Long-term relapses of breast cancer: a working hypothesis

The study of long-term relapses that present 8 years or more after mastectomy in breast cancer patients indicates these cases are strictly related to the presence of hormone receptors and particularly to estrogen receptors. It is possible to infer that the presence of estrogen receptors indirectly conditions the formation of antimitotic factors more effective than those used for therapy, to the point of determining in some cases the phenomenon of long-term relapses.     

Long-term relapses of breast cancer: a neglected but important issue

The relatively frequent finding of long-term relapses from breast cancer, eight years or more after the mastectomy, could indicate that breast cancer is a particular neoplasm and even suggests that it could be a systemic disease. The study of receptors in cases of long-term relapses instead indicate that breast cancer, with the exception of the presence of hormonal receptors which influence the clinical behavior, is similar to neoplasms that arise in other parts of the body. It is possible that the presence of receptors indirectly conditions the formation of antimitotic factors more effective than those known today, up to determining in some cases the phenomenon of long-term relapses. Such factors are presumably active also for neoplasms arising in other parts of the body.     

Stress-induced Parkinson's disease: a working hypothesis

Some cases of Parkinson's disease (PD) can be attributed to genetic mutations, others to specific environmental factors; yet the cause of a great majority of cases is unknown. Physical and emotional traumas were once briefly considered as factors in the pathophysiology of this disorder. With increasing evidence that stress can indeed increase neuronal loss in some brain regions, this hypothesis deserves to be reexamined. Stress increases the extracellular availability of glucocorticoids (GCs), dopamine (DA), and glutamate in the striatum as well as other brain regions. These factors undoubtedly can serve to enhance the functions of the striatum. However, each also has the capacity to be neurotoxic. Moreover, they can act synergistically to promote neuronal loss. Thus, we propose that stress might, indeed, be a key factor in the loss of DA neurons that underlies PD.     

Essential hypertension is lymphatic: a working hypothesis

Lymphatics, a third component of the circulation, may be deranged by the same factors as veins and arteries. Malfunctioning through overload or dyscrasia, they may foster high blood pressure. It is hypothesized that essential hypertension is caused by lymphatic system aberrations.     

Ciprofloxacin as a prophylactic agent against prostate cancer: a "two hit" hypothesis

More evidence indicate that prostate inflammation can lead to prostate cancer development. Prostate cancer affects elderly men. Prostate cancer prophylaxis is an important issue because life expectancy is very long now. Ciprofloxacin is an antibacterial agent used mainly in urinary tract infections and prostate inflammation. This drug acts also against cancer cells by the inhibition of topoisomerase II. These properties should allow it to inhibit the development of prostate cancer. Firstly, ciprofloxacin can stop the acute and chronic prostate inflammation which can lead to cancer development. Secondly, ciprofloxacin can potentially kill prostate cancer cells in their early stage of development. Ciprofloxacin accumulates mainly in the prostate after oral intake thus ciprofloxacin seems to be a perfect candidate as a prophylactic agent.     

The pathogenesis of vitreoretinal proliferation and traction: a working hypothesis

Traction retinal detachment due to proliferative vitreoretinopathy (PVR) is a serious complication of ocular trauma, retinal detachment, and previous vitreoretinal surgery. The cause is the active proliferation of fibroblasts, glial cells, and retinal pigment epithelial cells in the periretinal spaces, leading to the formation of contractile cellular membranes. The generation of growth and mitosis stimulation for these cells has remained obscure. We postulate that invading macrophages and local microglia secrete growth factors, notably PDGF (platelet-derived growth factor), which in turn mediates the mitogenic effects of transferrin (TF), a protein present in huge amounts in native vitreous, in plasma and in intraocular proliferative tissue.     

Recurrent extreme breast involution following pregnancy and susceptibility to breast cancer: A hypothesis

Nine multiparous women were found to have breast development resembling the prepubertal “flat-chested” state. During their pregnancies, the breasts of all nine women had developed and enlarged, and five had successfully nursed for two or more months. The remaining four women did not attempt to breastfeed. Following cessation of lactation in the women who had breastfed, and after delivery in those who had not suckled, the breasts of all nine women completely regressed to their prepregnant “flat-chested” physical state. Based on the findings of normal health and regular menses in these women, we hypothesize that the breast epithelium of these and other flat-chested women may have an elevated threshold of estrogen sensitivity in the nonpregnant state which may reduce susceptibility to mechanisms of carcinogenesis.     

An interstitial hypothesis for breast cancer related lymphoedema

Breast cancer related lymphoedema (BCRL), the chronically swollen arm of patients that have been treated for breast cancer, is no longer considered to be a result of lymphatic obstruction as recent studies have identified failing peripheral lymphatic function as a principal contributing factor. The aetiology and pathophysiology that results in this lymphatic failure is not clearly understood, but it can occur with minimal or even in some cases no damage to the axillary lymph nodes, and evidence suggests that some patients are pre-disposed to develop the disease, and have poor lymphatic function in their non-affected arms. It has been shown that interstitial forces such as hydrostatic pressure, and interstitial fluid velocity, can regulate both lymph flow, and lymph formation, and there is good evidence that interstitial forces are dysregulated in lymphoedema patients. Here I outline a hypothesis for how dysregulation of interstitial parameters could contribute to the generation of breast cancer related lymphoedema, by combining disparate strands of current evidence on the molecular and physiological control of interstitial and lymph flows. One mechanism by which lymphoedema could be generated is that a reduction in interstitial velocity results in increased VEGF-C production, which in low flow conditions, instead of acting on the lymphatics to increase pumping and lymphangiogenesis, acts on vasculature to increase fluid filtration. The resulting increase in interstitial pressure restores flow, but at the expense of increased volume and hence oedema. The evidence supporting the hypothesis and possible tests of it are presented and discussed.     

Long-term prognosis of teenagers with breast cancer

We report 4 new cases of breast carcinoma in teenage girls diagnosed by use of histochemical and immunohistochemical methods. These cases of breast carcinoma in women under 20 years of age were found in the files of our department in the last 24 years (1976-2000). The patients had operable breast carcinomas corresponding to various histologic types (1 invasive ductal carcinoma associated with fibroadenoma, 2 secretory carcinomas, and 1 invasive lobular-type carcinoma). Simple mastectomy with low axillary lymph node dissection was performed in 2 postpubertal patients. Only 1 patient received adjuvant chemotherapy (case 4). After follow-up ranging from 76 to 126 months, 3 patients are alive and disease-free and 1 has disseminated metastatic disease. The correlations with prognosis-related risk factors (stage, age, previous benign lesions, family history, histologic types, hormonal receptors, and pregnancy) were examined.     

Review of stem cell deregulation and breast cancer: an emerging hypothesis

Cancer is fundamentally a cellular genetic disease capable of transferring the "disease" to the next generation of mutated cells. Similar proliferative and information transferring capacity exists in the stem cells of various organ systems in the human body. Understanding the bio-mechanism of stem cell metabolism and its regulation by signaling molecules and extracellular micro-environment is an important step toward successful prevention and treatment of cancer. According to the cancer stem cell hypothesis, both hereditary and sporadic cancers can arise from deregulation of these cancer stem cells (CSCs), triggered by genetic and environmental factors. It is shown that deregulation of normal self-renewal pathways in undifferentiated breast stem cells or progenitor cells had altered mammary system or progenitor cells, resulting in abnormally differentiated cells in human and rodent breast cancer cell lines. Breakthroughs in molecular pathways have important therapeutic implications. Hence, significant stress is laid on targeting signaling molecules and their micromilieu in breast cancer therapy.     

Long-term effects of levonorgestrel-releasing intrauterine system on tamoxifen-treated breast cancer patients: a meta-analysis

Objective: The aim of the study is to assess the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) on the tamoxifen-induced endometrial lesions in breast cancer patients. Methods: PubMed and EMBASE databases were searched for eligible studies. Odds ratios were obtained to estimate the association between the LNG-IUS and tamoxifen-induced endometrial lesions. The fixed effects or random-effects model was used to combine data depending on heterogeneity. Results: With three eligible randomized clinical trials involving 359 patients, this analysis demonstrated tamoxifen-treated breast cancer patients using the LNG-IUS derived benefit from de novo polyps prevention (P < 0.0001, OR 0.18, 95% CI: 0.08-0.42). However, the LNG-IUS only showed a trend of maintaining endometrial proliferation or secretory status (P = 0.05, OR 0.36, 95% CI 0.13-1.02) and no statistical difference in atrophic or inactive changes (P = 0.13, OR 0.24, 95% CI 0.04-1.53) or endometrial hyperplasia without atypia (P = 0.08, OR 0.20, 95% CI 0.04-1.18). The LNG-IUS didn’t have an increased incidence in breast cancer recurrence (P = 0.28, OR 1.75, 95% CI: 0.64-4.80) and cancer-induced death (P = 0.71, OR 1.22, 95% CI: 0.42-3.52). Bleeding in the treatment group was statistically more frequent than that in the control group (OR 6.20, 95% CI: 2.99-12.85, P < 0.00001). Conclusions: This analysis verifies the efficacy of the LNG-IUS in preventing tamoxifen-induced polyps. The LNG-IUS didn’t have an increased incidence in breast cancer recurrence and cancer-induced death. Long-term, large randomized studies of the LNG-IUS will be necessary to determine the benefit and risk in tamoxifen-treated breast cancer patients.     

Gastric cancer etiology: a biochemical hypothesis.

We have proposed a two-stage biochemical model for the etiology of "intestinal" gastric cancer. The model postulates that the gastric mucosal barrier is biochemically pierced as a result of chemical interactions between the mucoproteins and mucopolysaccharides of the barrier and ingested polysaccharrides (starches). This would allow the growth of gastric flora which could produce carcinogenic nitrosamines and/or nitrosamides. Observational and experimental evidence in favor of the model is provided. The model suggests various research initiatives, the results of which might provide the basis for biochemical and physiological methods for the prevention and/or treatment of gastric cancer. Various ways in which the model may be tested are also noted.     

Dairy products and breast cancer: the IGF-I, estrogen, and bGH hypothesis

Research on the role of dietary factors in breast cancer causation has focused predominantly on fat intake. While some studies have examined associations between breast cancer rates and consumption of whole milk, there has been less attention given to dairy products in general. Dairy products contain both hormones and growth factors, in addition to fat and various chemical contaminants, that have been implicated in the proliferation of human breast cancer cells. This literature review evaluates the epidemiological and mechanistic evidence linking dairy consumption with breast cancer risk.     

Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis

Chronic fatigue syndrome (CFS) is a relatively common disorder defined as a status of severe persistent disabling fatigue and subjective unwellness. While the biological basis of the pathology of this disease has recently been confirmed, its pathophysiology remains to be elucidated. Moreover, since the causes of CFS have not been identified, treatment programs are directed at symptom relief, with the ultimate goal of the patient regaining some level of pre-existing function and well-being. Several studies have examined whether CFS is associated with: (i) a range of infectious agents and or immune disturbance; (ii) specific changes of activity in the central or peripheral nervous systems; and (iii) elevated stress periods, which may be associated with the pathology via genetic mechanisms. The role of oxidative stress in CFS is an emerging focus of research due to evidence of its association with some pathological features of this syndrome. New data collectively support the presence of specific critical points in the muscle that are affected by free radicals and in view of these considerations, the possible role of skeletal muscle oxidative imbalance in the genesis of CFS is discussed.