1,721,122 research outputs found
Hypercalcemia Pathophysiology & Treatment. Foreword
No full textHypercalcemia is a relatively common disorder, which requires specific treatment in order to control symptoms and prevent the development of organ damage. Since primary hyperparathyroidism and malignancy are responsible for more than 90% of all cases of hypercalcemia, greater interest was given in terms of developing the best strategy to manage these two critical situations. The aim of this book is to present up-to-date knowledge on hypercalcemia, its association with renal disorders, and benign and malignant diseases, diagnostic methodologies, as well as surgical and medical treatment. Insights into the etiology, pathogenesis and pathophysiology of hypercalcemia are included in the first four chapters, also providing comprehensive descriptions of clinical features, diagnostic and treatment procedures in the specific diseases associated with hypercalcemia. The other chapters present details on biochemical findings and ways to monitor complications and therapy, giving suggestions on the current imaging techniques, and deal with the criteria, procedures and results of surgical treatment of hypercalcemia, including unilateral and minimally-invasive parathyroidectomy. Finally, a specific chapter describes the pharmacology of anti-hypercalcemic drugs, also providing information on new drugs and future perspectives. Uniquely, this book will serve as a complete reference source for oncologists, nephrologists, endocrinologists and other clinicians, as well as for biochemists and pharmacologists, and all those involved in hypercalcemia management and research
Leading article. Sentinel lymph node biopsy in breast cancer
Full text linkSince the first radical mastectomy proposed by William S Halsted in the 1890s, axillary lymph node dissection (ALND) has been considered the standard procedure for surgical treatment of breast cancer. Although the extent of surgery decreased, ALND was extensively performed for a century. ALN status is the most important prognostic factor for patients with breast cancer. However, although ALND is accurate in determining nodal status, this is at the expense of significant morbidity, both physical (pain, lymphedema, loss of strength) and psychological (worsening of body image). The concept of the “sentinel lymph node” (SLN) in breast cancer was introduced in the 1990s, following research on penile cancer and melanoma [4]. The objective was to perform less invasive surgery in a targeted population, given the risk of postoperative complications and discomfort experienced after ALND
Primary hyperparathyroidism due to parathyroid tumors: how the disease has changed. Analysis of results in 335 patients who underwent surgery during the last 20 years
No full textSporadic primary hyperparathyroidism is a relatively common disease and is the main cause of hypercalcemia in outpatients, with an incidence ranging between 5 and 20 cases per 100,000. The estimated prevalence of PHPT in women aged over 60 years-old may reach 4 per 1,000.
In hypercalcemic patients, when serum PTH is elevated, the diagnosis of PHPT is easily made, especially if there are clinical manifestations. Hypercalcemic patients with high PTH serum levels are unlikely to be due to causes other than primary hyperparathyroidism. Occasionally, a normocalcemic primary hyperparathyroidism can also occur in patients with low serum protein, renal failure, increased dietary phosphate intake or vitamin D deficiency. Currently, 80-90% of patients with confirmed primary hyperparathyroidism are asymptomatic, as the disease is commonly an incidental finding during routine hematologic screening or is discovered among postmenopausal women who undergo dual-energy X-ray absorptiometry for the diagnosis of possible bone alterations and risk of fracture
Serum tumor markers in patients with breast cancer
No full textSeveral serum tumor markers have been investigated in patients with breast cancer for assessing outcome, predicting recurrence and monitoring the therapeutic response. There is a general consensus concerning their limited application in diagnosing malignancy; however, serum tumor markers can be considered for the early detection of recurrence. The most effective markers for this indication are cancer antigens (CA)15-3 and 27.29, and c-erbB-2, although their efficacy in establishing disease progression has not been determined to date. In terms of evaluating prognosis and predicting response to therapy, only the expression of c-erbB-2 has clinical evidence. To conclude, at present, no serum tumor marker is cost effective, and none can be used with confidence in the decision making regarding breast cancer patients
Medical Treatment of Hirsutism in Women
No full textAbstract: Hirsutism is the presence of excess hair growth in women in the typical male hair growth areas, thereby reflecting a deviation from the normal female hair pattern. It affects from 5% to 10% of women, depending on age, menopausal status and ethnic background. The presence of hirsutism is very distressing for women, and subsequently may have a negative impact on their psychosocial life. In the treatment of hirsutism several options are now available, including pharmacologic regimens and cosmetic measures. Both the hormonal profile of the patient and her expectations and preferences should guide the therapeutic approach. The aims of the medical therapy are suppression of excessive androgen production, inhibition of peripheral action of androgens, and treatment of patients at risk for metabolic disorders or reproductive cancers. For other diseases related to endocrine abnormalities, such as thyroid disorders or Cushing’s syndrome, specific treatment is mandatory. After an ineffective local approach by direct hair removal, a pharmacological treatment should be suggested, using estrogen and progestin combinations, antiandrogens (i.e. cyproterone acetate, spironolactone) or both as a first line. Finasteride, gonadotropin-releasing hormone agonists, and glucocorticoids should be used in selected cases. Adequate contraception is also recommended if antiandrogens are used. Unfortunately, since systemic therapy reduces hair growth in less than 50% of cases, hirsute women frequently require cosmetic measures. The use of a logical combination of different options has been shown to achieve a satisfactory result in most cases. This review provides information and suggestions about the current options of treating hirsutism
Apoptosis: life through planned cellular death. Regulating mechanism, control systems, and relations with thyroid diseases
No full textApoptosis is an active biologic process that represents a form of programmed cellular suicide, activated either by genetic factors or by cellular lesions caused by various extracellular traumatic agents. The alterations of its functional mechanisms control cellular homeostasis are involved in the genesis of many illnesses. There are different control systems that can both stimulate and inhibit apoptosis, such as the p53 and Bcl-2 proteins. Different injuries may cause a rapid increase in the levels of p53 and the activation of the complex mechanism which leads either to damage repair or cellular apoptosis. The concept of tumor growth as a dynamic balance between cellular development and death is well applicable to differentiated thyroid carcinomas, which are generally not highly invasive and present excellent prognosis. On the contrary, in aggressive anaplastic thyroid carcinoma there is an increase in p53, whereas in normal thyroid cells there is a high expression of Bcl-2, so as to interfere with apoptosis when physiologic hormone levels are normal. However, only some of the biomolecular mechanisms behind the genesis of thyroid tumors have been explained, and the role of apoptosis in thyroid diseases has not been well defined. T his review provides information about relationship between apoptosis and thyroid diseases
Hypercalcemia of malignancy
No full textHypercalcemia of malignancy (HM) is the most common metabolic disorder in cancer patients, representing the second cause of hypercalcemia in the general population. HM is observed in 10-15% of patients with malignancy, especially in those with advanced cancer, usually indicating a poor prognosis1. In patients with HM, tumor cells may activate osteoclasts through several pathways, and the disruption of the balance between osteoblast and osteoclast activity in the bone marrow results in osteolysis, calcium loss and hypercalcemia. Two different mechanisms may lead to HM. Osteolytic hypercalcemia is directly induced by cancer cells invading the bone, leading to the degradation of mineral matrix and involving various cytokines, including interleukin (IL)-1β, IL-3, IL-6, tumor necrosis factor (TNF)-α, TNF-β, MIP, prostaglandins and chemokines, locally produced by tumor cells2. Both normal and malignant bone marrow cells interact with this network of cytokines, increasing receptor activator of nuclear factor-kappaB ligand (RANKL) and other mediators, ultimately leading to osteoclast activation adjacent to cancer cells. The secretion of parathyroid hormone-related protein (PTHrP) by the malignant cells represents the main cause of HM: the so-called humoral hypercalcemia. PTHrP is a polypeptide exhibiting PTH-like activity that stimulates RANKL expression in bone marrow stromal cells and osteoblasts, resulting in osteoclast formation in the bone microenvironment and hypercalcemia3. Up to 80% of patients with HM exhibit elevated PTHrP serum levels, which is usually observed in the presence of advanced or metastatic solid tumors, thus predicting short survival. Drugs that are capable of inhibiting osteoclast activity, such as bisphosphonates, lead to a reduction in progressive bone resorption and to the correction of hypercalcemia. The monoclonal antibody denosumab, mimicking the effects of osteoprotegerin that inhibits RANKL-RANK interactions by binding to RANKL, may decrease osteoclast-related bone resorption, normalizing or reducing serum calcium levels in most patients with HM.
References: (1) Hu et al., J Natl Cancer Inst 105:1417-20, 2013; (2) Lumachi et al., Curr Med Chem 18:3529-36, 2011; (3) Lumachi et al., Med Chem 8:551-5, 2012
Pathophysiology and Treatment of Nonfamilial Hyperparathyroidism
No full textPrimary hyperparathyroidism (HPT) is the main cause of hypercalcemia and the most common parathyroid glands disease. The diagnosis is easy in patients with hypercalcemia and elevated PTH serum level. Minimally invasive parathyroidectomy (PTx) represents the treatment of choice for symptomatic patients, leading to several advantages, including immediate normalization of hypercalcemia and significant improvement of bone mineral density, cardiovascular dysfunctions, neuropsychological symptoms and quality of life. Secondary and tertiary HPT are relatively common complications in patients with chronic kidney disease (CKD) or advanced kidney failure, and in kidney transplant recipients who did not achieve complete calcium/phosphate metabolism normalization, respectively. The drugs available for patients with secondary HPT, and to treat hyperphosphatemia include non-calcium-containing phosphate binder, calcitriol analogues, calcimimetic agents, or a combination of two or more drugs. Although recent studies report that PTx significantly improves survival also in patients with CKD and severe secondary HPT, the indications for surgery are not yet well established. Subtotal or total PTx with or without autotransplantation are the surgical options for treating all patients with secondary HPT. Total PTx leads to a faster reduction in serum calcium level and normalization of PTH, but the risk of hypoparathyroidism is higher than after subtotal PTx. Further studies are needed to confirm the usefulness of the drugs currently recommended, and others will have to be tested in the near future
Severe cancer-related hypercalcemia in a patient with unresectable neuroendocrine pancreatic malignant tumor treated with NAB-P/GEM chemotherapy and denosumab
No full textBackground: Pancreatic cancer (PC) is an aggressive tumor that accounts for 3-4% of all cancers. Unfortunately, 80% of PCs are diagnosed when the disease has already given regional or distant metastases, and the 5-year overall survival rate is approximately 5%. Neuroendocrine pancreatic tumors (pNETs) are much less common (<5%) than exocrine tumors and are usually nonfunctional. The rare functional pNETs overproduce hormones, consequently exhibiting different hormone-related symptoms. In all patients with PC unsuitable for surgery or who refuse surgery, two 4-drug regimens, named PEFG (cisplatin, epirubicin, 5FU, gemcitabine) and FOLFIRINOX (folinic acid, 5FU, irinotecan, oxaliplatin), have been shown to give better results towards gemcitabine alone. Recently, nab-paclitaxel (nanoparticle albumin-bound paclitaxel) plus gemcitabine (NAB-P/GEM) use has been suggested.
Clinical case: A 57-year-old man, with a history of hyperthyroidism and type II diabetes mellitus, underwent hematological screening complaining indolent abdominal and lumbar pain, progressive weight loss, and mild jaundice. The main biochemical data were hyperbilirubinemia, hypercalcemia (3.8 mmol/L), elevated chromogranin A (1,237 ng/mL), low TSH, low PTH (0.9 ng/L), and high levels of parathyroid hormone-related protein (PTHrP=72 pmol/L). The CT-scan depicted a 4-cm mass at the head of pancreas involving the surrounding structures, multiple focal liver lesions, and several vertebral and rib metastases. MRI confirmed the presence of liver metastases, and a CT-guided cutting needle biopsy revealed liver metastasis from a moderately differentiated (G2) NET (Ki-67 index=15%). The ECOG performance status of the patient was 4. However, he refused surgery, and thus a NAB-P/GEM was proposed and accepted. NAB-P (125 mg/m2) and GEM (1000 mg/m2) on day 1, 8, 15 every 28 days for 4 cycles plus octreotide long-acting release (LAR), 30 mg every 4 weeks, were administered. With the aim of reducing hypercalcemia, zoledronic acid (ZA), 4 mg every 4 weeks was used. No grade 3-4 adverse events occurred, and the treatment continued until 6 cycles. A significant objective response detected on CT was obtained at 4-month follow-up. Unfortunately, serum calcium levels did not change significantly, and thus the patient received denosumab (120 mg on days 1, 2, 4, 8, 12, 16, 20 and then 120 mg every 2 weeks). A normalization of serum calcium levels was obtained after 2 weeks.
Conclusions: Cancer-related hypercalcemia (CRH) is the second cause of hypercalcemia, and is observed in up to 20% of patients with advanced malignancy. In patients with pNETs, CRH is very uncommon, and is usually related to PTHrP production by the cancer cells (humoral hypercalcemia). Patients with CRH due to pNETs can be treated with a combination of chemotherapy, and ZA or denosumab. Peptide receptor radionuclide therapy with 177Lutetium DOTA-octreotate administration should be reserved for unresponsive patients
Surgical Treatment of Hypercalcemia
No full textIn patients with hypercalcemia the surgical treatment is likely limited to those with primary hyperparathyroidism (HPT), which represents the most frequent cause of this biochemical alteration. Hypercalcemia may also occur in up to 30% of patients with cancer, but unfortunately they are usually unsuitable for surgery. Surgery of parathyroid glands is particularly challenging,
because PT anatomy is one of the variables of our organism. The treatment of choice for patients with symptomatic primary HPT is removal of the affected parathyroid(s), that can be achieved both by surgical and non-surgical techniques. The latter is used only in selected patients, when surgery is contraindicated. In asymptomatic patients, surgical parathyroidectomy is usually suggested to prevent complications, but its role is controversial. Bilateral cervical exploration has been the procedure of choice for decades, and it is still mandatory in case of suspicion of multiglandular
disease or malignancy, and multiple endocrine neoplasia or familial syndromes. Recent advances in preoperative localization studies, and intraoperative adjuncts, such as quick parathyroid hormone assay, encouraged as a less invasive surgery. Currently, minimally invasive arathyroidectomy is widely performed, both videoassisted and radioguided. Considering the significant improvements of
clinical features of the disease after surgery, and the effectiveness and safety of minimally invasive surgical techniques, parathyroidectomy should be suggested both in symptomatic patients and in those with minimally symptomatic primary HPT. However, each patient should be referred to an
experienced parathyroid surgeon or endocrinologist, with the aim of having a better definition of the disease, and the best recommendation for treatment
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