Janardan D. Khandekar

Symptomatology as an indicator of recurrent or metastatic breast cancer

Eight‐seven patients with recurrent breast cancer after mastectomy were analyzed for patterns of recurrence and methods of detection. After an average disease‐free interval of 30 months, 38% developed osseous metastases, 16% recurred locally, 10% had local plus systemic disease, 10% showed pulmonary metastases and the remainder were distributed among liver, brain, and remaining breast disease. In 79 patients recurrence was heralded by symptoms. Physical examination in five asymptomatic patients revealed local or supraclavicular recurrence. In only three asymptomatic patients was recurrence documented by “routine” chest x‐rays (in two), or liver enzymes/liver scan (in one). No asymptomatic disease was found by bone scan. It is concluded that periodic history, physical examination, and chest x‐rays are the most important components in the follow‐up of breast cancer patients. Radioisotope scans and other radiographs are valuable in confirming symptomatic disease and detecting additional disease, but cannot be recommended routinely in the asymptomatic patient because of low yield and cost. Cancer 43:956–960, 1979.

Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells.

The polycomb group (PcG) protein, enhancer of zeste homologue 2 (EZH2), is overexpressed in several human malignancies including breast cancer. Aberrant expression of EZH2 has been associated with metastasis and poor prognosis in cancer patients. Despite the clear role of EZH2 in oncogenesis and therapy failure, not much is known about chemotherapeutics and chemopreventive agents that can suppress its expression and activity. Here, we show that dietary omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) can regulate the expression of EZH2 in breast cancer cells. The treatment of breast cancer cells with omega-3 PUFAs, but not omega-6 PUFAs, led to downregulation of EZH2. Studies using proteosome inhibitor MG132 suggested that omega-3 PUFAs induce degradation of the PcG protein EZH2 through posttranslational mechanisms. Furthermore, downregulation of EZH2 by omega-3 PUFAs was accompanied by a decrease in histone 3 lysine 27 trimethylation (H3K27me3) activity of EZH2 and upregulation of E-cadherin and insulin-like growth factor binding protein 3, which are known targets of EZH2. Treatment with omega-3 PUFAs also led to decrease in invasion of breast cancer cells, an oncogenic phenotype that is known to be associated with EZH2. Thus, our studies suggest that the PcG protein EZH2 is an important target of omega-3 PUFAs and that downregulation of EZH2 may be involved in the mediation of anti-oncogenic and chemopreventive effects of omega-3 PUFAs.

Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract.

From October 1978 to October 1981, 135 patients with disseminated transitional cell carcinomas of the urinary tract, with either measurable or evaluable disease, were randomized to receive either cis-diamminedichloroplatinum (DDP) or cyclophosphamide (CTX), Adriamycin (ADR) (Adria Laboratories, Columbus, Ohio), and DDP (CAD). DDP was given at a dose of 60 mg/m2, CTX at 400 mg/m2, and ADR at 40 mg/m2 intravenously every three weeks. Patients over the age of 65 and those with prior radiation received 75% of the dose initially. The dose was escalated if only mild toxicity developed. Of the patients on the CAD arm, 34% developed grade 3 or 4 hematologic toxicity, as compared to 3% in patients on the DDP therapy. Of the 93 patients with measurable disease, 48 received DDP. Seventeen percent had a partial or complete remission, as compared to 33% of the 45 patients on the CAD arm (P = .09). The crude median survival of patients on DDP was 6.0 months as compared to 7.3 months in patients receiving CAD (P = .17). We conclude that the CAD combination is more toxic than DDP with, at best, very marginal benefit in survival.

Preoperative and follow‐up procedures on patients with breast cancer

From July 1, 1975 to June 30, 1979, 194 patients were enrolled in a program under a contract from the NCI to study chemoimmunotherapy in patients with Stage II and Stage III breast cancer. Patients were treated in six‐week cycles for one year and were later followed at six month intervals. Pretreatment evaluation included complete blood count, SMA‐12, xerogram, chest x‐ray, and bone scan. The blood count and SMA‐12 were repeated every six weeks before each course of treatment, and all of the preoperative tests were repeated at the completion of one year of treatment. After the year of treatment, testing was variable depending upon the stage of the disease, the patients symptoms, and the individual preferences of the responsible physician. Up to the present time, there have been 38 recurrences in the 194 patients entered into this protocol. Twenty‐nine of the recurrences were symptomatic at the time of discovery, four were asymptomatic and detected on physical examination, and five asymptomatic recurrences were detected by routine testing. Review of 60 patients who developed recurrence during approximately the same interval but who were not on the protocol shows that 43 were symptomatic and 14 were discovered on routine physical examination; 3 patients were asymptomatic. During this time, five new breast cancers were discovered in patients included in this report. Three were discovered by xerogram and two by physical examination. Further studies need to be made to provide sound data for optimal follow‐up procedures on previously treated breast cancer patients. Careful history, physical examination, and evaluation of symptoms will identify most recurrences at a relatively early stage and extensive routine testing may not be worthwhile.

Changes in Performance After Implementation of a Multifaceted Electronic-Health-Record-Based Quality Improvement System

Background:Electronic health record (EHR) systems have the potential to revolutionize quality improvement (QI) methods by enhancing quality measurement and integrating multiple proven QI strategies. Objectives:To implement and evaluate a multifaceted QI intervention using EHR tools to improve quality measurement (including capture of contraindications and patient refusals), make point-of-care reminders more accurate, and provide more valid and responsive clinician feedback (including lists of patients not receiving essential medications) for 16 chronic disease and preventive service measures. Design:Time series analysis at a large internal medicine practice using a commercial EHR. Subjects:All adult patients eligible for each measure (range approximately 100–7500). Measures:The proportion of eligible patients who satisfied each measure after removing those with exceptions from the denominator. Results:During the year before the intervention, performance improved significantly for 8 measures. During the year after the intervention, performance improved significantly for 14 measures. For 9 measures, the primary outcome improved more rapidly during the intervention year than during the previous year (P < 0.001 for 8 measures, P = 0.02 for 1). Four other measures improved at rates that were not significantly different from the previous year. Improvements resulted from increases in patients receiving the service, documentation of exceptions, or a combination of both. For 5 drug-prescribing measures, more than half of physicians achieved 100% performance. Conclusions:Implementation of a multifaceted QI intervention using EHR tools to improve quality measurement and the accuracy and timeliness of clinician feedback improved performance and/or accelerated the rate of improvement for multiple measures simultaneously.

The polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors.

Polycomb group (PcG) proteins are overexpressed in several human malignancies including breast cancer. In particular, aberrant expression of BMI1 and EZH2 has been linked to metastasis and poor prognosis in cancer patients. At present, very little is known about the pharmacological inhibitors of PcG proteins. Here we show that histone deacetylase inhibitors (HDACi) downregulate expression of BMI1. Treatment of MCF10A cells, which are immortal non-transformed breast epithelial cells, and breast cancer cells with HDACi led to decreased expression of BMI1. We further show that downregulation of BMI1 by HDACi results due to the transcriptional downregulation of BMI1 gene. Specifically, we show that primary transcription and promoter activity of BMI1 is suppressed upon treatment with HDACi. Furthermore, downregulation of BMI1 was accompanied by a decrease in histone 2A lysine 119 ubiquitination (H2AK119Ub), which is catalyzed by BMI1 containing polycomb repressive complex 1. HDACi treatment also led to derepression of growth inhibitory genes and putative tumor suppressors, which are known to be silenced by PcG proteins and polycomb repressive complexes (PRCs). In summary, our findings suggest that BMI1 is an important therapy target of HDACi, and that HDACi can be used alone or in combination with other therapies to inhibit growth of tumors that overexpress PcG proteins such as BMI1.

The spectrum of vascular lesions in the mammary skin, including angiosarcoma, after breast conservation treatment for breast cancer

BACKGROUND With the general acceptance of lumpectomy, axillary staging, and radiotherapy as local treatment for infiltrating breast cancer, an appreciation is evolving for the spectrum of vascular lesions that occur in the mammary skin after this treatment. Most of these lesions develop within the prior radiation field after breast conservation treatment. STUDY DESIGN A retrospective chart and slide review was conducted, consisting of five patients with cutaneous vascular lesions after breast conservation treatment for infiltrating breast cancer. RESULTS The latent time interval from definitive treatment of breast cancer to the clinical recognition of vascular lesions ranged from 5 to 11 years. Two patients did not have either arm or breast edema, two patients had breast edema, and the fifth patient had arm edema. Lesions arising in the irradiated mammary skin included extensive lymphangiectasia (one), atypical vascular lesions (two), and cutaneous angiosarcoma (four). CONCLUSIONS Atypical vascular lesions at the skin margins of mastectomy may be predictive of recurrence after resection of angiosarcoma. Excision of skin from the entire radiation field may be necessary to secure local control of the chest wall in patients with cutaneous angiosarcoma after therapeutic breast radiotherapy.

Parietal pleurectomy for malignant pleural effusion

AbstractBackground: Malignant pleural effusions are seen frequently in clinical practice and are most commonly caused by breast cancer and lung cancer. Standard treatment usually consists of complete drainage of the pleural space via a chest tube and instillation of a pleural irritant to obtain pleural symphysis. In a majority of instances, such treatment effectively controls the pleural space; however, standard treatment fails in some cases. Methods: Twenty-four patients who did not respond to standard treatment for malignant pleural effusion were subjects for parietal pleurectomy, which was usually performed through an axillary thoracotomy. In several cases, decortication was also necessary. The study population was composed of 18 women and six men. Twelve of the patients had carcinoma of the breast, five carcinoma of the lung, and four carcinoma of the ovary. Results: Three patients died in the perioperative period to give an operative mortality of 12.5%. The other 21 patients all had satisfactory control of their recurrent malignant effusions. Their survival time ranged from 2 to 30 months (average 10.6). Conclusions: Parietal pleurectomy is an effective operation for recurrent malignant pleural effusion. However, because of its significant morbidity and mortality, it should be reserved for failures of standard treatment, and patient selection is important.

A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain

PURPOSE This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%. METHODS AND MATERIALS In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). CONCLUSIONS (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death

BACKGROUND Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. OBJECTIVE To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. DESIGN, SETTING, AND PARTICIPANTS A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Mutation carrier rates and their effect on lethal PCa were analyzed using the Fishers exact test and Cox regression analysis, respectively. RESULTS AND LIMITATIONS The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed. CONCLUSIONS Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. PATIENT SUMMARY Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.