Association between autophagy and KRAS mutation with clinicopathological variables in colorectal cancer patients.

Autophagy is a host defensive mechanism responsible for eliminating harmful cellular components through lysosomal degradation. Autophagy has been known to either promote or suppress various cancers including colorectal cancer (CRC). KRAS mutation serves as an important predictive marker for epidermal growth factor receptor (EGFR)-targeted therapies in CRC. However, the relationship between autophagy and KRAS mutation in CRC is not well-studied. In this single-centre study, 92 formalin-fixed paraffin-embedded (FFPE) tissues of CRC patients (42 Malaysian Chinese and 50 Indonesian) were collected and KRAS mutational status was determined by quantitative PCR (qPCR) (n=92) while the expression of autophagy effector (p62, LC3A and LC3B) was examined by immunohistochemistry (IHC) (n=48). The outcomes of each were then associated with the clinicopathological variables (n=48). Our findings demonstrated that the female CRC patients have a higher tendency in developing KRAS mutation in the Malaysian Chinese population (p<0.05). Expression of autophagy effector LC3A was highly associated with the tumour grade in CRC (p<0.001) but not with other clinicopathological parameters. Lastly, the survival analysis did not yield a statistically significant outcome. Overall, this small cohort study concluded that KRAS mutation and autophagy effectors are not good prognostic markers for CRC patients.

A review of the Turned-down Onto Pericapsular-tissue Hemisectioned Amputated Toe (TOPHAT) flap for wound coverage during ray amputations of the toes.

INTRODUCTION: Exposure of the adjacent Metatarsal-Phalangeal Joint (MTPJ) commonly occurs after application of Topical Negative Pressure Wound Therapy (TNPWT) for a ray amputation wound. This is due to mechanical soft tissue erosion or trauma to the adjacent digital artery from direct pressure effect. This results in toe gangrene requiring a ray amputation and ultimately a larger wound bed. We describe the use of the Turned-down Onto Pericapsular-tissue Hemisectioned Amputated Toe (TOPHAT) flap - a filleted toe flap to protect the adjacent MTPJ capsule combined with a novel Negative Pressure Wound Therapy with instillation and dwell-time (NPWTi-d) dressing technique. The flap protects the adjacent joint capsule and reduces the wound burden whilst allowing the wound to benefit from TNPWT, thereby accelerating wound healing. MATERIAL AND METHODS: A retrospective review was conducted of patients with toe gangrene requiring ray amputation that underwent the TOPHAT flap on in our institution from 2019 and 2020. Complications such as wound dehiscence, hematoma, flap necrosis and secondary infection were recorded. Other outcomes recorded were time taken to final skin grafting and time taken for complete wound epithelialization. RESULTS: 9 patients underwent treatment with the TOPHAT flap. 2 patients had flap necrosis. 7 patients progressed to definitive skin coverage with skin grafting. One patient subsequently had progressive arterial disease despite successful skin grafting and required above knee amputation. The mean time to final skin grafting and complete wound epithelialization was 49.5 days and 107.5 days respectively. All patients were satisfied with the outcomes and were able to return to their pre-morbid function. CONCLUSIONS: The TOPHAT flap has a consistent vascular supply that provides durable soft tissue coverage. It is a robust and easily reproducible technique to accelerate wound healing after ray amputations even in patients with peripheral vascular disease.

Epidemiology and outcome of Candida bloodstream infection in an intensive care unit in Hong Kong.

OBJECTIVE: To study the epidemiology of Candida bloodstream infection in the Intensive Care Unit. DESIGN: Retrospective study. SETTING: A 22-bed, mixed medical and surgical Intensive Care Unit of a 1400-bed university teaching hospital in Hong Kong. PATIENTS: All adult patients (>18 years) who had at least one blood culture positive for Candida. RESULTS: During the 9 years of the study period, there were 128 patients with episodes of candidaemia (point prevalence, 9.6 per 1000 Intensive Care Unit admissions), 72 entailed albicans candidaemia and 56 non-albicans candidaemia. Albicans was still the predominant species, but the incidence of tropicalis was increasing. The median lengths of hospital and Intensive Care Unit stays prior to taking of the culture revealing candidaemia were 15 and 6 days, respectively. In all, 61% of patients did not have Candida colonisation within 2 weeks of their candidaemia. The main anti-fungal agents used were fluconazole and amphotericin B, but only 89 (70%) of the patients received appropriate anti-fungal treatment. Intensive Care Unit and hospital mortalities were 70% and 78%, respectively. Patients who did not receive appropriate treatment within 3 days had a worse outcome than those who did. CONCLUSIONS: Our data showed a high point prevalence of candidaemia in the Intensive Care Unit. Albicans was still the predominant species. Candidaemia occurred early during Intensive Care Unit stay, and a significant proportion of patients did not have prior fungal colonisation. Candidaemia in the Intensive Care Unit was associated with high morbidity and mortality. Many patients did not receive appropriately early anti-fungal therapy, and endured higher mortality than in the remainder.

Characteristics, management process, and outcome of patients suffering in-hospital cardiopulmonary arrests in a teaching hospital in Hong Kong.

OBJECTIVES: To examine the demographics, process indicators of adult in-hospital cardiopulmonary arrest resuscitation, and outcomes in a teaching hospital in Hong Kong. DESIGN: Retrospective study. SETTING: A university-affiliated tertiary referral hospital with 997 acute adult beds in Hong Kong. PATIENTS: Those who suffered a cardiopulmonary resuscitation event, as documented in retrieved records of all in-patients during the inclusive period January 2002 to December 2005. RESULTS: There were 531 resuscitation events; the mean (standard deviation) age of the corresponding patients was 70.7 (15.4) years. Most (83%) occurred in non-monitored areas and most (97%) were cardiopulmonary arrests. The predominant initial rhythm was asystole (52%); only 8% of patients had ventricular tachycardia/fibrillation. All the resuscitations were initiated by on-site first responders. The median times from collapse to arrival of the resuscitation team, to defibrillation, to administration of adrenaline, and to intubation were: 5 (interquartile range, 2-6) minutes, 5 (1-7) minutes, 5 (3-10) minutes, and 9 (5-13) minutes, respectively. The overall hospital survival (discharge) rate was 5%. The survival rate was higher among patients in monitored areas (9 vs 4%, P=0.046), among patients with isolated respiratory arrests (61 vs 3%, P<0.001), primary ventricular tachycardia/fibrillation arrests (13 vs 4%, P<0.001), shorter interval times from collapse to medication (1.5 vs 5 min, P=0.013), and longer interval times to intubation (12 vs 8 min, P=0.013). CONCLUSION: Hospital survival after in-hospital cardiopulmonary arrests was poor. Possible strategies to improve survival include shorten time interval to defibrillation, and provision of more monitored beds.

Clinical pharmacokinetics of vinblastine by continuous intravenous infusion.

Vinblastine (VLB) is moderately active clinically against advanced breast cancer. Since VLB is extensively taken up by platelets and thus only partially available to tumor cells, to enhance the therapeutic index of VLB we have therefore administered this agent by continuous i.v. infusion to patients with advanced breast cancer. In conjunction with the clinical trial, we conducted pharmacokinetic studies of generally tritiated VLB, using radiochemical and chromatographic techniques. The elimination of VLB from the plasma of patients who received it by 5-day i.v. infusion at 1 to 2 mg/sq m daily was biphasic. In four patients who achieved partial remission, the average plasma half-life of VLB during the terminal phase was 29.4 +/- 14.6 days, with a total clearance of 36 +/- 8 ml/kg/hr, and a steady-state apparent volume of distribution of 28.1 +/- 8.5 liters/kg. However, in three patients whose disease merely stabilized, the plasma half-life was 6.4 +/- 1.6 days, the total clearance was 137 +/- 2.9 ml/kg/hr, and the volume of distribution was 33.0 +/- 11.6 liters/kg. In contrast, in five patients with refractory disease, these parameters were 2.3 +/- 0.3 days, 541 +/- 124 ml/kg/hr, and 37.6 +/- 8.6 liters/kg. Since the apparent volumes of distributions at steady state did not differ significantly among these three groups, whereas the values of the total clearance were markedly dissimilar, the plasma half-lives of VLB were significantly shorter in patients not responsive to continuous infusion therapy with this drug. Although the number of patients studied was small, it nevertheless appears that favorable clinical response of patients with advanced breast cancer is associated with slow total clearance of the drug.

Bisantrene, an active new drug in the treatment of metastatic breast cancer.

Forty-four patients with metastatic breast cancer who had previously received extensive conventional systemic therapy, including combination chemotherapy with doxorubicin, were treated with Bisantrene, a new anthracene derivative. The dose schedule was 250 to 300 mg/sq m body surface administered as a 1- to 2-hr i.v. infusion. Of 40 evaluable patients, there were nine partial responses, and 18 patients had stable disease. Responses were seen in all major sites of organ involvement with a median time to progression of 28 weeks. Moreover, responses were seen among patients who had either failed to respond or had demonstrated refractoriness to prior therapy with doxorubicin, suggesting an apparent lack of cross-resistance between doxorubicin and Bisantrene. Except for myelosuppression and one incidence of acute anaphylactoid reaction, Bisantrene was generally well tolerated by most patients. We believe that Bisantrene may ultimately have a major role in the effective treatment of metastatic breast cancer, and further clinical trials are warranted.

Prognostic factors in metastatic breast cancer treated with combination chemotherapy.

Six hundred nineteen patients with metastatic breast cancer, treated with a combination of 5-fluorouracil, Adriamycin, and cyclophosphamide, or close variations of this program, with or without immunotherapy were analyzed retrospectively to identify those host, tumor, or treatment characteristics that might be of prognostic importance in predicting response to chemotherapy and survival from onset of the 5-fluorouracil-Adriamycin-cyclophosphamide treatments. Primary tumor characteristics such as size of primary, number of axillary nodes involved, stage at diagnosis, and type of surgery used for primary treatment were not found to be of prognostic significance. Host characteristics such as age, menstrual status, or family history of breast cancer were similarly unrelated to outcome. Non-Caucasian patients had a lower response rate and somewhat shorter survival than did Caucasians. Pretreatment weight loss, poor performance status, and abnormal biochemical and hematological values were of adverse prognostic significance. An estimate of total extent of disease based on criteria for rating extent of involvement at 12 potential sites was a much more important prognostic factor related to response and survival than actual sites of involvement or the traditional "dominant site" classification. There was a trend, however, for patients with bone involvement to have a longer survival than did patients with metastases to other organ sites. Shorter survival times were observed among patients exposed to extensive prior radiotherapy and those who failed to respond to prior hormonal treatment. The prognostic variables identified in this paper should be used for the design and comparison of clinical trials in the future.

High-dose induction chemotherapy of metastatic breast cancer in protected environment: a prospective randomized study.

To test the hypothesis of whether high doses of chemotherapy in combination achieve higher response rates and longer durations of response and survival, we treated 33 pre- and perimenopausal patients with good performance status in a prospective trial with escalating doses of fluorouracil, doxorubicin and cyclophosphamide (FAC). Patients were randomly assigned to be treated within a protected environment (laminar air flow room), with prophylactic antibiotics, or in a standard hospital room. Important patient characteristics were equally distributed in the two treatment arms. A major objective response was observed in 27 of the 32 evaluable patients (84%), and 11 (34%) achieved a complete remission (CR). There was no significant difference in overall and complete response rates between the two treatment arms, nor was there a substantial difference in times to progression or survival between the groups treated in or out of the protected environment. Comparison of the results of this study with previously reported programs of FAC chemotherapy in patients with metastatic breast cancer shows that this study achieved higher overall and complete response rates. However, neither the time to progression, nor the survival of responders or the entire patient group was different from our previous experience with standard FAC chemotherapy. When the study was initiated in 1976, the proposed dose escalation represented high-dose chemotherapy. In retrospect, even the "high" doses used in this study represent only a modest increase over standard doses of chemotherapy. Much steeper dose escalations will be needed to evaluate the efficacy of high-dose chemotherapy in breast cancer, as well as the protective value of the protected environment and prophylactic antibiotics in metastatic breast cancer.

Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: a prospective randomized study.

Fifty-nine evaluable patients under 65 years of age with measurable metastatic breast cancer and without prior chemotherapy were randomly assigned to treatment with fluorouracil, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (FAC) at standard or high doses (100% to 260% higher than standard FAC) following a dose escalation schedule. Patients randomized to the high-dose FAC received the first three cycles of therapy within a protected environment. Subsequent cycles for this group were administered at standard doses of FAC in an ambulatory setting, the same as for the control group. After reaching 450 mg/m2 of Adriamycin, patients in both groups continued treatment with cyclophosphamide, methotrexate, and fluorouracil until there was disease progression. Analysis of pretreatment patient characteristics showed an even distribution for most known pretreatment factors, although the control group had slightly (but nonsignificantly) more favorable prognostic characteristics. Fourteen patients (24%) achieved a complete remission (CR) and 32 (54%) achieved a partial remission (PR), for an overall major response rate of 78%. There were no differences in overall, CR, or PR rates between the high-dose FAC and control groups. The median response durations were 11 and 10 months for the protected environment and control groups, respectively, and the median survival was 20 months for both groups. Hematologic, gastrointestinal (GI), and infection-related complications were significantly more frequent and severe in the group treated with high-dose chemotherapy. Stomatitis, diarrhea, and skin toxicity were dose-limiting. However, there were no treatment-related deaths. High-dose induction combination chemotherapy with the agents used in this study failed to increase the response rate or survival duration, and resulted in a substantial increase in toxicity.

Multivariate analysis of prognostic factors in metastatic breast cancer.

Univariate and multivariate analyses were conducted on data collected from the records of 619 patients with metastatic breast cancer in whom an Adriamycin-containing chemotherapeutic regimen was used. Using a forward, stepwise logistic regression procedure, several models or equations in which a small number of pretreatment factors were incorporated were generated and the probability of response to therapy was accurately predicted. The predictive ability of these models was tested retrospectively in 546 of the 619 patients from whom the data were derived and prospectively in a new population of 200 patients with metastatic breast cancer also treated with a therapeutically equivalent Adriamycin combination. Using similar univariate techniques, pretreatment factors were correlated with the length of survival after therapy. The proportional hazard model of Cox was used to develop a regression model relating survival to pretreatment characteristics in much the same manner as that of the response model. The total population of the initial group of patients was divided according to four levels of hazard ratio, and survival distributions were compared. This model also was tested progressively and its predictive capability was confirmed. The prediction of individual outcome is a valuable capability in the comparison of clinical trials and the continuing evaluation of biologic changes in patients with metastatic carcinoma; such a method is described in this paper.

Hormonal therapy for metastatic male breast cancer.

Forty-one men with metastatic breast cancer were treated with 70 trials of hormone therapy. These included 25 orchiectomies and 45 additive hormonal treatments. The overall response rate was 31%. The response rate was 32% to orchiectomy, 17% to estrogens, 43% to steroids, 25% to tamoxifen citrate, and 60% to androgens. The response to additive hormonal therapy was 31% and was not affected by prior orchiectomy (33% v 30%). Median overall response duration was 12 months, 17.5 months following orchiectomy, 8.5 months following additive hormonal therapy, five months following estrogens, 11 months following steroids, and eight months following androgens. Median survival from first metastasis was significantly prolonged in patients responding to orchiectomy and additive hormonal therapy. Patients with a disease-free interval (DFI) longer than 12 months had a 59% response rate to hormonal therapy compared with 9% of those with a DFI no more than 12 months. Response to one form of hormonal therapy did not predict later hormonal response. Ablative and additive hormonal therapy offer effective palliation to one third of male breast cancer patients, produce little toxic effects and morbidity, and improve survival duration after metastasis in responders.

Diabetes insipidus and breast cancer.

Diabetes insipidus, resulting from metastatic involvement of the neurohypophysial system, is a rare complication of breast cancer. This review examined the clinical features, metastatic pattern, and radiological and postmortem findings of 39 breast cancer patients with this complication. All patients had polyuria and polydipsia, and all had evidence of advanced metastatic breast cancer. A high incidence of meningeal carcinoma carcinomatosis and/or sellar metastases was observed. In view of the anatomical proximity of the posterior pituitary to the dura mater and the sella turcica, our findings suggest that metastases to the neurohypophysis can occur not only as a result of hematogenous dissemination of malignant cells, but also from direct tumor extension and/or invasion from adjacent structures. Although satisfactory symptomatic relief can be obtained with vasopressin tannate, complete resolution of the diabetic insipidus syndrome was evident only in those patients who had achieved control of the underlying breast disease.

A multi-criteria analysis of options for energy recovery from municipal solid waste in India and the UK.

Energy recovery from municipal solid waste plays a key role in sustainable waste management and energy security. However, there are numerous technologies that vary in suitability for different economic and social climates. This study sets out to develop and apply a multi-criteria decision making methodology that can be used to evaluate the trade-offs between the benefits, opportunities, costs and risks of alternative energy from waste technologies in both developed and developing countries. The technologies considered are mass burn incineration, refuse derived fuel incineration, gasification, anaerobic digestion and landfill gas recovery. By incorporating qualitative and quantitative assessments, a preference ranking of the alternative technologies is produced. The effect of variations in decision criteria weightings are analysed in a sensitivity analysis. The methodology is applied principally to compare and assess energy recovery from waste options in the UK and India. These two countries have been selected as they could both benefit from further development of their waste-to-energy strategies, but have different technical and socio-economic challenges to consider. It is concluded that gasification is the preferred technology for the UK, whereas anaerobic digestion is the preferred technology for India. We believe that the presented methodology will be of particular value for waste-to-energy decision-makers in both developed and developing countries.

Mitoxantrone, cyclophosphamide, and 5-fluorouracil in the treatment of hormonally unresponsive metastatic breast cancer.

Fifty-five patients with newly diagnosed, estrogen receptor negative, metastatic breast cancer were entered in a trial of mitoxantrone, 10 mg/m2 intravenous (IV), cyclophosphamide, 500 mg/m2 IV, and 5-fluorouracil, 1000 mg/m2 IV, which were given on day 1 of a 21-day treatment interval. This trial was designed to test the efficacy of substituting mitoxantrone for doxorubicin as part of a combination that has proved to be effective in inducing remission. The trial was also intended to evaluate the response of resistant disease and of stable metastatic disease to a combination of doxorubicin and vinblastine sulfate. The cardiotoxic potential of mitoxantrone was evaluated in all the patients by serial measurements of ejection fraction and by endocardial biopsy of the right ventricle. Patients who achieved a complete response or a partial response (with bone as the only site of disease) on the three-drug combination were continued on this treatment for 2 years, or for 1 year following a complete response, whichever was shorter or as cardiac monitoring permitted. Therapy with doxorubicin, 25 mg/m2/d for two days, followed by continuous infusion vinblastine sulfate, 1.4 mg/m2/d for four days, was given to all patients who progressed after two courses or were stable after six courses of three-drug therapy. The preliminary results from 50 patients show that 4 attained a complete response and 30 a partial response, giving a total response rate of 68%. The median duration of response was more than 7 months (range greater than 5 to greater than 15 months). One patient in complete remission relapsed after 8 months and failed reinduction therapy with doxorubicin-vinblastine sulfate. Myelosuppression, principally granulocytopenia, was the major side effect of cyclophosphamide-mitoxantrone-5-fluorouracil. Mild to moderate vomiting occurred in 76% of patients and alopecia in 88%. This therapy was discontinued in four patients because of a decreased cardiac ejection fraction and/or symptoms of heart failure. No cardiac biopsy score, however, has been greater than 1.0. These results suggest that a combination of cyclophosphamide-mitoxantrone-5-fluorouracil is effective in untreated, estrogen receptor negative, metastatic breast cancer and is comparable to the doxorubicin combination. Myocardial injury occurs with mitoxantrone, and a safe cumulative dose has yet to be established.

Treatment of locoregionally advanced breast cancer with surgery, radiotherapy, and combination chemoimmunotherapy.

Fifty-two patients with locally advanced primary breast cancer (T3, T4, N2, N3) but no evidence of distant metastases were treated with three cycles of combination chemotherapy. The regimen consisted of 5-fluorouracil, Adriamycin, cyclophosphamide, and Bacillus Calmette-Guerin (FAC-BCG), followed by local therapy (simple mastectomy and/or radiotherapy to the breast/chest wall and the regional lymphatic system) and adjuvant chemotherapy for two full years. The results were compared with those in an historical control group of 52 patients matched for initial stage of disease who were treated by a simple mastectomy and postoperative radiotherapy only. Forty-nine (94%) of 52 FAC-treated patients and 48 (92%) of the control patients became free of clinically detectable disease. At the median follow-up time of 56 months, 37.5% of the FAC-treated patients and 19.5% of the control patients had remained free of disease. FAC-treated patients who completed 2 years of therapy and in whom adjuvant chemotherapy was started promptly after local treatment had a 48% disease-free survival rate of 4 years. In those in whom the initial manifestation was supraclavicular involvement, the estimated 5-year disease-free survival rate was 42% for patients treated with FAC and 9% for control patients. There were local recurrences in 25% of FAC-treated patients and 23% of control patients (not significant). Distant metastases developed in 50% of FAC-treated patients and 77% of control patients (p less than 0.01). The median disease-free interval was 25 months in the FAC-treated group and 11 months in the control group (p = 0.025). The greatest improvement in prognosis was in patients with supraclavicular involvement; the median disease-free survival was 26 months in FAC-treated patients and 6 months in the control group (p = 0.007). This multimodal approach effectively renders the majority of patients with locoregionally advanced breast cancer free of disease and prolongs the disease-free survival period.

Clinical pharmacology of intramuscularly administered L-asparaginase.

Clinical pharmacology of L-asparaginase was compared by intramuscular and intravenous injections in 12 patients with metastatic cancer or leukemia. Following a single intramuscular injection at the gluteal site of L-asparaginase (10,000 IU/m2), the enzyme appeared in plasma as measured initially at 1 hour, but plateau levels were not reached in plasma until 14 to 24 hours after drug administration. The peak plasma level was 1.12 IU/ml, only one fourth of that seen when L-asparaginase was given intravenously at equal doses. However, the enzyme level decrease in the plasma after intramuscular injections was slower, with a half-life ot 46 hours, compared to 7 to 28 hours for intravenously administered drug. The apparent volume of distribution indicated that the intravenously injected enzyme was mostly distributed in plasma, whereas the intramuscularly injected enzyme yielded a much larger volume of distribution (63 versus 245 ml/kg). In addition, only 19 per cent of the intramuscularly injected dose was in plasma, and the area under the curve (C X t) was only 1/24 that by intravenous route (20 versus 487 IU/ml.hr). No enzyme was measurable in patients' urine samples collected for three days after intramuscular injections of the enzyme, and only a trace (less than 1 per cent) of the enzyme was detected in urine after intravenous administration.

A comparative study of bisantrene given by two dose schedules in patients with metastatic breast cancer.

Schedule dependency of bisantrene was evaluated in refractory metastatic breast cancer. Patients were randomly assigned to receive either a single (S) bolus injection of 300 mg/m2 (37 patients) or an injection of 80 mg/m2 daily for 5 days (D x 5) (35 patients) every 3-4 weeks after stratification by performance status, dominant disease site, and response to prior doxorubicin therapy. All but one patient had received prior doxorubicin. Partial remission (PR) was achieved by 5 of 35 patients (14%) in the S arm and 7 of 35 patients (20%) in the D X 5 arm (P = NS). There were 4 patients who had primary refractoriness to doxorubicin but responded to bisantrene. The median number of courses was two for both arms. The median time to progression was 5 months for the responders in each arm and 3 and 4 months, respectively, for patients who showed no change in the S and D X 5 arms. Myelo-suppression was dose-limiting and greater for the D X 5 arm. Drug fever (34% versus 21% of courses; P = 0.02) and myalgia (22% versus 10% of courses; P = 0.02) were reported more often in the D X 5 arm; malaise was greater in the S arm. Grade 2-3 nausea and vomiting occurred more often in the S arm (40% versus 10% of courses; P less than 0.01). Significant hypotension that was not symptomatic occurred in 1 patient in the D X 5 arm. Phlebitis occurred in 3 patients without a central line. One patient who had previously received doxorubicin and mitomycin C developed heart failure, which was controlled with medication. Bisantrene is an effective drug for metastatic breast cancer that has incomplete cross resistance to doxorubicin, and there was no schedule dependency in this study.

A phase I-II study of continuous 5-day infusion mitomycin-C.

A phase I-II study was undertaken to establish the maximum-tolerated dose of a continuous 5-day infusion of mitomycin-C and its efficacy in patients with advanced metastatic drug-resistant breast and gastrointestinal malignancies. The dose-limiting toxicity was myelosuppression, predominantly thrombocytopenia, and was severe and cumulative. Nonhematologic toxicity was infrequent, and no renal or cardiac toxicity was seen. For patients with breast cancer who had received extensive prior therapy, 3 mg/m2/day for 5 days repeated every 6-8 weeks were well-tolerated doses; and for patients with gastrointestinal cancer, the maximum-tolerated dose was 4 mg/m2/day. One patient with breast cancer had a partial response lasting 4 months, and no responses were observed in patients with gastrointestinal cancer. The administration of mitomycin-C by continuous infusion did not appear to have improved its therapeutic index.

Phase II clinical evaluation of AZQ in metastatic breast cancer.

Thirty-three patients with metastatic breast cancer who have failed prior combination chemotherapy including adriamycin, cyclophosphamide, 5-fluorouracil and methotrexate, were treated with AZQ given on a 5-day I.V. schedule repeated every 4 weeks. The starting doses were 6 or 8 mg/m2/day for poor- and good-risk patients, respectively. There were two partial responses among 29 evaluable patients. Both had soft tissue and/or lymph node involvement. Six patients had stable disease. Myelosuppression, predominantly thrombocytopenia, was dose-limiting. Other toxicities were mild, including nausea, vomiting, anorexia, diarrhea, stomatitis, and malaise. Our results indicate that AZQ given on the 5-day schedule is unlikely to be effective in the treatment of refractory breast cancer.

Phase II trail of PCNU in refractory advanced breast cancer.

An evaluation of PCNU was carried out in 28 patients with extensively treated refractory breast cancer. The starting dose was 60 mg/m2 in 13 patients and 90 mg/m2 in 15 patients given intravenously every 6 weeks. The major side effect was myelosuppression, manifested mainly as thrombocytopenia. Nonhematologic side effects were minimal, consisting mainly of transient nausea. One mixed response was seen. Four patients had stable disease. PCNU demonstrated limited activity in advanced breast cancer and was not effective in the treatment of central nervous system metastases.