Head and neck cancer associated with herpes simplex virus 1 and 2 and other risk factors

We investigated whether herpes simplex viruses, HSV-1 and HSV-2, are cofactors of head and neck cancer (HNC) in association with tobacco, alcohol, or HPV-16 infection. The study included 164 HNC cases and 295 controls. Serologic tests were used to distinguish HSV-1 and HSV-2. Antibodies to anti-VLP HPV-16 and HPV-16 E6 and E7 were evaluated by ELISA. After adjusting for age, tobacco, alcohol use, and number of sexual partners, risk of cancer was not significantly increased in those with HSV-1 [adjusted odds ratio (OR)=0.7] or HSV-2 (OR=0.8) compared to HSV-negative patients. Although heavy use of tobacco, alcohol and HPV-16 infection was associated with an increased risk of HNC, the adjusted risk among those infected with HSV-1 or HSV-2 lowered the odds compared to those who were not infected. Heavy smokers (OR=1.7) and heavy drinkers infected with HSV-1 (OR=4.2) or HSV-2 (smokers: OR=1.6; drinkers: OR=3.2) had lower odds compared to seronegative HSV-1 heavy users (smokers: OR=2.5; drinkers: OR=5.5) or HSV-2 (smokers: OR=1.9; drinkers: OR=6.2). Those seropositive to HPV-16 E6 and/or E7 but not HSV-1 (OR=27.4) or HSV-2 (OR=18.0) had higher risk of HNC compared to those infected with HSV-1 (OR=16.7) or HSV-2 (not estimable). These findings suggest that seropositivity to HSV-1 and HSV-2, although not independent risk factors for HNC, may modify the risk of HNC associated with exposure to tobacco, alcohol, or HPV-HR.     

European Organization for Research and Treatment of Cancer and Groupe d'Etude des Lymphomes de l'Adulte very favorable and favorable, lymphocyte-predominant Hodgkin disease

BACKGROUND: Lymphocyte-predominant Hodgkin disease (LPHD) is rare and has a natural history different from that of classic Hodgkin disease. There is little information in the literature regarding the role of chemotherapy in patients with early-stage LPHD. The objective of this study was to examine recurrence free survival (RFS), overall survival (OS), and patterns of first recurrence in patients with LPHD who were treated with radiotherapy alone or with chemotherapy followed by radiotherapy. METHODS: From 1963 to 1996, 48 consecutive patients ages 16-49 years (median, 28 years) with Ann Arbor Stage I (n = 30 patients) or Stage II (n = 18 patients), very favorable (VF; n = 5 patients) or favorable (F; n = 43 patients) LPHD, according to the European Organization for Research and Treatment of Cancer and Groupe d'Etude des Lymphomes de l'Adulte (EORTC-GELA) criteria, received radiotherapy alone (n = 37 patients) or received chemotherapy followed by radiotherapy (n = 11 patients). The percentages of patients with VF disease (11% vs. 9% in the radiotherapy group vs. the chemotherapy plus radiotherapy group, respectively) or F disease (89% vs. 91%, respectively) within the two treatment groups were similar (P = 1.00). A median of three cycles of chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or with mitoxantrone, vincristine, vinblastine, and prednisone (NOVP) was given initially to six patients and five patients, respectively. A median total radiotherapy dose of 40 grays (Gy) given in daily fractions of 2.0 Gy was delivered to both treatment groups. RESULTS: The median follow-up was 9.3 years, and 98% of patients were observed for > or = 3.0 years. RFS was similar for patients who were treated with radiotherapy alone and patients who were treated with chemotherapy followed by radiotherapy (10-year survival rates: 77% and 68%, respectively; P = 0.89). The OS rate also was similar for the two groups (10-year survival rates: 90% and 100%, respectively; P = 0.43). MOPP or NOVP chemotherapy did not reduce the risk of recurrence outside of the radiotherapy fields. CONCLUSIONS: MOPP or NOVP chemotherapy did not improve RFS or OS significantly in patients with VF or F LPHD, although the statistical power was limited. Ongoing clinical trials will help to clarify the role of a watch-and-wait strategy or systemic therapy, including anthracycline (epirubicin or doxorubicin), bleomycin, and vinblastine-based chemotherapy or antibody-based approaches, in the treatment of these patients.     

Multimodality treatment and two-stage resection for unresectable hepatocellular carcinoma--experimental and clinical studies

During the period 1978-1987, 255 patients with pathologically proven hepatocellular carcinoma (HCC) were assessed to be unresectable by laparotomy. Of them 155 had their tumors chiefly confined in the right or left lobe. Second stage resection was performed in 26 (16.8%) after marked reduction of the tumor by combination treatment with hepatic artery ligation (HAL) + hepatic artery infusion chemotherapy (HAI) + multifractionated radiotherapy (MFD) with linear accelerator, or radioimmunotherapy using 131I-anti human HCC ferritin antibody (131I-FtAb), which yielded the highest second stage resection rate (29.8%, 14/47) as compared to HAL + HAI or HAL + cryosurgery (16.9%, 12/71), HAL or HAI (0%, 0/37) alone. The 3 year survival rate of the 26 patients with second stage resection was 74.3%, comparable with those of small HCC resection (82.7%, n = 111) and radical resection of large HCC (56.1%, n = 122) in the same period. Experimental study using nude mice bearing human HCC also showed the superiority of triple (MFD or 131I-FtAb + Cisplatin PDD + mixed bacterial vaccine MBV) versus double (MFD or 131I-FtAb + PDD, or MFD or 131I-FtAb + MBV) and double versus single treatment modality. Both experimental and clinical data indicated that immunosuppression after radiotherapy was prevented by adjuvant immunotherapy (MBV). Thus, this treatment model provides an opportunity for resection or even cure in a part of patients with unresectable HCC confined in one lobe.     

TLD skin dose measurements and acute and late effects after lumpectomy and high-dose-rate brachytherapy only for early breast cancer

PURPOSE: This report examines the relationships between measured skin doses and the acute and late skin and soft tissue changes in a pilot study of lumpectomy and high-dose-rate brachytherapy only for breast cancer. METHODS AND MATERIALS: Thirty-seven of 39 women enrolled in this pilot study of high-dose-rate brachytherapy (37.2 Gy in 10 fractions b.i.d.) each had thermoluminescent dosimetry (TLD) at 5 points on the skin of the breast overlying the implant volume. Skin changes at TLD dose points and fibrosis at the lumpectomy site were documented every 6 to 12 months posttreatment using a standardized physician-rated cosmesis questionnaire. The relationships between TLD dose and acute skin reaction, pigmentation, or telangiectasia at 5 years were analyzed using the GEE algorithm and the GENMOD procedure in the SAS statistical package. Fisher's exact test was used to determine whether there were any significant associations between acute skin reaction and late pigmentation or telangiectasia or between the volumes encompassed by various isodoses and fibrosis or fat necrosis. RESULTS: The median TLD dose per fraction (185 dose points) multiplied by 10 was 9.2 Gy. In all 37 patients, acute skin reaction Grade 1 or higher was observed at 5.9% (6 of 102) of dose points receiving 10 Gy or less vs. 44.6% (37 of 83) of dose points receiving more than 10 Gy (p < 0.0001). In 25 patients at 60 months, 1.5% telangiectasia was seen at dose points receiving 10 Gy or less (1 of 69) vs. 18% (10 of 56) telangiectasia at dose points receiving more than 10 Gy (p = 0.004). Grade 1 or more pigmentation developed at 1.5% (1 of 69) of dose points receiving less than 10 Gy vs. 25% (14 of 56) of dose points receiving more than 10 Gy (p < 0.001). A Grade 1 or more acute skin reaction was also significantly associated with development of Grade 1 or more pigmentation or telangiectasia at 60 months. This association was most significant for acute reaction and telangiectasia directly over the lumpectomy site (p < 0.001). Grade 1 or more fibrosis, in 25 patients with a 60-month follow-up, occurred in 47.4% (9 of 19) of patients with a volume of 45 cm3 or less covered by the 100% isodose vs. 83.3% (5 of 6) of patients with a larger volume (p = 0.180). Asymptomatic and biopsy-proven fat necrosis occurred in 5 patients. No significant differences in fat necrosis rates according to volume were detected. CONCLUSIONS: For high-dose-rate brachytherapy to the lumpectomy site, TLD skin dose was significantly related to acute skin reaction and to pigmentation and telangiectasia at 60 months. An acute skin reaction was also significantly associated with the development of telangiectasia at 60 months. TLD skin dose measurement may allow modification of the brachytherapy implant geometry (dwell times and position) to minimize late skin toxicity.     

Expression of CDX2 and Hepatocyte Antigen in Benign and Malignant Lesions of Gallbladder and Its Correlation with Histopathologic Type and Clinical Outcome

Recent studies have shown that both CDX2 and Hepatocyte antigen (Hep) are detected in different types of cancer and associated with clinical prognosis. However, fever studies have examined gallbladder cancer specimens, and little is known about the clinicopathological significance of both CDX2 and Hep expression in gallbladder adenocarcinomas. In present study, we examined the expression frequencies of CDX2 and Hepatocyte antigen (Hep), and explored their clinicopathologic significances in gallbladder adenocarcinoma. Immunohistochemistry was used to detect and compare the frequencies of CDX2 and Hep expression in 108 samples of gallbladder adenocarcinoma, 46 peri-tumor tissues and 35 chronic cholecystitis. The expression frequencies for CDX2 and Hep were 49/108 (45.4%) and 45/108 (41.7%) in gallbladder carcinoma; 13/46 (28.3%) and 11/46 (23.9) in peri-tumor tissues; 5/35 (14.3%) and 2/35 (5.7%) in chronic cholecystitis. The positive staining of CDX2 or Hep in gallbladder adenocarcinoma was significantly higher than that in peritumoral tissues (both, P?相似文献   

Medical history and risk of Hodgkin's and non-Hodgkin's lymphomas.

The relationship between a history of selected medical conditions and risk of lymphomas was investigated in a hospital-based case-control study conducted in Northern Italy on 429 incident, histologically confirmed cases of non-Hodgkin's lymphoma (NHL), 158 cases of Hodgkin's disease (HD) and 1157 controls admitted to hospitals for acute conditions. The odds ratios (OR) for NHL were above unity in patients with a history of infectious mononucleosis (OR 2.9), herpes zoster (OR 1.8), pyelonephritis (OR 4.9), tuberculosis (OR 1.8), malaria (OR 1.9), any chronic bacterial diseases (OR 1.7), rheumatoid arthritis (OR 1.7) and psoriasis (OR 2.5). With reference to HD, the ORs were 4.0 for infectious mononucleosis, 2.9 for herpes zoster, 3.3 for pyelonephritis, 2.3 for tuberculosis, 1.4 for chronic bacterial diseases, 2.4 for rheumatoid arthritis, 2.7 for psoriasis and 2.1 for diabetes. The association of NHL and HD with herpes zoster was restricted to the first ten years since the onset of the disease. The relationships between NHL and mononucleosis (OR 12.9), malaria (OR 2.8) and psoriasis (OR 14.0) were stronger for cases aged > or = 60 years, and that with tuberculosis (OR 3.5) was stronger for younger cases. For HD, the positive association was stronger for cases aged > or = 40 years for herpes zoster (OR 3.8) and diabetes (OR 2.6). An increased risk of NHL was found in association with poliomyelitis (OR 1.6) (restricted to cases aged > or = 60 years, OR 4.0) and BCG immunizations (OR 1.6), but not with vaccination against smallpox, tetanus and diphtheria; increased risks of HD were found in relation to poliomyelitis and BCG immunization in cases aged > or = 40 years (OR respectively 2.5 and 2.1), or > or = 50 years (OR 4.3 and 2.2). Thus, our results confirm the association between a history of several chronic infectious and inflammatory diseases and the risk of NHL or HD, and are compatible with a role of chronic immunological alterations in the aetiology of lymphomas.     

Chromosome abnormalities and karyotypic evolution in 83 patients with myelodysplastic syndrome and predictive value for prognosis

In a chromosome study of 83 patients with myelodysplastic syndrome (MDS), 50 showed a clonally abnormal karyotype. The most frequent abnormalities were the whole or a partial loss of the long arm of chromosome 7 (-7 or 7q-) (14 patients) and a partial loss of the long arm of chromosome 5 (5q-) (11 patients). Twenty patients with 5q- and/or -7 or 7q- had a shorter survival (median, 5 months) than those with other abnormal karyotypes (22 months) or those with a normal karyotype (28 months). In this series 30 patients were examined cytogenetically on two or more occasions during the course of their illness. Ten patients showed a further karyotypic alteration from the initial findings, and, concomitantly, their disease progressed in severity including overt leukemia. These patients had a shorter survival (median, 2 months) after the chromosome reanalysis than the other 20 patients who did not have further karyotypic changes (21 months). Thus, the prognosis of patients with MDS can be predicted more accurately by reanalyzing the chromosomes after the initial analysis.     

Modulator activity of PSC 833 and cyclosporin-A in vincristine and doxorubicin-selected multidrug resistant murine leukemic cells

Multidrug resistance (MDR) lines from a murine T-cell leukemia were selected in increasing vincristine (VCR) or doxorubicin (DOX) concentrations. Daunorubicin (DNR) efflux was evidenced after 25 additional passages with constant 160 ng ml(-1) of either VCR or DOX, an effect that was inhibited by verapamil, cyclosporin-A (CsA) and PSC 833. The expression of Pgp was not evidenced in the resistant cell lines using anti-human Pgp antibodies. Cell proliferation assay showed that cell lines resistant to VCR (LBR-V160) or DOX (LBR-D160) required higher doses of either drug to produce GI50 compared with control cell line obtained after culture in the absence of VCR or DOX. When resistant cell lines were maintained during 60 days in the absence of either VCR or DOX, MDR phenotype reversal was obtained in LBR-D160 while LBR-V160 remained resistant to the drug, as shown by cell proliferation assays and by drug efflux pump functionality. When VCR or DOX were used together with either CsA or PSC 833, the latter was more effective to produce reversal of resistance than the former, whereas CsA presented greater cytotoxic effect than PSC 833 for sensitive and resistant cells. Cross-resistance was found between VCR, DOX and other antineoplasic agents on murine leukemic cell line. VCR was more effective to induce MDR since the resistant cell lines were more stable to the MDR phenotype.     

Prevention and therapy for BRCA1/2 mutation carriers and women at high risk for breast and ovarian cancer.

The hereditary breast (BC) and ovarian (OC) cancer syndrome (HBOC) includes genetic alterations of various susceptibility genes such as TP53, ATM, PTEN or MSH2, MLH1, PMS1, PMS2, MSH3 and MSH6, BRCA1 and BRCA2. Germline mutations of the cancer-susceptibility genes BRCA1 and BRCA2 seem to be the major aetiology of the HBOC. Genetic counselling and identification of high-risk families may be essential (1) to provide the best method for genetic testing by explaining the sensitivity and specificity of the methods, (2) to offer the opportunity to participate in specific early cancer detection programmes (breast (self) palpation, ultrasound, mammography and magnetic resonance tomography for breast cancer; vaginal exploration and ultrasound for ovarian cancer), (3) to inform them about prophylactic medication (oral contraceptive pill (OCP), chemoprevention (tamoxifen, raloxifen, aromatase inhibitors)) or surgery (bilateral prophylactic mastectomy or oophorectomy) and (4) to provide individualized psychological support. To fulfil these broad demands, an inter-disciplinary counselling approach (gynaecological oncology, human genetics, molecular biology, psychotherapy) in the setting of a cancer genetic clinic seems the most appropriate. There, participation in predictive genetic testing or the use of preventive or therapeutic options may be discussed extensively with the subjects. In particular, preventive options are emotionally disturbing for the subjects, and in cases of previous cancer. BC chemoprevention for high-risk women does not seem to be as effective as expected. However, OCP reduces the risk for OC. For prophylactic surgery, various points have to be considered, including: (1) individual risk assessment and gain in life expectancy, (2) value of screening and early detection methods or medical prevention, (3) disease characteristics and prognosis, and (4) anxiety and quality of life. Decisions regarding these options have to be individualized and psychological support must be offered during the period of decision and follow-up.     

2-[(18)F]Fluoro-2-deoxyglucose and glucose uptake in malignant gliomas before and after radiotherapy: correlation with outcome.

PURPOSE: To examine whether quantitative 1-[(11)C]glucose- or 2-[(18)F]fluoro-2-deoxyglucose (FDG)-positron emission tomography performed before and/or after radiotherapy (RT) of malignant gliomas correlates with treatment outcome. Changes in metabolism between the start and finish of RT, and immediate post-RT studies have received little attention. EXPERIMENTAL DESIGN: Adults with malignant gliomas were imaged within 2 weeks before and/or 2 weeks after RT. Four patients were imaged only before RT, 12 only after RT, and 14 both before and after RT. Each 1-[(11)C]glucose and FDG study included arterial plasma sampling. Kinetic parameters, glucose metabolic rate (MRGlc), and FDG metabolic rate (MRFDG) were estimated by an optimization program based on a three compartment, four rate constant model. Changes in MRGlc or MRFDG from pre-RT to post-RT were calculated for the 14 patients studied at both times. Overall survival was examined, and survival was computed relative to historical controls in matched prognostic classes. RESULTS: Low pre-RT MRGlc (P < 0.02) or MRFDG (P < 0.03), or an increase from pre- to post-RT in MRGlc (P < 0.004) or MRFDG (P < 0.006) are correlating with longer survival (4 patients still alive). Strikingly, the post-RT studies (n = 26) showed no correlation between MRGlc or MRFDG and survival (P = 0.73 and P = 0.46 respectively). CONCLUSIONS: Low MRGlc or MRFDG before RT probably indicates less aggressive disease. An increase in MRGlc or MRFDG from pre- to post-RT in the tumors of patients with longer survival could be because of one or more of the following or other reasons: (a) apoptosis of tumor cells in response to RT requires energy; (b) decreased tumor cell density by the RT leaving normal cells with higher metabolism; or (c) inflammatory cells infiltrate and take up glucose or FDG where tumor cells are dying. Quantitative 1-[(11)C]glucose or FDG uptake in the early weeks post-RT correlates poorly with survival.     

Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab

Background: The aim of this study was to compare the extent of pathologic response in patients with HER2-positive (HER2+) breast cancer treated with standard neoadjuvant chemotherapy, with or without trastuzumab (H), according to hormone receptor (HR) status.Patients and methods: We included 199 patients with HER2+ breast cancer from three successive cohorts of neo-adjuvant chemotherapy on the basis of paclitaxel (Taxol) (P) administered weekly (w) or three weekly (3-w), followed by 5-fluorouracil (F), doxorubicin (A) or epirubicin (E), and cyclophosphamide (C). Residual cancer burden (RCB) was determined from pathologic review of the primary tumor and lymph nodes and was classified as pathologic complete response (pCR) or minimal (RCB-I), moderate (RCB-II), or extensive (RCB-III) residual disease.Results: In HR-positive (HR+) cancers, a higher rate of pathologic response (pCR/RCB-I) was observed with concurrent H + 3-wP/FEC (73%) than with 3-wP/FEC (34%, P = 0.002) or wP/FAC (47%; P = 0.02) chemotherapy alone. In HR-negative (HR-) cancers, there were no significant differences in the rate of pathologic response (pCR/RCB-I) from 3-wP/FAC (50%), wP/FAC (68%), or concurrent H + 3-wP/FEC (72%).Conclusions: Patients with HR+/HER2+ breast cancer obtained significant benefit from addition of trastuzumab to P/FEC chemotherapy; pathologic response rate was similar to that seen in HR-/HER2+ breast cancers.     

Aspirin and nonsteroidal anti-inflammatory drug use and risk of pancreatic cancer: a meta-analysis.

BACKGROUND: The association between use of nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, and risk of pancreatic cancer is controversial. We did a meta-analysis to summarize available evidence from epidemiologic studies investigating the relation between use of aspirin or other NSAIDs and the risk of pancreatic cancer. METHODS: We identified potential studies by searching the MEDLINE database (from 1966 to October 2006) and by reviewing the reference lists of pertinent publications. Studies were eligible for inclusion if they met the following criteria: (a) had a case-control or prospective design, (b) examined exposure to aspirin or NSAIDs, (c) the outcome was pancreatic cancer incidence or mortality, and (d) they provided a relative risk (RR) estimate with corresponding confidence interval or sufficient information to permit their calculation. Study-specific RR estimates were pooled using a random effects model. RESULTS: A total of 11 studies (3 case-control studies, 7 cohort studies, and 1 randomized trial), involving 6,386 pancreatic cancer cases, was included in the meta-analysis. The summary RR estimate did not indicate any association between aspirin/NSAID use and risk of pancreatic cancer [any/regular use versus nonregular/never use: RR, 1.01; 95% confidence interval (95% CI), 0.91-1.11; P(heterogeneity) = 0.09]. Neither use of aspirin, nonaspirin NSAIDs, nor overall NSAIDs were associated with pancreatic cancer risk. There was also no overall association with frequent (six or more tablets/times per week versus none: RR, 0.86; 95% CI, 0.61-1.23) or long-term (>or=20 years) use of aspirin (RR, 1.21; 95% CI, 0.74-1.96). CONCLUSIONS: Current epidemiologic evidence does not indicate that use of aspirin or NSAIDs is associated with the risk of pancreatic cancer.     

EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups

BACKGROUND: Preclinical evidence suggests that retinoids and antioxidants may prevent or delay the occurrence of cancer in the upper or lower airways, but such effects have not been reliably established in clinical studies. To assess the chemopreventive effects of vitamin A (retinyl palmitate) and N-acetylcysteine, we conducted a large randomized intervention study in patients with head and neck cancer or with lung cancer, most of whom had a history of smoking. METHODS: From June 1988 through July 1994, a total of 2592 patients (60% with head and neck cancer and 40% with lung cancer) were randomly assigned to receive 1) retinyl palmitate (300000 IU daily for 1 year followed by 150000 IU for a 2(nd) year), 2) N-acetylcysteine (600 mg daily for 2 years), 3) both compounds, or 4) no intervention. All statistical tests were two-sided. RESULTS: Of the patients, 93.5% had smoked tobacco at sometime in their lives (and 25% continued to smoke after cancer diagnosis). After a median follow-up of 49 months, 916 patients were reported with an event (recurrence, second primary tumor, or death). No statistically significant difference was observed in overall survival or event-free survival between patients who received retinyl palmitate and patients who did not. Similarly, no difference was seen in overall survival or event-free survival between patients who received N-acetylcysteine and patients who did not. There was a lower incidence of second primary tumors in the no intervention arm, but the difference was not statistically significant. CONCLUSION: A 2-year supplementation of retinyl palmitate and/or N-acetylcysteine resulted in no benefit-in terms of survival, event-free survival, or second primary tumors-for patients with head and neck cancer or with lung cancer, most of whom were previous or current smokers.     

Enhanced detection and comprehensive in situ phenotypic characterization of circulating and disseminated heteroploid epithelial and glioma tumor cells

Conventional strategy of anti-EpCAM capture and immunostaining of cytokeratins (CKs) to detect circulating tumor cells (CTCs) is limited by highly heterogeneous and dynamic expression or absence of EpCAM and/or CKs in CTCs. In this study, a novel integrated cellular and molecular approach of subtraction enrichment (SE) and immunostaining-FISH (iFISH) was successfully developed. Both large or small size CTCs and circulating tumor microemboli (CTM) in various biofluid samples including cerebrospinal fluid (CSF) of cancer patients and patient-derived-xenograft (PDX) mouse models were efficiently enriched and comprehensively identified and characterized by SE-iFISH. Non-hematopoietic CTCs with heteroploid chromosome 8 were detected in 87–92% of lung, esophageal and gastric cancer patients. Characterization of CTCs performed by CK18-iFISH showed that CK18, the dual epithelial marker and tumor biomarker, was strong positive in only 14% of lung and 24% of esophageal CTCs, respectively. Unlike conventional methodologies restricted only to the large and/or both EpCAM and CK positive CTCs, SE-iFISH enables efficient enrichment and performing in situ phenotypic and karyotypic identification and characterization of the highly heterogeneous CTC subtypes classified by both chromosome ploidy and the expression of various tumor biomarkers. Each CTC subtype may possess distinct clinical significance relative to tumor metastasis, relapse, therapeutic drug sensitivity or resistance, etc.     

Anastrozole and letrozole: an investigation and comparison of quality of life and tolerability

Previous studies have demonstrated that both anastrozole and letrozole are well tolerated. Letrozole suppresses estrogen to a greater degree than anastrozole in the serum and breast tumor. Concerns have been raised that greater potency may adversely affect patients?? quality of life (QOL). One hundred eighty-one postmenopausal women with invasive estrogen receptor-positive breast cancers were randomized to receive either 12 weeks of letrozole followed by 12 weeks of anastrozole or the reverse sequence. One hundred and six received immediate adjuvant aromatase inhibitors (AIs) following surgery, and 75 received extended adjuvant therapy. The Functional Assessment of Cancer Therapy Endocrine Subscale (FACT-B-ES) QOL questionnaires were completed to assess QOL on each drug. Additional side-effect profiles were collected. Each patient completed a patient preference form. Twenty-one patients withdrew before study end, 10/179 (5.6%) while taking letrozole and 4/173 (2.3%) while taking anastrozole (P = 0.12). Tamoxifen-naïve patients had a higher mean ES (endocrine symptoms subscale) score at entry versus those having extended therapy (66.0 vs. 61.9; P = 0.001). There was no significant change in FACT-B-ES (overall) scores or ES scores while patients were taking anastrozole or letrozole and no significant differences between drugs. Nearly 80% of patients reported one or more side effects with either agent. No differences in frequency, grade, or range of side effects were seen between drugs. Of 160 patients, 49 (30.6%) preferred letrozole, 57 (35.6%) preferred anastrozole, and 54 (33.8%) had no preference (P = 0.26, Pearson??s Chi-squared test). In conclusion, both AIs are equally well tolerated. There were no significant differences in QOL scores between the two drugs.     

The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration: a randomized cross-over study.

In a randomized cross-over trial, 11 patients received ifosfamide (IFOS) in 21-day cycles, which alternated between 3 g m(-2) x (2 or 3) days given as a 1-h bolus doses, or the same total dose as a continuous infusion. Patients who received four or more cycles also alternated between two cycles on dexamethasone 4 mg 8 hourly for 3 days starting 8 h before IFOS, and two cycles off dexamethasone. A total of 34 patient cycles were studied and serum and urinary levels of IFOS, 2 dechloroethylifosfamide (2DC), 3 dechloroethylifosfamide (3DC), carboxyifosfamide (CX) and isophosphoramide mustard (IPM) were measured by thin-layer chromatography. No significant differences could be detected in the areas under the curve (AUCs) of serum concentration, nor in the proportion of IFOS or its metabolites found in the urine. There was no significant effect of dexamethasone on IFOS metabolism. These results indicate that there is no identifiable pharmacokinetic basis for insistence on either bolus or infusional methods of IFOS administration.     

Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia

One hundred five untreated adult patients with acute lymphocytic leukemia (ALL) were entered on the vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and Decadron (dexamethasone; Merck Sharp and Dohme, West Point, PA) (VAD) regimen. Induction therapy with VAD and VAD plus cyclophosphamide (CVAD) was followed by a 2-year rotating maintenance program with multiple antileukemic combinations, and included early intensifications with Adriamycin and high-dose cytarabine (ara-C) and a late intensification with cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) followed by autologous bone marrow transplantation (BMT). Duration of therapy was 24 to 30 months. Eight-eight patients (84%) achieved complete remission (CR) with VAD-CVAD, and 94 (90%) ultimately had CR with continuation of the maintenance as planned. Induction mortality was 3%; only half of the patients required prolonged hospitalization of 1 week or longer, or intravenous antibiotics. Maintenance therapy was given to 79 patients, while nine with histocompatibility locus antigen (HLA)-matched related donors underwent allogeneic BMT. The median remission duration was 22 months, and the median survival was 19 months. Factors associated with significantly worse CR rates were older age, the presence of hypoalbuminemia or hyperbilirubinemia, L2 or L3 morphology, and myeloid markers on leukemic cells. Those associated with significantly worse remission durations were the presence of elevated leukocyte or absolute peripheral blast counts, Philadelphia chromosome (Ph)-positive or B-cell ALL, L2 morphology, and more than one course to achieve CR. Patients could be divided into standard-risk ALL (28% of patients) and high-risk ALL (72% of patients) with long-term remission rates of 70% versus less than 30%. The 26 patients who underwent CBV autologous BMT had similar long-term outcome compared with 21 patients who did not (older age, medical contraindications, or socioeconomic problems). The presence or absence of myeloid markers on leukemic cells did not affect long-term prognosis. We conclude that VAD therapy is a well-tolerated effective induction regimen. High-risk ALL patients require alternative maintenance investigational approaches.     

Leukemic and lymphomatous meningitis: incidence,prognosis and treatment

Summary Neoplastic meningitis (NM) is a common problem in neuro-oncology occurring in approximately 5% of all patients with cancer. Notwithstanding frequent focal signs and symptoms in NM, NM is a disease affecting the entire neuraxis and therefore staging and treatment need encompass all cerebrospinal fluid (CSF) compartments. Central nervous system (CNS) staging of NM includes contrast enhanced cranial computerized tomography (CE-CT) or magnetic resonance imaging (MR-Gd), contrast enhanced spine magnetic resonance imaging (MR-S) or computerized tomographic myelography (CT-M) and radionuclide CSF flow study (FS). Treatment of NM involves involved-field radiotherapy of bulky or symptomatic disease sites and intra-CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with NM and may obviate the need for intra-CSF chemotherapy. At present, intra-CSF drug therapy is confined to three chemotherapeutic agents (i.e. methotrexate, cytosine arabinoside and thio-TEPA) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Although treatment of NM is palliative with an expected median patient survival of 4 to 6 months, it often affords stabilization and protection from further neurologic deterioration in patients with NM. In patients with leukemia or lymphoma, prophylaxis of the CNS is used (utilizing a combination of high-dose systemic chemotherapy and intra-CSF chemotherapy) for patients at high risk as defined by specific tumor-related laboratory markers. Using such a risk-stratified approach, the late occurrence of CNS relapse has decreased dramatically attesting to the value of CNS prophylaxis.     

Predictive value of p53 and pRb expression in superficial bladder cancer patients treated with BCG and interferon-alpha

BACKGROUND: Nuclear p53 and retinoblastoma protein (pRb) were reported to be poor prognostic indicators for transitional cell carcinoma of the bladder. The authors sought to determine the prognostic value of nuclear p53 and pRb in superficial bladder transitional cell carcinoma patients who were treated with intravesical bacille Calmette-Guerin (BCG) or BCG with interferon-alpha (IFN-alpha). METHODS: A prospective histological review was performed for 80 superficial bladder transitional cell carcinoma patients who underwent postresection intravesical regimes of BCG (81 mg, n = 33 or 27 mg, n = 20) or BCG (27 mg) with IFN-alpha (n = 27), and followed for a mean of 4.5 years. Hematoxylin and eosin (H & E) and immunoperoxidase staining were performed on tissue sections. Nuclear p53 and pRb immunoreactivity were assessed semiquantitatively, by using a combination of staining extent and intensity, to categorize overexpression or underexpression. Data were analyzed by using chi-square analysis, multiple logistic regression, and Kaplan-Meier curves. RESULTS: pRb expression was not associated with patient outcome after BCG-alone therapy, but pRb underexpression was significantly associated with BCG nonresponse and tumor recurrence (P = .047) after BCG and IFN-alpha (BCG + IFN-alpha) therapy. Low-grade tumors were associated with pRb overexpression, with or without nuclear p53 underexpression (P = .019; P = .043, respectively). p53 expression alone or in combination with pRb expression had no significant relation with tumor response to BCG alone or BCG + IFN-alpha with respect to recurrence, progression, or cancer-specific death. CONCLUSIONS: Nuclear pRb underexpression may be predictive of nonresponse and cancer recurrence after intravesical BCG + IFN-alpha therapy. Nuclear p53 expression or its combination with pRb expression is not associated with post-BCG clinical outcome, so p53 expression or p53 with pRb expression should not be used to influence decisions concerning BCG-alone or BCG + IFN-alpha therapy.     

Nipple aspirate cytology and pathologic parameters predict residual cancer and nodal involvement after excisional breast biopsy.

We previously demonstrated that abnormal nipple aspirate fluid (NAF) cytology predicted residual breast cancer (RC) and tumour size after excisional biopsy (EB), although normal NAF cytology did not exclude RC. Tumour size correlates with the risk of lymph node (LN) metastases. LN metastases provide prognostic information allowing medical and radiation oncologists to determine the need for adjuvant therapy. We hypothesized that pathologic factors known after EB, combined with NAF cytology, would predict with a high degree of accuracy the presence of RC and LN spread. NAF cytology and pathologic parameters: tumour distance from biopsy margins, multifocal and multicentric disease, sub-type of ductal carcinoma in situ (DCIS) or invasive cancer (IC), grade of DCIS or IC, tumour and specimen size, tumour and biopsy cavity location, presence or absence of extensive DCIS, and biopsy scar distance from the nipple were evaluated bivariately and then by logistic regression (LR) for their association with RC and involved LN (> or = 1 (+) LN, useful to determine chemotherapy need, and > or = 4 (+) LN, useful to determine radiation need to the chest and axilla). Data were analysed using NAF cytology alone, pathologic parameters alone, and NAF cytology and pathologic parameters combined. The combined LR model was superior in predicting residual cancer (94%) to LR models using NAF cytology (36%) or pathologic parameters (75%) alone. When only subjects with normal NAF cytology were evaluated by LR, the model was 92% sensitive in predicting RC. Tumour size and NAF cytology predicted which patients had > or = 1 (+) LN, whereas tumour and specimen size predicted which patients had > or = 4 (+) LN. We propose an algorithm which, if confirmed in a larger study, may allow clinicians to be more selective in their recommendations of re-excision breast biopsy or mastectomy.