival has been seen yet.

Synchronously administered cis-platinum (cis-DDP) and radiation therapy have been used to treat unresectable squamous cell carcinomas of the head and neck. The purpose of this study was to evaluate the efficacy and tolerance of preoperative adjuvant cis-DDP plus radiation therapy in operable stage III and IV head and neck cancers. Radiation therapy (4,500 rad) was delivered in 180-rad daily fractions. Cis-DDP (20 mg/M2) was given before radiotherapy on days 1-4 and 21-24. Eighteen patients began therapy; 16 completed the combined regimen. Toxicity included stomatitis and WBC below 2,500/mm3. One patient died from therapy of a cerebrovascular accident. Sixteen patients (89%) achieved a complete or partial response to therapy. Complete responses were observed in 13 of 18 primary tumors (72%), and in all three patients with cervical lymphadenopathy. Complete responses were noted for lesions of the nasopharynx, oral cavity, pharynx, hypopharynx, and larynx, for all histologic grades of squamous cell carcinoma. Twelve patients underwent curative surgery. Site-related morbidity occurred in two patients (15%) and a third patient developed postoperative pneumonia. Five of 10 resected primary tumors with preoperative complete responses were pathologically negative for tumor. Concurrent bolus cis-DDP and radiation therapy are well-tolerated and result in impressive tumor reduction. Morbidity after subsequent curative surgery is low, and histologic complete responses are frequent.(ABSTRACT TRUNCATED AT 250 WORDS)

A cell line was established from a portion of a 25-cm stromal sarcoma of the left breast of a 65-year-old woman. The clinical course was rapid with tumor recurrence on the chest wall less than 1 month after mastectomy. Other cutaneous and abdominal metastases occurred shortly thereafter, and death followed within 3 months despite chemotherapy. The cultured cells, designated RW-972, produced large amounts of acid mucopolysaccharides (hyaluronic acid) and mimicked the aggressive growth characteristics seen in the patient. After injection into nude mice, the tumor grew rapidly and occasionally produced metastases. This unique cell line, RW-972, presumably derived from the stromal component of a human malignant cystosarcoma phyllodes, might be useful in studies of experimental therapy of this rare tumor type and of lobular stromal cells of breast. It may also be used to investigate hyaluronic acid production by tumor cells.

An expression is derived for both the Gauss and the Mean curvature of a surface, in terms of three simple cell parameters. The surface is thought of as composed of a single-cell thick sheet of cells joined laterally. The three cellular parameters involved are the ratios of (linear) basal to apical dimension in two orthogonal directions, S1 and S2, and the cell thickness "h". These three parameters may be envisioned as functions of a morphogen or morphogens which vary from point to point over the (middle) surface. As an example, the "reaction-diffusion" equations which are often used to describe pattern-formation in early development can be seen as possible candidates for these morphogens, when the resultant surface deformations are given when the dependence of the three cellular parameters are specified as a function of morphogen concentration. The coupling back of the surface deformations to the set of reaction-diffusion equations is simply given, and is through the dependence on geometry of the Laplacian operator which enters these equations.

Twenty-two patients with metastatic colorectal carcinoma were treated in a Phase I-II study of combination therapy with 5-fluorouracil (5-FU) and etoposide (VP-16). Treatment consisted of weekly intravenous VP-16, 100-120 mg/M2, followed by 5-FU, 400-480 mg/M2, in 28-day cycles. Myelosuppression was the dose-limiting toxicity with a mean nadir leukocyte count of 3,600/mm3 and a mean nadir thrombocyte count of 101,000/mm3. There were no episodes of sepsis or bleeding. The tolerable dose for this regimen is VP-16, 110 mg/M2, and 5-FU, 440 mg/M2, weekly. A total of 63 cycles of chemotherapy were given. Although 10 patients had stabilization of disease, no partial or complete responses were documented. We conclude that there is no clinical support for the in vitro synergy observed with this combination. Further trials of this combination using this schedule in colorectal carcinoma are not indicated.

Two human breast carcinoma cell lines, EP and MW, were established in culture from malignant pleural effusions. In addition to producing tumors in antithymocyte serum-immunosuppressed mice, both cell lines showed epithelial characteristics and anchorage-independent growth in soft agar. EP and MW differed in morphology (spindle-shaped versus round), chromosomal mode (hyperdiploid versus near triploid), estrogen receptor content (43.8 versus 5.1 fmol/mg protein), cloning efficiency (0.24 versus 15%), and activities (milliunits/10(6) cells) of creatine phosphokinase (25.7 versus 62.6) and lactate dehydrogenase (346.7 versus 778.5). Electron microscopy revealed that MW cells had more perinuclear filamentous material and more frequent intracytoplasmic vacuole formation than did EP cells. While having no effect on MW cells at the concentrations studied (10(-5) to 10(-11) M), beta-estradiol (10(-7) M) stimulated the growth of EP cells by 106% over the hormone-depleted control. In a variety of systems, EP was consistently the more drug sensitive of the two lines. In vitro, EP was significantly (p less than 0.001) more sensitive to methotrexate, vincristine, and 5-fluorouracil, respectively. In antithymocyte serum-mouse xenografts, EP displayed a greater response to three different dosages of a combination of cyclophosphamide, methotrexate, and 5-fluorouracil. One such dosage (cyclophosphamide, 32.0 mg/kg/day; methotrexate, 13.0 mg/kg/day; 5-fluorouracil, 190.0 mg/kg/day; for 1 day) reduced EP and MW tumor weights to 5.9 and 41% of controls, respectively. These results correlated well with the clinical responses.

Data on 162 women (90 premenopausal and 72 postmenopausal) with metastatic breast cancer randomized to receive cyclophosphamide, Adriamycin (doxorubicin) and 5-fluorouracil (CAF) on two Eastern Cooperative Oncology Group (ECOG) protocols were analyzed. Twenty-three percent had complete remission; 39% had partial remission; 28% had no change; and 3% had disease progression. Of those patients in whom receptors were known, response rates were 65% for estrogen (ER)-receptor positive and 70% for ER-negative patients. The median duration of response was 11.4 months. The median survival time from the start of CAF was 20.2 months. The response rate, time to treatment failure (TTF), and median survival time were superior in the premenopausal women. These differences ceased, however, to be statistically significant in logistic models. Factors significantly associated with longer TTF and longer survival were as follows: one or two organs with metastases (TTF, P less than 0.0001; survival, P less than 0.0001); dominant site other than soft tissue (TTF, P less than 0.0001; survival, P = 0.05); and an initial good performance status (TTF, P = 0.007; survival, P = 0.02). Patients with ER-positive disease had a significantly longer median survival time (P = 0.003).

In a randomized crossover study, 181 patients over the age of 65 with recurrent breast cancer received either tamoxifen or cyclophosphamide, methotrexate, and fluorouracil (CMF). After progression on tamoxifen, a hormone withdrawal period was required. Because of altered pharmacokinetics with aging, creatinine clearance was used in calculating the dose of CMF. Response rates were 45% on tamoxifen and 38% on CMF, with median durations of 10.4 and 7.9 months, respectively. Survival rates tended to favor tamoxifen as the initial treatment even in estrogen-receptor-negative patients. Additional disease control with hormone withdrawal occurred in 23% of patients, and this benefit was highly correlated with prior hormone response. We conclude that initiation of hormone therapy rather than CMF chemotherapy is justified in almost all situations in elderly patients, and combination chemotherapy, is safe and useful after hormone failure if modified on the basis of renal dysfunction.

One hundred eighty-one elderly women with stage II breast cancer were prospectively randomized to receive tamoxifen or placebo for 24 months in a double-blind adjuvant trial conducted by the Eastern Cooperative Oncology Group. They were stratified prior to randomization on the basis of the number of positive axillary nodes and the estrogen receptor status of their primary tumor. One hundred seventy were considered eligible and analyzed in this trial. The median age was 71 years with a range from 65 to 84 years. Twenty-one percent of the patients were over the age of 75 and 33% were between 71 and 75 years. Estrogen receptor status was positive in 85% of the patients and unknown in another 12%. Progesterone receptor status was positive in 35%, negative in 16%, and unknown in 49%. With a median follow-up of 55 months, the overall percent disease free at 4 years is 73 for the tamoxifen arm and 52 for the placebo arm (P = .003). Significant benefit is seen following tamoxifen in the subsets with 4-10 positive axillary lymph nodes, those who were estrogen receptor positive, or progesterone receptor unknown, and those who had a tumor size less than 3 cm. Most other subsets benefited as well. There were more distant (29 vs. 13) and bone only (15 vs. 3) sites of first recurrence in the placebo arm, whereas locoregional recurrences were similar (8 each). The recorded toxicity was similar, except for more hot flashes observed among women in the tamoxifen arm.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequential assays for cell-mediated reactivity (CMR) and serum blocking factor (SBF) were performed in a group of 12 melanoma patients who were treated with one or both of the clinically available imidazole carboxamide derivatives, DTIC and TIC Mustard, in order to consider the effects of treatment and changing patterns of disease on the results of in vitro tests in individual patients. Microcytotoxicity assays and the dilute agar colony inhibition test were employed. Of the 12 patients, 8 had no change in CMR and 5 had no change in SBF. Three patients demonstrated a fall in both CMR and SBF to nondetectable levels, and 3 additional patients showed a fall in SBF only. From these results, we conclude that there is no significant depression of CMR in melanoma patients by either of the imidazole carboxamide derivatives used. The results of SBF are less conclusive and more open to question, since it is just a likely that any depression to undetectable levels may be due to a change in disease status rather than to coincident drug use. It appears that microcytotoxicity assay results on individual patients may be fortuitous and difficult to interpret, even though results seen in patients as a group indicate important trends. The microcytotoxicity assay is a useful tool for the experimental tumor immunologist, but its clinical usefulness in individual patients is limited.

Pyrazofurin was administered to 21 patients with solid tumors at a dose of 200 mg/m2 iv weekly, because this dose had been shown to be well-tolerated and pharmacologic effects of a single dose at this level persisted for up to 7 days. An anemia consistent with a disturbance in rbc production was seen in most patients. Other toxic effects included stomatitis, rash, and myelosuppression. No complete or partial responses were noted, but two patients with alveolar cell carcinoma of the lung each had stable disease for 12 months. Most of the patients in this study tolerated the weekly dosage schedule well with only minimal myelosuppression, suggesting that this agent and schedule might be acceptable for use in combination chemotherapy. Several theoretic reasons favor the use of pyrazofurin in this manner. Pyrazofurin should also be evaluated more fully in patients with polycythemia vera, mycosis fungoides, and psoriasis, since other orotidylate decarboxylase inhibitors have been shown to be effective in these diseases.

Total and filterable platinum in plasma were monitored for seven courses (five patients, 25 mg/m2/day) using continuous 5-day infusions and one 30-minute infusion at a similar dose level (120 mg/m2). Maximum filterable (non-protein-bound) platinum levels (0.1-0.3 mg/L) for the extended infusions were ten to 40 times lower than that for the short-term infusion (4.0 mg/L). Filterable drug exposure as measured by the area under the [Pt]filterable-time curve is greater for the extended infusions (9.6 mg X hr/L) than that for the short-term infusion (4.8 mg X hr/L). Renal excretion of cisplatin (% of dose excreted/24-hour period after the beginning of the infusion) was measured for four courses of continuous 5-day infusions and for the 30-minute infusion. Urine excretion rates were lower for the continuous infusion (5%-8% of dose/24-hour period during the infusion) compared to the short-term infusion (33% of dose/24-hour period after the beginning of the 30-minute infusion).

Twenty-one evaluable patients with metastatic colorectal carcinoma were treated with a combination of continuous-infusion cisplatin (25 mg/m2/day X 3 days) and bolus 5-fluorouracil (400 mg/m2/day X 3 days). Toxicity was minimal. Seven patients (33%) responded. All responses were observed among the 16 previously untreated patients (44%) and lasted a median of 30 weeks. The results indicate the need for phase III trials of this treatment.

6-Methylmercaptopurine riboside (MMPR) and 5-fluorouracil (5-FU) were administered sequentially to 12 patients in a phase I clinical trial. Toxicities included mild nausea and vomiting, as well as reversible leukopenia and thrombocytopenia. Maximal accumulation of 6-methylmercaptopurine ribonucleoside 5'-monophosphate (MMPR-P), the active metabolite of MMPR, in patients' erythrocytes occurred between 2 and 6 h after the administration of MMPR and the degree of accumulation was dose-related. At 96 h after MMPR administration, MMPR-P was still detectable in patients' erythrocytes. Although no clinical responses were documented, a modified dosage schedule of these drugs should be pursued based on the pharmacokinetic data obtained.

Treatment with continuous infusions of cisplatin results in increased filterable drug exposures as measured by the area under the curve (AUC) of nonprotein-bound plasma platinum levels. To determine the dose-limiting toxicity and optimal method of administration, 24 patients were treated with continuous infusions of cisplatin at a dose rate of 25 mg/M2/day in a limited Phase I trial. A total of 47 courses were given. Nine patients received 13 courses of 4 days duration, 19 received 29 courses of 5 days duration, and five received courses of 6 or 7 days duration. Dose-limiting toxicity was found to be leukopenia: 42% of patients receiving the 5-day treatment developed a nadir count of less than 3000 cells/mm3. Nausea and vomiting were easily controlled. Minimal nephrotoxicity occurred in five patients and was associated with daily volume expansion with 2 l of 0.9% NaCl solution in four patients. All other patients were given 3 l of daily volume expansion during treatment. Responses were seen in 6 of 22 evaluable patients (27%). It is concluded that continuous infusion cisplatin at a dose rate of 25 mg/M2/day can be given safely for 5 days as a single agent if concomitant volume expansion with at least 3 l of 0.9% NaCl solution is given daily. Phase III comparative trials with a conventional bolus and newer high-dose regimens for response and toxicity are indicated.

Adenosine (Ado) and Ado analogues produce multiple hemodynamic effects including coronary vasodilation, bradycardia, alterations in left ventricular contractility, and peripheral vasodilation or vasoconstriction depending on the vascular bed. The intact anesthetized Sprague-Dawley rat was examined in relation to electrocardiogram and blood pressure alterations induced by a series of potentially useful antineoplastic agents that are purine or pyrimidine analogues as part of a preclinical evaluation of these agents. The drugs tested were arabinosyladenine and its 5'-monophosphate derivative arabinosyladenine-5'-monophosphate (ara-AMP), the 2-fluoro derivative of ara-AMP, the pyrazolo[4,3-d]pyrimidines (formycin and formycin B), 8-azaadenosine, 6-methylmercaptopurine riboside, tricyclic nucleoside-5'-monophosphate, 5-fluorouracil, arabinosylcytosine, and 3-deazauridine. Those Ado analogues subject to deamination by adenosine deaminase (ADA) were also studied in the intact Sprague-Dawley rat after pretreatment with the ADA inhibitor 2'-deoxycoformycin. The results indicate that these agents have significant hemodynamic effects and should alert clinicians to potential adverse reactions when infusing these drugs.

Lymphocytes from control donors and from cancer patients have been tested for antitumor, cell-mediated immunity against various melanoma and breast cancer target cell cultures with a microcytotoxicity assay. Control lymphocytes inhibited growth of target cells with high frequency, particularly with cell line, as opposed to short-term, cultures. Inhibition was not found for all target cells tested at a given time with a single preparation of lymphocytes. Sequential studies over a 2-year period with lymphocytes from the same control donors showed fluctuations of inhibition against the same target cells. With serial passage, the target cells also changed in their susceptibility to destruction by control lymphocytes. Lymphocytes from melanoma patients were more inhibitory than control lymphocytes for one melanoma target cell culture but not for two other melanoma cultures. Significant inhibition by lymphocytes from melanoma patients was not seen against two cultures derived from breast cancer patients. Lymphocytes from breast cancer patients were more inhibitory than control lymphocytes for 4 of 5 breast cancer cultures and they did not inhibit two melanoma cultures. Significantly specific inhibition was seen with short-term, but not cell line, breast cultures. The over-all data show specificity for target cells of the appropriate histological type. However, the high and inconstant reactivity of control lymphocytes in this assay suggests that nonspecific inhibition of tumor target cells by patient lymphocytes is found in many experiments. It is concluded that the microcytotoxicity assay is not suitable for clinical studies, since sequential data obtained in individual patients are difficult to interpret.

Ipsilateral stapedius reflex testing has been evaluated in 166 patients. It proves of value in defining the state of an ear (1) opposite to a unilateral conductive loss; (2) the less hard-of-hearing ear in the presence of bilateral asymmetrical sensorineural hearing losses where the worse ear has sufficiently severe loss to prevent a contralateral reflex from being elicited; (3) in patients with absent contralateral acoustic reflexes at 500, 1000, and 2000 Hz; and (4) in suspected central lesions. The test is still bedevilled by artifacts which are produced in the ear rather than the machine; atypical results must be evaluated with extreme caution.

The bone marrow of a patient with multiple myeloma of the IgG2 Kappa type with spontaneously crystallizing cryoglobulin was studied by electron microscopy. The ultrastructure of the myeloma cells disclosed the presence of a crystalline material in the cytoplasm within the rough endoplasmic reticulum (RER) as well as in extracisternal sites. The crystalline material was also seen extracellulary with a distinctly unique subunit structure. The tubular units measured 200 +/- A (SEM) externally with an internal diameter of 100 +/- A (SEM). The intracellular distribution did not indicate a characteristic organelle association usually observed in protein synthesizing cells. It is suggested, based on the present observations and the findings of others, that the crystalline material may represent polymerized protein synthesized by free ribosomes mostly in extracisternal locations, a pattern often seen in neoplastic plasma cells. Diffusion to extracisternal sites of precrystalline material through the membranes of the RER is a possible alternative mechanism.

A total of 268 patients with metastatic breast cancer were prospectively randomized to receive Adriamycin-vincristine (AV) alone, AV plus dibromodulcitol (AVD), or AV plus ICRF-159 (AVI). Two hundred thirty were eligible and had received prior chemotherapy. The objective response rates were 27%, 23%, and 16% for AV, AVD and AVI, respectively, and an additional 44% had stabilization of disease. Duration of responses ranged from 4.1 to 4.6 months and the times to treatment failure from 2.9 to 3.8 months. Median survivals ranged from 7.1 to 8.3 months. Performance status and the presence of liver or brain metastases were significant prognostic variables for outcome. These studies show that AVI is inferior to AV with respect to survival when prognostic variables are taken into account in a multivariate model, whereas AVD which utilizes a lower dose of Adriamycin appears to have comparable antitumor activity to AV. This does not appear to offer any benefit to patients previously treated with chemotherapy, as in this trial, but it may be an advantage to previously untreated patients since Adriamycin can be administered to responding patients over a longer period of time before an unacceptable total cumulative dose is reached.

Sudden profound bilateral sensorineural hearing loss is a serious complication of bacterial meningitis. With high dosage Dexamethasone it is possible to halt, and, in some instances, to reverse the progression of the hearing loss. The efficacy of treatment depends upon early diagnosis. Hearing may worsen upon steroid cessation and low dosage oral steroid may be required for several months. The eventual hearing loss may be considerably worse than anticipated. Two cases illustrating differing aspects of the disease are described.

A phase I trial was conducted in 30 patients with solid tumors, using infusions of 5-fluorodeoxyuridine (5-FUdR) plus cytosine arabinoside (ara-C). Doses of 5-FUdR administered over 2 hours daily X 5 ranged from 0.02 to 1.0 mg/kg, and these doses immediately preceded a 1-hour infusion of ara-C. These schedules were selected because 5-FUdR pretreatment had been shown to sensitize L5178Y cells in culture to acute cell death by ara-C. Dose-limiting toxicity was myelosuppression. Based upon results in this study, the recommended dose of 5-FUdR to be used in phase II trials of this combination is 0.04--0.05 mg/kg (1.6--2.0 mg/m2) given prior to ara-C at a dose of 100 mg/m2. Antitumor responses were seen in patients with head and neck cancer, breast carcinoma, and carcinoid syndrome.

Successful therapy for a case of multiple myeloma with a spontaneously crystallizing cryoglobulin of the IgG2-kappa light chain variety was achieved, using both continuous-flow cell centrifugation plasmapheresis to rapidly lower the M component and combination chemotherapy with phenylalanine mustard, prednisone, procarbazine, and vincristine to control the myeloma process. This resulted in resolution of incapacitating large and small necrotic cutaneous ulcerations of the extremities. Physicochemical studies of the crystalcryoprotein demonstrated that cryoprecipitation was rapid and accompanied by the formation of needle-shaped crystals, yet was completely reversible at 37 degrees C. Cryocrit determinations varied depending upon relative centrifugal forces and temperature and did not always relate linearly to the amount of abnormal protein, thus making these alone unreliable in assessing response to therapy.

One hundred thirty-one premenopausal women with metastatic breast cancer who had received no prior systemic treatment for metastases were entered on study. Patients without prior chemotherapy with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) or surgical oophorectomy followed directly by CAF (O + CAF). ER-negative patients without prior chemotherapy were directly assigned to treatment with CAF. Among randomized patients 83% have responded, and 37% have achieved a complete remission. Among ER-negative patients the complete response rate was 38%, and the complete plus partial response rate was 70%. Characteristics significantly associated with a longer time to treatment failure were age 45 or over, one or two organ sites, and performance status O. The median survival time of ER-positive patients treated with CAF is 29 months, and with O + CAF it has not yet been reached, whereas for ER-unknown patients the equivalent survival times are 41 months and 43 months respectively. For ER-negative patients treated with CAF the median survival time is 17 months. Characteristics associated with significantly longer survival among randomized patients were age 35 or over (P = .009) and only one or two organ sites involved (P = .02). Neither treatment (P = .33) nor ER status (P = .70) was significant.

Separate trials for premenopausal and postmenopausal (less than or equal to 65 yr of age) patients with node-positive breast carcinoma were initiated by the Eastern Cooperative Oncology Group in 1978 to evaluate adjuvant chemotherapy and chemohormonal therapy approaches. Postoperative patients were stratified by degree of axillary nodal involvement and estrogen receptor (ER) status prior to randomization. Premenopausal patients received 12 monthly cycles of intermittent cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus continuous tamoxifen (CMFPT). Postmenopausal patients received either observation or 12 monthly cycles of CMFPT or CMFP. The median follow-up for the analyzed patients is 54 months for the 553 premenopausal patients and 59 months for the 223 postmenopausal patients. The premenopausal trial has not demonstrated any significant differences between the regimens for either relapse-free or overall survival. The relapse-free survival in the postmenopausal trial has demonstrated a trend for CMFPT over observation (P = .07). Both CMFP and CMFPT are associated with an improved relapse-free survival over observation alone in ER-negative patients (P = .01) and in progesterone receptor-negative patients (P = .01). However, the relapse-free survival advantages have not translated to survival. Side effects were significantly increased with the addition of P to CMF in the premenopausal trial. The addition of T to CMFP was associated with an increased incidence of edema and hot flashes in premenopausal patients; however, the latter was decreased in postmenopausal patients relative to CMFP.(ABSTRACT TRUNCATED AT 250 WORDS)

Increases in cancer incidence and mortality reflect the larger numbers of elderly in the population. Using a mortality sample of 1891 biopsy-confirmed cancer patients, analyses reveal older breast, prostate, and cervical-uterine cancer victims were more likely to be diagnosed with metastases. Logistic regression analyses of subsamples of breast (N = 224), lung (N = 513), and colorectal (N = 299) cancer patients indicate that age is significantly inversely related to receipt of both subsequent chemotherapy and radiation therapy, controlling for stage of disease and presence of co-morbid disease. Exceptions to this relationship are the use of radiation therapy among nonmetastatic lung cancer patients and all breast cancer patients. The implications of these findings for current cancer control programs are discussed.