Comparison of gene expression patterns across 12 tumor types identifies a cancer supercluster characterized by TP53 mutations and cell cycle defects.

Transcriptional profile-based subtypes of cancer are often viewed as identifying different diseases from the same tissue origin. Understanding the mechanisms driving the subtypes may be key in development of novel therapeutics but is challenged by lineage-specific expression signals. Using a t-test statistics approach, we compared gene expression subtypes across 12 tumor types, which identified eight transcriptional superclusters characterized by commonly activated disease pathways and similarities in gene expression. One of the largest superclusters was determined by the upregulation of a proliferation signature, significant enrichment in TP53 mutations, genomic loss of CDKN2A (p16(ARF)), evidence of increased numbers of DNA double strand breaks and high expression of cyclin B1 protein. These correlations suggested that abrogation of the P53-mediated apoptosis response to DNA damage results in activation of cell cycle pathways and represents a common theme in cancer. A second consistent pattern, observed in 9 of 11 solid tumor types, was a subtype related to an activated tumor-associated stroma. The similarity in transcriptional footprints across cancers suggested that tumor subtypes are commonly unified by a limited number of molecular themes.

Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Chemotherapy-induced peripheral neuropathy is frequently a dose-limiting factor in cancer treatment and may cause pain and irreversible function loss in cancer survivors. We tested whether alpha-lipoic acid (ALA) could decrease the severity of peripheral neuropathy symptoms in patients undergoing platinum-based chemotherapy. METHODS: Cancer patients 18 years or older were randomly selected to receive either 600 mg ALA or a placebo three times a day orally for 24 weeks while receiving chemotherapy regimens including cisplatin or oxaliplatin. Neuropathy was measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) scale and the NCI Common Toxicity Criteria for Adverse Events neurotoxicity grades. Results from timed functional tests and the Brief Pain Inventory (BPI) were secondary endpoints. RESULTS: Seventy of 243 (29 %) patients completed the study (24 weeks). Both the ALA and the placebo arms had a comparable drop-out rate. No statistically significant differences were found between the ALA and the placebo groups for FACT/GOG-Ntx scores, BPI scores, and patients' functional outcomes. CONCLUSION: This strategy of oral ALA administration was ineffective at preventing neurotoxicity caused by oxaliplatin or cisplatin. High attrition rates due to poor patient compliance and manner of dosage administration in this trial demonstrated a lack of feasibility for this intervention. Future studies to explore ALA as a neuroprotective agent should take heed of the barriers confronted in this study.

Cauda equina compression in breast cancer--incidence and treatment outcome.

PURPOSE: To determine the incidence and treatment outcome of compression of the cauda equina by metastatic disease in patients with breast cancer. METHODS: A retrospective study of individuals diagnosed with breast cancer at a single institution during a 16-year period was undertaken. RESULTS: Of the 1,283 patients studied, 15 (1.2%) developed cauda equina syndrome from metastatic disease. The median survival was eight months; ten (67%) survived for at least six months. Among the evaluable patients, pain was completely relieved in eight of ten women; complete resolution of neurologic deficits was observed in five of nine patients. CONCLUSION: Metastatic breast cancer compression of the cauda equina and long-term survival of patients are infrequent occurrences. Beneficial responses can be mediated by radiotherapy.

Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study.

A phase II trial of gemcitabine (Gemzar), a nucleoside analogue with broad activity in solid tumors, was performed in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. A total of 26 eligible patients were registered to receive a dose of 1250 mg/m2 weekly for 3 weeks, followed by a 1 week rest. Toxicity was evaluable in 26 patients. Nausea and vomiting occured in 11 and 6 patients, repectively. Grade 3 or 4 hematologic toxicities were infrequent. Two patients developed neutropenic infections. One patient developed fatal liver failure which was thought due to progressive liver metastases or infection 14 days after a single dose of gemcitabine. There were no objective treatment responses (95% CI 0-13%), with a median survival of 6 months in this highly resistant disease population. Gemcitabine is not considered active enough as monotherapy for further evaluation in this disease population.

A phase II trial of estramustine and etoposide in hormone refractory prostate cancer: A Southwest Oncology Group trial (SWOG 9407).

BACKGROUND: The combination of oral estramustine and oral etoposide has generated response rates of 40-50% in patients with hormone refractory prostate cancer in single institution trials. This study tested this regimen in a multi-institutional setting. METHODS: Fifty-five patients were accrued over a period of 4 months between 1 March 1996 and 1 July 1996. Two patients were not analyzable and two patients were ineligible. They were given an oral regimen consisting of estramustine 15 mg/kg/day (capped at 1120 mg per day) and etoposide 50 mg/M(2)/day, days 1-21 every 28 days. Patients received a median of two cycles of therapy. RESULTS: Toxicities included 11 patients (20%) with grades 3 or 4 granulocytopenia, 5 patients (10%) with grades 3 or 4 edema, and 3 patients (6%) with a thrombotic event. There were two treatment-related deaths, one as a result of anemia and the other as a result of a myocardial infarction. Of the 32 men who received at least 2 cycles of therapy, 7 men (22%) demonstrated a partial response to this regimen as measured by prostate-specific antigen (PSA) criteria of a 50% decline from pretreatment values. CONCLUSIONS: This trial demonstrates the toxicity of estramustine delivered in high dose. It also illustrates the difficulty of conducting phase II trials in prostate cancer in the cooperative group setting where the experience and comfort level of oncologists with new agents is less than that of the physicians at the institution where the therapy was developed. As the activity of this regimen with low-dose estramustine is defined, further multi-institutional studies may be warranted.

Radical combined treatment of locally extensive head and neck cancer in the elderly.

PURPOSE: Few studies have described the effects of aggressive combined therapy for locally extensive head and neck cancer in the elderly. Our study evaluated the outcome of this particular cohort of patients after such treatments. METHODS: Survival, failure, morbidity, and complication rates were determined retrospectively in 43 elderly patients with stage III or IV head and neck cancer who underwent curative surgery and postoperative radiotherapy (n = 33) or neoadjuvant, 3-drug chemotherapy plus radiotherapy (n = 10) between the years 1977 and 1992. RESULTS: The crude survival rate at 3 years was 27% in patients managed by surgery plus radiotherapy, and 30% in individuals treated with chemoradiation; the corresponding locoregional failure rates were 23% and 30%; and the distant failure rates were 13% and 0%, respectively. The acute toxicity rate was 12% in the surgery plus radiotherapy group and 30% in the chemoradiation patients; the corresponding late complication rates were 0% and 10%. There were no toxic deaths. CONCLUSION: Radical combined treatments can be performed safely and achieve long-term, disease-free survival in selected elderly patients with locally extensive head and neck cancer.

Infusional CHOP chemotherapy (CVAD) with or without chemosensitizers offers no advantage over standard CHOP therapy in the treatment of lymphoma: a Southwest Oncology Group Study.

PURPOSE: Two phase II studies were conducted to evaluate infusional cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy, termed the CVAD regimen, alone (Southwest Oncology Group [SWOG] 9240) and with the chemosensitizers verapamil and quinine (SWOG 9125) to assess effects on response, survival, and toxicity in intermediate- and high-grade advanced-stage non-Hodgkin's lymphoma (NHL). The results were compared with the historic group of patients randomized to CHOP chemotherapy on Intergroup (INT) 0067 (SWOG 8516). PATIENTS AND METHODS: All patients had biopsy-proven intermediate- or high-grade NHL (lymphoblastic histology excluded), were ambulatory and previously untreated, and had bulky stage II, III, or IV disease. One hundred twelve patients were registered on SWOG 9240 and received cyclophosphamide 750 mg/m(2) by intravenous bolus day 1, doxorubicin 12.5 mg/m(2)/d and vincristine 0.5 mg/d delivered as a continuous 96-hour infusion on days 1 through 4, and dexamethasone 40 mg/d orally on days 1 through 4 (CVAD). Cycles were repeated every 21 days for eight cycles. One hundred patients on SWOG 9125 received the same chemotherapy and the chemosensitizers verapamil 240 mg bid and quinine 40 mg tid. Chemosensitizers were begun 24 hours before chemotherapy and continued for a total of 6 days. RESULTS: Eighty-one patients were eligible for each study. The complete response (CR) rates were 39% on SWOG 9125 and 31% on SWOG 9240. With a median follow-up of 5.8 years on SWOG 9125 and 4.5 years on SWOG 9240, the 2-year failure-free survival (FFS) rate was 42% on SWOG 9125 and 41% on SWOG 9240. Two-year overall survival (OS) rate was 64% on SWOG 9125 and 58% on SWOG 9240. These results are comparable to a 44% CR rate, a 2-year FFS of 46%, and 2-year OS of 63% observed in 225 patients treated with CHOP on INT 0067 (SWOG 8516). CONCLUSION: CVAD combination chemotherapy alone or with the chemosensitizers verapamil and quinine is not promising therapy with respect to improved response or OS in intermediate- and high-grade advanced-stage NHL.

Cranial irradiation in patients with brain metastasis: a retrospective study of timing.

PURPOSE: A retrospective study was conducted to determine the importance of the interval between diagnosis of brain metastasis (BRM) and cranial irradiation (CI). METHODS: The charts of 92 patients with a known diagnosis of cancer and suspected BRM as shown on radioimaging studies were reviewed retrospectively. The median interval between diagnosis and the onset of CI for BRM was five days; one group of 48 individuals received CI within an interval of five days, and another group of 44 patients after an interval of five days. Symptom palliation, objective responses to CI and survival were evaluated in both groups. RESULTS: Neither symptomatic and objective responses to treatment nor overall survival differed significantly between the patient groups. CONCLUSION: These observations suggest that while CI is beneficial to most patients with BRM, its timing after the diagnosis of BRM may not seriously affect patient outcome.

Radiotherapy with and without chemotherapy after breast conservation surgery for early stage breast cancer: a review of timing.

PURPOSE: To evaluate the effects in women of the timing of breast irradiation (BI) in relation to the application or non-application of adjuvant chemotherapy after breast conservation surgery (BCS) for early stage cancer. METHODS: Between October 1981 and June 1995, 47 women with stage I and II breast cancer underwent BCS. Twenty-six patients did not receive adjuvant chemotherapy (NAC) and 21 women did (AC). In the NAC group, BI commenced within (n = 9) or after (n = 17) seven weeks following BCS; in the AC group, 18 women received BI more than 24 weeks after BCS and three patients within 24 weeks. RESULTS: In the NAC group, there was a trend toward more local and systemic failures plus a definite correlation with poorer survival (p = 0.05) when BI was initiated more than 7 weeks after BCS. In the AC group, the locoregional and systemic failures occurred only in women with a delay of BI exceeding 24 weeks; survival was not different between the subgroups. CONCLUSION: An undue delay of BI should be avoided in patients after BCS whether they require adjuvant chemotherapy for early stage breast cancer or not.

Multiple myeloma metastatic to the thigh: successful treatment with radiation therapy.

A 64-year-old man with metastatic multiple myeloma in the thigh was treated with radiation therapy. After a total dose of 30 Gy/10 fractions, significant resolution of the tumor in the thigh was observed. This case confirms the accepted dictum that multiple myeloma is a radioresponsive neoplastic disorder.

Neoadjuvant chemotherapy and radiotherapy for inoperable head and neck cancer: the LSU-Shreveport experience.

A retrospective review of 8 years of treatment in 2 hospitals in Shreveport showed that neoadjuvant chemotherapy with radiotherapy was performed in 39 patients with inoperable, locally advanced head and neck cancer. Twenty-two individuals treated by definitive radiotherapy alone served as historical controls. The cumulative survival rate at 4 years was 34% in patients managed by neoadjuvant chemotherapy with radiotherapy and 7% in patients treated by radiotherapy only. With the exception of greater acute toxicity seen in patients receiving neoadjuvant chemotherapy with radiotherapy, differences in locoregional failure, distant metastasis, and late complication rates were not observed between the patient groups.

Functional LCK Is required for optimal CD28-mediated activation of the TEC family tyrosine kinase EMT/ITK.

Activation of CD28 on T lymphocytes initiates a cascade of intracellular events, which in concert with activation of the T cell receptor, culminates in production of cytokines and a functional immune response. One of the earliest biochemical changes observed following stimulation of CD28 is tyrosine phosphorylation. We have demonstrated that both the LCK and the EMT/ITK/TSK (EMT) intracellular tyrosine kinases are activated following cross-linking of CD28. Utilizing somatic cell mutants lacking LCK, we demonstrate that functional LCK is required for CD28-induced activation of EMT as evidenced by increased tyrosine phosphorylation and kinase activity. In support of a role for LCK in EMT activation, reconstitution of a LCK-negative Jurkat T cell line by transfection with normal LCK recreates CD28-mediated EMT activation. Furthermore, co-transfection of LCK and EMT into COS-7 cells showed that EMT becomes phosphorylated in the presence of LCK. In addition, increases in EMT association with CD28 were eliminated in a LCK-negative Jurkat cell line, but were restored following transfection of wild type LCK. The data are most compatible with a model in which LCK, either directly or indirectly, initiates EMT activation and association with CD28 following ligation of CD28.

Solitary plasmacytoma of the sacrum presenting as a pelvic mass: report of two cases.

We describe two unusual cases of solitary plasmacytoma of the sacrum seen as a pelvic mass. Excessive bleeding, a distinct possibility, should be anticipated whenever a biopsy or resection of the tumor is considered. Because of the tumor's apparent radioresponsiveness and known evolution to multiple myeloma in some cases, radiotherapy and chemotherapy are recommended.

Long-term survival in small cell lung cancer with superior vena caval obstruction.

Two patients were diagnosed with small cell lung cancer and superior vena caval obstruction. Successful palliation of symptoms with significant reduction in size of the intrathoracic lesion was achieved with radiation therapy and chemotherapy. Treatment resulted in complete remission with long-term (more than 3 years) survival. These two cases affirm the fact that, despite the generally recognized poor prognosis of small cell lung cancer associated with this syndrome, aggressive therapy can sometimes provide rewarding results.

Heparin-induced thrombotic thrombocytopenia.

OBJECTIVE: To report a case of heparin-induced thrombotic thrombocytopenia (HITTS) and discuss the incidence, possible mechanisms, complications, and treatment for this syndrome. DATA SOURCES: Case reports and review articles identified by MEDLINE from 1980 through 1991. Older articles located by manual searches. DATA EXTRACTION: Data were extracted and reviewed from published sources. Cases were selected on the basis of case presentation, time of disease onset, pathophysiology of disease, and therapeutic options. SETTING: A 600-bed university teaching hospital and an affiliated community hospital. PATIENT: A 36-year-old woman with insulin-dependent diabetes mellitus, sepsis, adult respiratory distress syndrome, diabetic ketoacidosis, oliguric renal failure developed HITTS and subsequent gangrene of her right arm. INTERVENTION: Immediate cessation of all heparin use and amputation of the patient's right arm. RESULTS: The patient's condition improved progressively over the following 60 days and she was discharged to outpatient care. CONCLUSIONS: Heparin has been associated with thrombocytopenia and thrombotic events. Laboratory tests for HITTS are unreliable and the diagnosis is usually suspected by the clinical presentation of the patient. Platelet counts should be monitored closely during heparin use. In the event of a marked decrease in platelet count associated with venous or arterial thrombosis, heparin therapy should be stopped immediately. If further anticoagulation is necessary, oral anticoagulants such as warfarin may be used instead. As the onset of warfarin may take several days to become therapeutic, aspirin, dipyridamole, or both may be used effectively. Healthcare workers should be aware that in these patients, the use of even small amounts of heparin can produce catastrophic results.

Ischiogluteal bursitis in cancer patients: an infrequently recognized cause of pain.

We report eight patients with metastatic malignancy who developed severe back and leg pain caused by ischiogluteal bursitis. Careful evaluation excluded the possibility of bony metastases. Ischiogluteal bursitis is an easily diagnosed condition that can be effectively treated with local injection of corticosteroids. Recognition of this disorder will allow prompt therapy and unnecessary evaluation expenses.