Idiotype as a tumor-specific marker in childhood B cell acute lymphoblastic leukemia

Immunoglobulin (Ig) or idiotype (Id) is a tumor-specific target in those B cell malignancies that express this molecule on their surface. We explored the biology of B cell acute lymphoblastic leukemia (B cell ALL) using Id as a tumor marker. In this report we describe the development of anti-Id monoclonal antibodies (MAB) for two children with B cell ALL. These reagents were used retrospectively to study tumor kinetics and to detect residual disease after chemotherapy. In both cases serum Id values were strikingly high at diagnosis (1.2 mg/mL and 10.8 mg/mL), suggesting that the tumor cells were relatively mature B cells capable of significant antibody production. In both patients the serum Id levels fell with the institution of therapy and confirmed that the patients were in remission. Increasing serum Id predicted relapse four months before conventional methods in patient 1, and Id proved to be a more sensitive measure of tumor burden than Southern blot analysis of rearranged Ig genes in bone marrow samples. Surprisingly, low levels of Id were redetected in the second patient just before completing therapy and have persisted for over a year despite the absence of clinical evidence of recurrent disease. Thus, serum Id levels reflect tumor burden during initial therapy but may not necessarily predict tumor progression after a complete clinical remission.     

Variability in 4-hydroperoxycyclophosphamide activity during clinical purging for autologous bone marrow transplantation

We examined the effects of varying incubation conditions on the in vitro activity of 4-hydroperoxycyclophosphamide (4HC). 4HC activity against CFU-GM and against the K562 tumor cell line decreased with increasing the RBC concentration of the incubation mixture. Increasing the concentration of nucleated bone marrow cells in the incubation mixture also decreased the 4HC activity. Evaluation of 53 consecutive patients undergoing autologous bone marrow transplantation (BMT) revealed that the incubation RBC concentration during clinical purging showed a similar effect on CFU-GM recovery. Aldehyde dehydrogenase content of RBCs and nucleated marrow cells appears to be the cause of the inhibition of 4HC activity. Although there was no difference in individual CFU-GM sensitivity to 4HC among normals, previously treated patients undergoing autologous BMT showed significant variability in CFU-GM sensitivity to 4HC. The combined effects of incubation RBC concentration and individual patient 4HC sensitivity appear to account for most of the variability in CFU-GM recovery and speed of hematologic recovery after clinical purging with 4HC.     

Efficacy of ex vivo purging for autologous bone marrow transplantation in the treatment of acute nonlymphoblastic leukemia

We used an in vitro measure of drug activity to predict the efficacy of ex vivo purging of leukemic cells from autologous bone marrow grafts. We previously found that the myeloid progenitor cell (CFU-GM) content of the marrow grafts after ex vivo purging with 4- hydroperoxycyclophosphamide (4-HC) correlates with time to hematologic recovery after autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. We observed that variable red blood cell concentration of the bone marrow incubation mixture results in differential cytotoxic activity of 4-HC. The CFU-GM content of the graft after the ex vivo treatment is a measure of this 4-HC activity. We analyzed the disease-free survival of 45 patients with acute nonlymphoblastic leukemia undergoing autologous bone marrow transplantation with 4-HC purged grafts. Patients who relapsed after transplantation had 4.2 +/- 1.1% of graft CFU-GM surviving the ex vivo purge, compared with 1.1 +/- 0.4% for patients who achieved a sustained remission (P = .06). Twenty-three patients with a CFU-GM content after 4-HC purging of greater than 1% of the pretreatment value had an actuarial disease-free survival of 12%, compared to 36% for 22 patients with a less than or equal to 1% CFU-GM content after purging (P = .006). Therefore, percent CFU-GM survival as a measure of 4-HC cytotoxicity identified a group of patients with insufficient purging. Although no randomized clinical trials have documented the need for ex vivo purging, our results suggest that effective bone marrow purging is important for the optimal application of autologous transplantation in the treatment of acute nonlymphoblastic leukemia.     

ErbB receptors and fatty acid synthase expression in aggressive head and neck squamous cell carcinomas

Oral Diseases (2010) 16 , 774–780 Summary: Overexpression of ErbB receptors is frequent in head and neck squamous cell carcinomas (HNSCC) and seems to be correlated with tumor progression and metastasis. Fatty acid synthase (FASN), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, is regulated by ErbB2 and overexpressed in several human malignancies. Methods: This study was performed to examine the immunohistochemical expression patterns of ErbB1, ErbB2, ErbB3, ErbB4, and FASN in a tissue microarray, containing 33 representative areas from aggressive primary HNSCC (whose patients had distant metastasis), and 21 matched lung metastasis. Results: Strong correlation among the expression of ErbB family receptors was found (ErbB1–ErbB2 P = 0.008, ErbB1‐ErbB4 P = 0.018, EbB2‐ErbB3 P = 0.001, ErbB2‐ErbB4 P = 0.006, ErbB3‐ErbB4 P = 0.012) in the HNSCC. FASN expression was significantly associated with ErbB2 (P = 0.024). Lymphatic permeation was correlated with ErbB3 (P = 0.033) and histological grade with ErbB4 staining (P = 0.050). ErbB1 and ErbB2 were found mainly in patients with smoking habit (P = 0.011 and P = 0.027), and ErbB2 was associated with alcohol consumption and clinical stage (P = 0.014 and P = 0.031). Finally, FASN was overexpressed in lung metastasis, in comparison with matched HNSCC samples (P = 0.006). Conclusions: The results showed that high FASN immunohistochemical expression is a feature of HNSCC lung metastasis, and ErbB1‐ErbB2, ErbB1‐ErbB4, ErbB2‐ErbB3, ErbB2‐ErbB4, and ErbB3‐ErbB4 expression levels are correlated in the respective primary tumors, being ErbB2 the preferred coexpression partner of all the other ErbB receptors.     

Use of a Web-based Risk Appraisal Tool for Assessing Family History and Lifestyle Factors in Primary Care

BACKGROUND

Primary care clinicians can play an important role in identifying individuals at increased risk of cancer, but often do not obtain detailed information on family history or lifestyle factors from their patients.

OBJECTIVE

We evaluated the feasibility and effectiveness of using a web-based risk appraisal tool in the primary care setting.

DESIGN

Five primary care practices within an academic care network were assigned to the intervention or control group.

PARTICIPANTS

We included 15,495 patients who had a new patient visit or annual exam during an 8-month period in 2010–2011.

INTERVENTION

Intervention patients were asked to complete a web-based risk appraisal tool on a laptop computer immediately before their visit. Information on family history of cancer was sent to their electronic health record (EHR) for clinicians to view; if accepted, it populated coded fields and could trigger clinician reminders about colon and breast cancer screening.

MAIN MEASURES

The main outcome measure was new documentation of a positive family history of cancer in coded EHR fields. Secondary outcomes included clinician reminders about screening and discussion of family history, lifestyle factors, and screening.

KEY RESULTS

Among eligible intervention patients, 2.0 % had new information on family history of cancer entered in the EHR within 30 days after the visit, compared to 0.6 % of eligible control patients (adjusted odds ratio = 4.3, p = 0.03). There were no significant differences in the percent of patients who received moderate or high risk reminders for colon or breast cancer screening.

CONCLUSIONS

Use of this tool was associated with increased documentation of family history of cancer in the EHR, although the percentage of patients with new family history information was low in both groups. Further research is needed to determine how risk appraisal tools can be integrated with workflow and how they affect screening and health behaviors.     

Oral health‐related quality of life among rural‐dwelling Indigenous Australians

Background: There is limited information on the impact of poor oral health on Indigenous Australian quality of life. This study aimed to determine the prevalence, extent and severity of, and to calculate risk indicators for, poor oral health‐related quality of life among a convenience sample of rural‐dwelling Indigenous Australians. Methods: Participants (n = 468) completed a questionnaire that included socio‐demographic, lifestyle, dental service utilization, dental self‐care and oral health‐related quality of life (OHIP‐14) factors. Results: The prevalence of having experienced one or more of OHIP‐14 items ‘fairly often’ or ‘very often’ was 34.8%. The extent of OHIP‐14 scores was 1.88, while the severity was 15.0. Risk indicators for having experienced one or more of OHIP‐14 items ‘fairly often’ or ‘very often’ included problem‐based dental attendance, avoiding dental care because of cost, difficulty paying a $100 dental bill and non‐ownership of a toothbrush. An additional risk indicator for OHIP‐14 extent was healthcare card ownership, while additional indicators for OHIP‐14 severity were healthcare card ownership and having had 5+ teeth extracted. Conclusions: Risk indicators for poor oral health‐related quality of life among this marginalized population included socio‐economic factors, dentate status factors, dental service utilization patterns, financial factors and dental self‐care factors.     

Expression of steroid hormone receptors, proliferation and apoptotic markers in primate endometrium

In humans, circulating levels of steroid hormones vary during the menstrual cycle, with oestrogen elevated in the proliferative phase and progesterone increased during the secretory phase. In humans, oestrogen levels also increased during the mid-secretory phase, but this is not observed in non-human primates. In marmosets, the New World monkeys, plasma oestrogen and progesterone levels exhibit similar profiles as those found in Old World monkeys, however, these animals do not menstruate. Proliferative and apoptotic changes occur at specific phases of the menstrual cycle, suggesting regulation by steroid hormones. It was, therefore, of interest to compare expression of steroid hormone receptors, proliferation and apoptotic markers in the uterine endometrium of marmosets and humans. Localization of oestrogen receptor-alpha (ER-alpha) was observed in glandular epithelial cells during the proliferative phase in marmosets and in human endometria. A decrease in ER-alpha and progesterone receptor (PR-A) was observed during the mid luteal phase in both species although a postovulatory oestradiol peak is observed in human but not in marmoset. A decrease in PR-A in the late secretory phase was seen in marmoset as well as in human endometria. The proliferation marker PCNA was enhanced in the proliferative phase in both species, but it was increased in late secretory phase only in marmosets. Apoptosis as revealed by a TUNEL assay was moderate in early stage in both species. Surprisingly, apoptosis, as well as the localization of the pro-apoptotic Bcl-2 family member, Bax, was optimal in marmosets during the mid-secretory phase when plasma progesterone levels were high. On the other hand, in the human, apoptosis was maximal by TUNEL assay in late secretory phase, but Bax protein was highest in the mid-secretory phase. Thus, Bax may be initiating apoptosis in the endometrial glands as well as in the stroma. Although the pattern of steroid receptor expression in endometria of marmosets and humans are similar, proliferation and apoptosis markers appear to be regulated by other factors along with steroid hormones.     

Utility of topiramate for the treatment of patients with chronic migraine in the presence or absence of acute medication overuse

Chronic migraine has been linked to the excessive use of acute headache medications. Medication overuse (MO) is commonly considered the most significant risk factor for the progression of migraine from an episodic to a chronic condition. Managing MO is a challenge. Discontinuation of the acute medication can result in withdrawal headache, nausea, vomiting and sleep disturbances. This review summarizes the results from two similarly designed, randomized, placebo-controlled, multicentre studies of chronic migraine conducted in the USA and European Union. Both studies demonstrate the efficacy and safety of the migraine preventive medication, topiramate, for the treatment of chronic migraine in patient populations both with and without MO. These studies may have important implications for the future of chronic migraine management, suggesting that detoxification prior to initiating prophylactic therapy may not be required in all patients if MO is present.