Paul H. Levine

Dietary exposure to nitrite and nitrosamines and risk of nasopharyngeal carcinoma in Taiwan.

Previous studies of nasopharyngeal carcinoma (NPC) have found elevated risks with higher consumption of salted fish and preserved foods, particularly during childhood. These foods can contain high levels of nitrosamines; however, most studies have not estimated exposure to nitrosamines directly. We conducted a case‐control study in Taiwan to evaluate dietary intakes and NPC risk. A total of 375 cases (99% response rate) and 327 controls (88% response rate) were interviewed about their diet as an adult and at age 10 using a food‐frequency questionnaire. We interviewed mothers of participants about their childs diet at age 10, age 3 and during weaning and the mothers diet while she was breast‐feeding. Mothers of 96 cases and 120 controls were interviewed. Nitrosamine and nitrite levels were assigned to 66 foods based on published values. Intake of nitrosamines and nitrite as an adult was not associated with risk of NPC. High intakes of nitrosamines and nitrite during childhood and weaning were associated with increased risks of NPC for foods other than soy products. Adjusted odds ratios for the highest quartile were 2.2 [95% confidence interval (CI) 0.8–5.6] for age 10, 2.6 (95% CI 1.0–7.0) for age 3 and 3.9 (95% CI 1.4–10.4) for weaning diet. Intakes of nitrite and nitrosamines from soybean products during childhood and weaning were inversely associated with risk. Soybeans contain known inhibitors of nitrosation, and thus may explain the inverse association we observed. Our results suggest that nitrosamine and nitrite intake during childhood may play a role in the development of NPC. Int. J. Cancer 86:603–609, 2000. Published 2000 Wiley‐Liss, Inc.

Inflammatory breast cancer in Tunisia: epidemiological and clinical trends.

Inflammatory breast cancer (IBC) is characterized by a peculiar geographic distribution in incidence, being described as more common in Tunisia and the region of North Africa. The authors performed a systematic review of published literature on rapidly progressing breast cancer and IBC in Tunisia and analyzed the evolution in epidemiology, clinical presentation, treatment, and therapeutic results. They collected, analyzed, and compared all the indexed Tunisian articles about rapidly progressing breast cancer and IBC since the 1970s opening of the Institut Salah Azaiz Institute in Tunis. In the 1970s, rapidly progressing breast cancer diagnosis was based on the Poussée Évolutive classification (1‐3). Since the 1990s, IBC diagnosis has been based on the American Joint Committee on Cancer Poussée Évolutive 3/T4d staging. The authors compared the historical data to the most recent publications in terms of epidemiology, clinical features, treatment, and therapeutic results. The most important historical report of rapidly progressing breast cancer concerned 340 patients, representing 58.5% of a cohort of 581 breast cancer patients collected from 1969 to 1974, including 320 (55.2%) with inflammatory signs, 37(6.5%) with Poussée Évolutive 2, and 283 (48.7%) with Poussée Évolutive 3. Subsequent papers have documented a steady decrease in incidence to the current 5% to 7% T4d/IBC. Since the 1970s, Poussée Évolutive in premenopausal woman has increased from 52.5% to 75%; rural predominance has persisted. The 5‐year overall survival reached 28% by the year 2000. The authors analysis demonstrated a trend of decreasing incidence of IBC diagnoses from 50% to presently <10%, probably related to a combination of factors, including the use of more stringent criteria (Poussée Évolutive 3/T4d) for IBC diagnosis and an improvement in the socioeconomic level of Tunisia. Cancer 2010;116(11 suppl):2730–5.

Alternate estrogen receptors promote invasion of inflammatory breast cancer cells via non-genomic signaling.

Although Inflammatory Breast Cancer (IBC) is a rare and an aggressive type of locally advanced breast cancer with a generally worst prognosis, little work has been done in identifying the status of non-genomic signaling in the invasiveness of IBC. The present study was performed to explore the status of non-genomic signaling as affected by various estrogenic and anti-estrogenic agents in IBC cell lines SUM149 and SUM190. We have identified the presence of estrogen receptor α (ERα) variant, ERα36 in SUM149 and SUM190 cells. This variant as well as ERβ was present in a substantial concentration in IBC cells. The treatment with estradiol (E2), anti-estrogenic agents 4-hydroxytamoxifen and ICI 182780, ERβ specific ligand DPN and GPR30 agonist G1 led to a rapid activation of p-ERK1/2, suggesting the involvement of ERα36, ERβ and GPR30 in the non-genomic signaling pathway in these cells. We also found a substantial increase in the cell migration and invasiveness of SUM149 cells upon the treatment with these ligands. Both basal and ligand-induced migration and invasiveness of SUM149 cells were drastically reduced in the presence of MEK inhibitor U0126, implicating that the phosphorylation of ERK1/2 by MEK is involved in the observed motility and invasiveness of IBC cells. We also provide evidence for the upregulation of p-ERK1/2 through immunostaining in IBC patient samples. These findings suggest a role of non-genomic signaling through the activation of p-ERK1/2 in the hormonal dependence of IBC by a combination of estrogen receptors. These findings only explain the failure of traditional anti-estrogen therapies in ER-positive IBC which induces the non-genomic signaling, but also opens newer avenues for design of modified therapies targeting these estrogen receptors.

What we know about chronic fatigue syndrome and its relevance to the practicing physician

A number of recent reports have emphasized laboratory abnormalities, clinical tests, and therapeutic approaches that appear to have great promise in the evaluation and management of chronic fatigue syndrome (CFS). Because of the heterogeneity of CFS, the cost of many of these assays and procedures, and the frequent lack of skilled consultants able to apply relevant sophisticated procedures, the solo healthcare provider is often left with uncertain options in patient management. This article summarizes current approaches to patient management, utilizing available information relevant to CFS.

Epidemiologic advances in chronic fatigue syndrome

Epidemiologic studies of chronic fatigue syndrome (CFS) have been hampered by the absence of a specific diagnostic test, but with increasing interest in this disorder there has been a greater understanding of the risk factors, illness patterns, and other aspects of this multisystem disorder. Working case definitions have been developed for research purposes but they have continued to change over time and have not always been utilized precisely by various investigators. This has been a major factor in the widely varying estimates of prevalence rates, but two different studies using the same working definition and including a medical work-up have estimated the prevalence to be approximately 200/100,000. Clusters of CFS cases, which appear to be related to earlier reports of epidemic neuromyasthenia, have attracted considerable attention and appear to be well documented, although investigated with varying methodology and often with dissimilar case definitions. Risk factors for cases occurring in clusters and sporadically appear to be similar, the most consistent ones being female gender and the co-existence of some form of stress, either physical or psychological. The prognosis of CFS is difficult to predict, although cases occurring as part of clusters appear to have a better prognosis as a group than sporadic cases, and those with an acute onset have a better prognosis than those with gradual onset. It is highly unlikely that there is a single agent, infectious or noninfectious, that is responsible for more than a small proportion of CFS cases and, at the present time, the risk factors for developing CFS appear to lie more prominently in the host rather than the environment.

Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFR-PAR1-Pak1 pathway

Inflammatory breast cancer (IBC) accounts for a small fraction but aggressive form of epithelial breast cancer. Although the role of thrombin in cancer is beginning to be unfolded, its impact on the biology of IBC remains unknown. The purpose of this study was to establish the role of thrombin on the invasiveness of IBC cells. The IBC SUM149 cell line was treated with thrombin in the absence or presence of the epidermal growth factor receptor (EGFR) inhibitor erlotinib and protease-activated receptor 1 (PAR1) inhibitor. The effects of pharmacological inhibitors on the ability of thrombin to stimulate the growth rate and invasiveness were examined. We found that the inhibition of putative cellular targets of thrombin action suppresses both the growth and invasiveness of SUM149 cells in a concentration-dependent manner. In addition, thrombin-mediated increased invasion of SUM149 cells was routed through EGFR phosphorylation, and in turn, stimulation of the p21-activated kinase (Pak1) activity in a EGFR-sensitive manner. Interestingly, thrombin-mediated activation of the Pak1 pathway stimulation was blocked by erlotinib and PAR1 inhibitor. For proof-of-principle studies, we found immunohistochemical evidence of Pak1 activation as well as expression of PAR1 in IBC. Thrombin utilizes EGFR to relay signals promoting SUM149 cell growth and invasion via the Pak1 pathway. The study provides the rationale for future therapeutic approaches in mitigating the invasive nature of IBC by targeting Pak1 and/or EGFR.

BP1, a putative signature marker for inflammatory breast cancer and tumor aggressiveness.

Our previous studies revealed that beta protein 1 (BP1) was barely detectable in normal human breasts, but was seen in 21%, 46%, and 81% of hyperplastic, in situ, and invasive breast lesions, respectively. Our current study attempted to assess BP1 expression in inflammatory breast cancer (IBC), a very aggressive subtype of breast cancers characterized by extensive lympho-vascular invasion and involvement of dermal lymphatics. Paraffin-embedded tissue sections from 45 cases of IBC (nine with paired metastatic lymph nodes) and different controls were assayed immunohistochemically for BP1 expression. Positive BP1 immunoreactivities were present in all IBC cases. Strikingly, all cancer cells metastasized to lymph nodes and cells within lymphatic channels were uniformly and strongly immunoreactive to BP1. The percentage of BP1 positive cells and the intensity of BP1 immunostaining in IBC cases were significantly greater than those in non-IBC cases. Our findings suggest that BP1 may possess properties of onco-proteins that promote tumor progression, invasion, and metastasis, representing a putative signature marker for IBC and tumor aggressiveness.

Risk Factors for Human T Cell Lymphotropic Virus Type II Infection among the Guaymi Indians of Panama

To examine risk factors for human T cell lymphotropic virus type II (HTLV-II) infection, a case-control study was conducted among the Guaymi Indians of Panama. In females, HTLV-II seropositivity was associated with early sexual intercourse (</=13 vs. >15 years; odds ratio [OR], 2.50; 95% confidence interval [CI], 1.11-6.14) and number of lifetime sex partners. One partner increased risk of seropositivity by 30% (OR, 1.30; CI, 1.05-1.64), and risk increased with number of partners. Similar risk was associated with number of long-term sexual relationships. Among males, intercourse with prostitutes was associated with HTLV-II seropositivity (OR, 1.68; CI, 1.04-2.72). These data support a role for sexual transmission in HTLV-II infection. Association of seropositivity with primary residence in a traditional village (OR, 3.75; CI, 1.02-15.38) and lack of formal education (0 vs. >6 years [OR, 3.89; CI, 1.67-9.82]) observed in males may reflect differences in sexual practices associated with acculturation.

Longitudinal Network Patient Navigation: Development of a City-Wide Integrative Model to Reduce Breast Cancer Disparities in Washington, D.C.

(2010). Longitudinal Network Patient Navigation. Oncology Issues: Vol. 25, No. 2, pp. 28-35.

Monoclonal antipeptide antibodies against amino acid residues 1101-1106 of human C4 distinguish C4A from C4B.

Comparison of amino acid sequences of the alpha-chain fragment of human C4, C4d, has shown C4A- and C4B-specific sequences at residues 1101-1106 in which the aspartic acid-histidine substitution at position 1106 may be related to the amide and ester bond forming properties of these molecules. Peptides containing twelve amino acid residues of the C4A- or C4B-specific sequences were synthesized and injected into female Balb/c mice. Serum from 2 mice, one immunized with the C4A-specific peptide and the other with the C4B-specific peptide, gave strong isotype-specific responses in an enzyme-linked immunosorbent assay against affinity-purified C4A3 and C4B2B1. Spleen cells from these mice were fused with the mouse myeloma SP2/0-Ag 14, and two cloned cell lines, AII-1 and BII-1, were established from hybrids. Enzyme-linked immunosorbent assay and western blotting of monoclonal antibodies AII-1 and BII-1 show that the former reacts with the C4A but not with the C4B alpha-chain and the latter with C4B but not with the C4A alpha-chain. Furthermore, immunoblotting of C4 allelic variants showed that AII-1 reacted with all C4A allotypes tested, including A6, A4, A3 and A2, whereas BII-1 reacted with all C4B allotypes tested, including B5, B3, B2, and B1.