Genetic Determinants of Inherited Endocrine Tumors: Do They Have a Direct Role in Bone Metabolism Regulation and Osteoporosis?

Endocrine tumors are neoplasms originating from specialized hormone-secreting cells. They can develop as sporadic tumors, caused by somatic mutations, or in the context of familial Mendelian inherited diseases. Congenital forms, manifesting as syndromic or non-syndromic diseases, are caused by germinal heterozygote autosomal dominant mutations in oncogenes or tumor suppressor genes. The genetic defect leads to a loss of cell growth control in target endocrine tissues and to tumor development. In addition to the classical cancer manifestations, some affected patients can manifest alterations of bone and mineral metabolism, presenting both as pathognomonic and/or non-specific skeletal clinical features, which can be either secondary complications of endocrine functioning primary tumors and/or a direct consequence of the gene mutation. Here, we specifically review the current knowledge on possible direct roles of the genes that cause inherited endocrine tumors in the regulation of bone modeling and remodeling by exploring functional in vitro and in vivo studies highlighting how some of these genes participate in the regulation of molecular pathways involved in bone and mineral metabolism homeostasis, and by describing the potential direct effects of gene mutations on the development of skeletal and mineral metabolism clinical features in patients.

Is Systemic Anticancer Therapy Associated With Higher Rates of Malignant Pleural Effusion Control in People With Pharmacologically Sensitive Tumors?: A Retrospective Analysis of Prospectively Collected Data.

BACKGROUND: Malignant pleural effusions (MPEs) often cause symptoms, and guidelines recommend early definitive intervention. However, observational data suggest that systemic anticancer treatment (SACT) may control MPE caused by certain pharmacologically sensitive tumors. RESEARCH QUESTION: Is SACT associated with higher rates of MPE resolution in people with pharmacologically sensitive tumors? STUDY DESIGN AND METHODS: This was a retrospective analysis of prospectively collected data from an observational cohort study of people diagnosed with MPE from lung, breast, ovarian, and hematologic malignancy between May 11, 2008, and August 6, 2017. MPE resolution (defined as radiologic resolution with removal of drain or catheter and cessation of interventions) was compared in pharmacologically sensitive (high-grade lymphoma, small cell or target-mutation-positive lung cancer, and hormone-receptor-positive breast or ovarian cancer) and nonsensitive (remainder of cohort) tumors, with and without SACT. Secondary outcomes included time to resolution, 3-month resolution rates, and total pleural interventions. RESULTS: Of 280 patients, 127 had sensitive and 153 had nonsensitive tumors. One hundred seventy-one received SACT, and 109 did not. More patients with sensitive tumors achieved MPE resolution than those with nonsensitive tumors (53/127 [41.7%] vs 42/153 [27.5%]; P = .01), and this occurred predominantly after receipt of SACT. However, hematologic malignancies were overrepresented in the sensitive group, with high rates of SACT use and MPE resolution. After adjustment for this and other confounders, no relationship was found among pharmacologic sensitivity, SACT, and MPE resolution (adjusted OR, 1.4; 95% CI, 0.5-4.1). The strongest predictor of MPE resolution was administration of chemical pleurodesis (adjusted OR, 6.2; 95% CI, 3.3-11.7). In sensitive tumors, MPE resolution occurred without chemical pleurodesis in 14 of 52 patients (26.9%; 95% CI, 15.6%-41.1%) after SACT and in 5 of 22 patients (22.7%; 95% CI, 8.2%-47.2%) without SACT. INTERPRETATION: In this observational study, SACT was not associated independently on MPE resolution in pharmacologically sensitive tumors. Randomized trials are required, but with current data, patients with symptomatic MPE should receive early definitive pleural intervention regardless of underlying tumor or intended treatment.

Paget's disease of the male breast: case report and a point of view from actual literature.

INTRODUCTION: Paget disease of the nipple in man is a very rare breast cancer, and there are not standard procedures or guidelines. In any cases, a Paget's disease could hide an invasive ductal breast cancer. CASE DESCRIPTION: We report the case of a 77-years old man affected by Alzheimer's disease, who presented to our attention because of an ulcerated palpable mass in the right nipple. A biopsy of the lesion showed "intra-epidermic proliferation of epitelioid cells, associated with linfo-plasmacellular infiltration of superficial dermis, compatible with Paget's disease (pTis)". We discussed the case in the multidisciplinary meeting and decided to subject the patient to surgery, so a right mastectomy plus sentinel lymph node biopsy (SLNB) were performed. Histo-pathological examination revealed "invasive ductal carcinoma of the breast, associated with a small component of in situ ductal carcinoma and Paget's disease of the nipple with superficial ulceration". Resection margins were free. Sentinel lymph node was negative. Biological features were as follows: ER 95%, PR 60%, Her-2/neu 1+, Ki-67 35%. The patient was discharged in the third post-operative day in good conditions. In the following weeks the patient's healing process was good and free of complications. CONCLUSIONS: Clinical recognition of Paget's disease is very important also in man, because it can be the alarm bell for an underlying invasive ductal breast cancer, often more aggressive than in woman.

Androgen deprivation in prostate cancer and the long-term risk of fracture. / Deprivación andrógenica en cáncer de próstata y riesgo de fractura a largo plazo.

OBJECTIVES: To determine the rate of bone mass loss and the risk of fracture induced by androgen deprivation therapy in patients with prostate cancer. MATERIAL AND METHODS: Prospective study in 2 phases. In the first phase, demographic variables, FRAX®, bone mineral density and clinical fractures were collected, before starting the therapy and up to 1 year after ending the therapy. In the second phase, we conducted a telephone interview a mean of 8.5 years after the start of the study to assess new fractures. RESULTS: We included 150 patients with a mean age of 67 years and a mean therapy duration of 24 months. Before starting the treatment, 62 patients (41%) showed osteoporosis or low bone mass in the densitometry. After the first year of treatment, the bone mineral density decreased a mean of 3.7% and 2.1% in the lumbar spine and femoral neck, respectively. At the end of the second and third year, the loss rate was lower. During the first phase of the study, 4 patients (2.7%) experienced a fracture. In the telephone interviews with 80 patients (53%), only 1 had experienced a fracture. CONCLUSIONS: In the patients with prostate cancer and androgen deprivation therapy, greater bone loss occurred during the first year. When the treatment did not exceed 2 years, the absolute risk of fracture was low, and clinical fractures were uncommon in the short and long term.

Acne isolated within a Becker nevus of a 14 year-old girl.

Becker nevus (BN) is a common benign condition occurring most often in young men, much more often than in women. Acne isolated within a BN is a rare phenomenon hypothesized to occur, at least in part, due to increased androgen sensitivity within the nevus. We present a rare case of papular acne with in a BN of a 14 year-old girl.

The impact of endocrine therapy on sexual dysfunction in postmenopausal women with early stage breast cancer: encouraging results from a prospective study.

The goal of this project was to investigate the contentious issue of a possible effect of endocrine therapy (ET) on sexual dysfunction (SD) in postmenopausal early stage breast cancer survivors. To date, few studies have assessed sexual functioning prior to initiating ET and none have taken sexual distress into account when reporting the prevalence of ET-induced SD. We report the findings of a study on the change in SD (defined as experiencing sexual problems causing distress) during the first 6 months of ET usage. Between January 2009 and May 2011, 118 patients entered the study and 66 completed questionnaires prior to initiation of ET and after 6 months of use. Sexual functioning (SF) was evaluated with the female sexual function index while sexual distress was assessed with the female sexual distress scale (FSDS-R). Gynecological symptoms were measured with the FACT-B ES subscale. Over time, the level of gynecological symptoms increased (p < 0.001), whereas no decline in SF was observed. The percentage of women who reported experiencing at least one sexual problem (85 %) and the percentage who were sexually distressed (30 %) remained the same across time. Importantly, the change in the prevalence of SD between baseline (24 %) and 6 months (29 %) was not statistically significant. Women experiencing SD at baseline were more likely to experience SD after 6 months of ET usage (OR = 7.4, 95 % CI = 1.5-36.9) than women who had no SD prior to initiating ET. The observation that SF remained stable across time is encouraging news. However, longer follow-up and the inclusion of women who were premenopausal at diagnosis are needed to determine the potential influence of extended duration of ET (e.g., at least 5 years) on SD. Further studies, including assessing the impact of early identification of patients at risk of developing SD and timely intervention, are warranted.

Is polycystic ovary syndrome, a state of relative estrogen excess, a real risk factor for estrogen-dependant malignancies?

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting women of fertile age. It is associated with several risk factors and long-term health consequences. Chronic anovulation combined with relative estrogen excess and consequent prolonged stimulatory effect on the endometrium can lead to the pathogenesis of hormonal dependant carcinoma. PCOS is thus traditionally reported to be associated with increased risk of endometrial, as well as breast and ovarian cancers. This article provides a critical literature review of the relationship between PCOS and the incidence of estrogen-dependant gynecological tumours, and it then discusses whether the commonly cited risk factor association can be substantiated by high quality studies which comply with the requirements of "evidence-based medicine."

[Loss of bone mass in patients with prostate cancer subjected to androgenic deprivation]. / Pérdida de masa ósea en pacientes con cáncer de próstata sometidos a deprivación androgénica.

CONTEXT: Treatment based on androgenic deprivation is one of the standard treatments that many prostate cancer patients receive. Moreover, its use is increasing due to a clear expansion of the indications of this therapy in patients with localized cancer. SUMMARY OF EVIDENCE: In spite of being classically considered that it is well tolerated, androgenic deprivation has adverse effects. Of these, it is worth mentioning the loss of mineral bone mass, which can lead to osteoporosis and increase the risk of bone fracture. Some fractures may have serious consequences, as occurs with hip fractures. To make a diagnosis in this situation, there are useful procedures such as bone densitometry. Once diagnosed, the decrease in mineral bone mass can be managed with dietary recommendations, general changes in lifestyle, or with drugs such as denosumab. CONCLUSIONS: Following applicable recommendations, urologists must carefully monitor the bone health of patients with prostate cancer subjected to androgenic deprivation, in order to obtain an early diagnosis and to apply the appropriate general and/or therapeutic measures, if necessary.

Cranial nerve deficit caused by skull metastasis of prostate cancer: three Japanese castration-resistant prostate cancer cases.

We report 3 Japanese patients with cranial nerve deficit caused by skull metastasis of prostate cancer (PCa). Case 1 was a 75-year-old patient with a chief complaint of diplopia. The cause of diplopia was right oculomotor nerve palsy from the skull metastasis. External beam radiation therapy (EBRT) to the whole brain, 40 Gy in 20 fractions, was performed and the diplopia improved. Case 2 was a 72-year-old patient with a chief complaint of facioplegia. Bone scintigraphy and computed tomography (CT) of the head revealed right occipital bone metastasis of PCa resulting in right facial nerve palsy. EBRT to the right occipital bone, 50 Gy in 25 fractions, with daily oral dexamethasone (DEX) was performed and facioplegia showed complete recovery. At 12 months after onset, the patient was followed-up with no symptoms. Case 3 was a 74-year-old patient with a chief complaint of diplopia. Diffusion-weighted magnetic resonance imaging (MRI) and positron emission tomography (PET) showed right petrous bone metastasis resulting in right abducent nerve palsy. EBRT to the right petrous bone, 44 Gy in 22 fractions, with oral DEX was performed and diplopia showed complete recovery. At 13 months after onset, the patient was followed-up with no symptoms. MRI and PET may detect PCa metastasis in the skull base more clearly than other imaging modalities. EBRT with 40-50 Gy in 20-25 fractions in association with corticosteroid administration may be reasonable treatment of patients with metastatic PCa who develop cranial nerve dysfunction.

[A negative first-line work-up of Raynaud's phenomenon: And what if it were cancer?]. / Phénomène de Raynaud avec négativité du bilan de première intention : et si c'était un cancer ?

Raynaud's phenomenon is a transient paroxysmal vasomotor phenomenon affecting the extremities including manifestations of ischemia. It is a common phenomenon in the general population. In a routine clinical situation, the first step is to differentiate Raynaud's disease from a secondary Raynaud's phenomenon, the latter requiring complementary investigations. We report here the case of an 80-year-old woman who presented a secondary Raynaud's phenomenon. First-line investigations remained negative. A mammography was performed and revealed breast cancer. Raynaud's phenomenon disappeared after treatment of the breast carcinoma and did not recur during the 2-year follow-up.

Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study.

Denosumab increased lumbar spine bone mineral density (BMD) versus placebo in a 2-year, randomized, placebo-controlled, phase 3 study of patients with hormone-receptor-positive, non-metastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy. In subgroup analyses at 12 and 24 months, we evaluated factors (duration and type of aromatase inhibitor, tamoxifen use, age, time since menopause, body mass index, T-score) that might influence BMD at the lumbar spine, total hip, femoral neck, and 1/3 radius. Patients were randomized to receive placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months. In all subgroups, 12 or 24 months' treatment with denosumab was associated with larger BMD gains than placebo across multiple skeletal sites. Most increases were statistically significant (P < 0.05). Twice-yearly administration of denosumab, regardless of patient subgroup or skeletal site, resulted in consistent increases in BMD versus placebo at 12 and 24 months.

Management of metastatic prostate cancer: the crucial role of geriatric assessment.

Prostate cancer predominantly affects older men, with a median age at diagnosis of 68 years. Due to the increased life expectancy, management of prostate cancer in senior adults (aged >70 years) represents a major public health problem. This patient population may not receive optimal therapy for their disease, if decisions are made based on their chronological age alone. More so than age alone, health status is a major factor affecting individual life expectancy. Comorbidity is the key predictor of health status and should weigh more heavily on the treatment decision than age alone. Other important parameters to consider in senior adults are the degree of dependence in activities of daily living, the nutritional status and the presence or not of a geriatric syndrome. Although clinical trials are rarely designed specifically for senior adults, evidence suggests that healthy senior adults have similar treatment outcomes to their younger counterparts. The urological approach in senior adults with advanced prostate cancer should be fundamentally the same as in younger patients. In hormone-sensitive metastatic prostate cancer, androgen deprivation represents the first-line treatment. In senior adults, care should be given to the increased risk of metabolic syndrome, cardiovascular mortality and bone fracture. In hormone-refractory metastatic prostate cancer, chemotherapy with docetaxel (75 mg/m(2) every 3 weeks) plus low-dose prednisone is the standard and shows the same efficacy in healthy senior adults as in younger patients. The tolerance of docetaxel (3-weekly schedule) has not been specifically studied in vulnerable and frail senior adults. The place of weekly docetaxel in this setting should be further evaluated. Palliative treatments (palliative surgery, radiopharmaceutics, radiotherapy, medical treatments for pain and symptoms, pharmacological palliative therapies) should also be integrated in the global management of these patients. In conclusion, treatment decisions in senior adults should be adapted to health status. Healthy senior adults should be treated the same as younger patients. The development of guidelines for the management of localized and advanced prostate cancer in senior adults is underway.

Approach to the prostate cancer patient with bone disease.

Prostate cancer is the most common visceral malignancy in men. Androgen deprivation therapy (ADT) is commonly used in patients with nonmetastatic prostate cancer and is associated with significant bone loss and fractures. The greatest bone loss occurs during initiation of ADT. Men should have assessment of skeletal integrity with bone mineral density examination by dual x-ray absorptiometry of the hip and spine. Men with fragility fractures or osteoporosis by bone density should be considered for bisphosphonate therapy. Men with low bone mass may need antiresorptive therapy, depending on other risk factors. Men with a normal bone mineral density should be followed up closely with bone densitometry while on ADT. All men should receive preventive measures with calcium (1200 mg daily in divided doses), vitamin D (800-1000 IU/d), and weight-bearing exercise. Men should be evaluated for additional secondary causes of bone loss including vitamin D insufficiency. Guidelines are needed for androgen-induced bone loss screening and treatment.

The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid.

BACKGROUND: Bisphosphonates have been used to treat bone metastases in hormone-refractory prostate cancer (HRPC), but certain agents have been associated with renal toxicity. For this observational study, the authors assessed the risk of renal impairment in patients with HRPC who received zoledronic acid from December 1999 to April 2005. METHODS: A comprehensive medical records review was performed in a major tertiary oncology center (n = 122 patients). The primary outcome of renal impairment was defined as an increase >or=0.5 mg/dL or >or=1.0 mg/dL over baseline creatinine value if the baseline value was <1.4 mg/dL or >or=1.4 mg/dL, respectively. A risk factor analysis was conducted using the Andersen-Gill extension to the Cox proportional hazards model. RESULTS: Renal impairment was observed in 23.8% of patients. The risk of renal impairment increased with an extended duration of zoledronic acid therapy (<6 months, 11.1%; >or=24 months, 26.3%) and previous pamidronate treatment (45.5% vs 19.0% for patients with no prior pamidronate). A significantly greater risk of renal impairment was associated with increasing age at zoledronic acid initiation, prior pamidronate use, and a history of renal disease, hypertension, or smoking (P