Efficacy and Safety of Tyrosine Kinase Inhibitors in Patients with Metastatic Pheochromocytomas/Paragangliomas.

CONTEXT: Tyrosine kinase inhibitors (TKIs) can be used to treat locally unresectable or distantly metastatic pheochromocytomas/paragangliomas (PPGLs), such as sunitinib, according to the National Comprehensive Cancer Network guidelines in 2022. However, the precise effect of different TKIs in metastatic PPGLs is still unclear. OBJECTIVE: The aim of this meta-analysis is to assess the efficacy and safety of TKIs in metastatic PPGLs. METHODS: The PubMed, Cochrane Library, Scopus, Clinical Trial, and Embase databases were searched by synonyms of 48 TKIs and metastatic PPGLs from inception up to August 2022. Outcomes were tumor response or survival data and the incidence of adverse events (AEs) after treatment. The MIONRS scale and the JBI's tools for case series were used for interventional and observational studies to assess risk of bias, respectively. The combined effects with fixed- or random-effect models, the combined median with the weighted median of medians method and their 95% CIs were reported. RESULTS: A total of 7 studies with 160 patients were included. Tumor responses in metastatic PPGLs in 5 studies with available data showed the pooled proportion of partial response (PR), stable disease, and disease control rate (DCR) of, respectively, 0.320 (95% CI 0.155-0.486), 0.520 (95% CI 0.409-0.630), and 0.856 (95% CI 0.734-0.979). The combined median progressive-free survival in 6 studies was 8.9 months (95% CI 4.1-13.5) and the proportion of those who discontinued due to AEs in 5 studies was 0.143 (95% CI 0.077-0.209). CONCLUSION: This meta-analysis suggests that patients with metastatic PPGLs can benefit from TKI therapy with PR and DCR up to more than 30% and 80%. However, because of restricted studies, larger clinical trials should be performed in the future.

Mass spectrometry-based steroid profiling in primary bilateral macronodular adrenocortical hyperplasia.

Biochemical characterization of primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by distinct plasma steroid profiles and its putative correlation to disease has not been previously studied. LC-MS/MS-based steroid profiling of 16 plasma steroids was applied to 36 subjects (22 females, 14 males) with PBMAH, 19 subjects (16 females, 3 males) with other forms of adrenal Cushing's syndrome (ACS), and an age and sex-matched control group. Germline ARMC5 sequencing was performed in all PBMAH cases. Compared to controls, PBMAH showed increased plasma 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, and aldosterone, but lower progesterone, DHEA, and DHEA-S with distinct differences in subjects with and without pathogenic variants in ARMC5. Steroids that showed isolated differences included cortisol and 18-oxocortisol with higher (P < 0.05) concentrations in ACS than in controls and aldosterone with higher concentrations in PBMAH when compared to controls. Larger differences in PBMAH than with ACS were most clear for corticosterone, but there were also trends in this direction for 18-hydroxycortisol and aldosterone. Logistic regression analysis indicated four steroids - DHEA, 11-deoxycortisol, 18-oxocortisol, and corticosterone - with the most power for distinguishing the groups. Discriminant analyses with step-wise variable selection indicated correct classification of 95.2% of all subjects of the four groups using a panel of nine steroids; correct classification of subjects with and without germline variants in ARMC5 was achieved in 91.7% of subjects with PBMAH. Subjects with PBMAH show distinctive plasma steroid profiles that may offer a supplementary single-test alternative for screening purposes.

Isolation and Characterization of NP-POL Nonapeptide for Possible Therapeutic Use in Parkinson's Disease.

Colostrum and milk are the initial mammalian nourishment and rich reservoir of essential nutrients for newborn development. Bioactive peptides isolated from natural sources, such as colostrum, serve as endogenous regulators and can be used as alternative therapeutic agents in the treatment of neurodegenerative diseases. One example is the previously unknown NP-POL nonapeptide isolated from Colostrinin. In the present study, we investigated a method of NP-POL nonapeptide isolation using Bio-Gel P2 molecular sieve chromatography. We showed the protective effect of NP-POL on 6-hydroxydopamine- (6-OHDA-) induced neurotoxicity using rat adrenal pheochromocytoma (PC12 Tet On) cells. Treatment of PC12 cells with NP-POL nonapeptide reduced 6-OHDA-induced apoptosis and caused transient phosphorylation of extracellular signal-regulated kinases (ERK 1/2), which were shown to promote cell survival. NP-POL nonapeptide also protected neuronal cells against oxidative injury induced by 6-OHDA. These results showed a potential use of NP-POL in the therapy of Parkinson's disease.

Total Laparoscopic Management for Stage IV Colorectal Cancer Requiring Multivisceral Resection.

BACKGROUND: Surgical resection of all sites of disease, in combination with effective systemic chemotherapy, offers the only potential chance for cure for patients with stage IV colorectal cancer (CRC). Coordinated multistage resection using a minimally invasive approach may provide optimal oncologic outcome while potentially offering the benefit of decreased morbidity. PATIENT: A 66-year-old women presented with transverse colon cancer and synchronous metastasis (CRLM) in segment IV involving the middle hepatic vein and main left portal pedicle, as well as the left adrenal gland. Due to favorable response to neoadjuvant chemotherapy (FOLFOX/bevacizumab), the patient was considered for resection but developed some obstructive symptoms from the primary tumor, necessitating re-coordination of treatment sequencing from the 'liver-first' approach. METHODS: The first procedure combined laparoscopic subtotal colectomy (extracorporeal anastomosis) with left adrenalectomy. After restaging, CRLM was removed separately 2 months later via laparoscopic left hepatectomy extending beyond the middle hepatic vein. Successful completion of the two procedures depended on optimal patient/port positioning for the combined colon/adrenal surgery and the second-stage liver resection. Postoperative lengths of stay were 4 and 3 days, respectively, and were without complication. Adjuvant FOLFOX was initiated 21 days following liver surgery, and the patient has been disease-free for 36 months. CONCLUSION: This case illustrates the feasibility of the total laparoscopic approach to multivisceral resection for synchronous stage IV CRC in the context of a preplanned, staged multidisciplinary strategy. This approach may offer optimal cancer management, including early return to systemic therapy, shortened time intervals between stages, and minimal postoperative morbidity.1 - 3.

Assessment of the potential activity of major dietary compounds as selective estrogen receptor modulators in two distinct cell models for proliferation and differentiation.

Estrogen receptors (ERs) α and ß are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as a model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases.

Prolonged Isotretinoin in Ultra High-Risk Neuroblastoma.

Patients with high-risk neuroblastoma remain a therapeutic challenge with significant numbers of patients failing to respond sufficiently to initial therapy. These patients with poor response to induction are considered as ultra high-risk and are in need of novel treatment strategies. Isotretinoin is part of the standard of care treatment for patients with high-risk disease who undergo high-dose chemotherapy with autologous stem cell rescue although some have questioned the optimal administration schedule. Prolonged use of isotretinoin was well tolerated and may have contributed to long-term survival in a group of patients with ultra high-risk neuroblastoma.

Neurite outgrowth stimulatory effects of myco synthesized AuNPs from Hericium erinaceus (Bull.: Fr.) Pers. on pheochromocytoma (PC-12) cells.

BACKGROUND: Hericium erinaceus has been reported to have a wide range of medicinal properties such as stimulation of neurite outgrowth, promotion of functional recovery of axonotmetic peroneal nerve injury, antioxidant, antihypertensive, and antidiabetic properties. In recent years, the green synthesis of gold nanoparticles (AuNPs) has attracted intense interest due to the potential use in biomedical applications. The aim of this study was to investigate the effects of AuNPs from aqueous extract of H. erinaceus on neurite outgrowth of rat pheochromocytoma (PC-12) cells. METHODS: The formation of AuNPs was characterized by UV-visible spectrum, energy dispersive X-ray (EDX), field-emission scanning electron microscope (FESEM), transmission electron microscopy (TEM), particle size distribution, and Fourier transform-infrared spectroscopy (FTIR). Furthermore, the neurite extension study of synthesized AuNPs was evaluated by in vitro assay. RESULTS: The AuNPs exhibited maximum absorbance between 510 and 600 nm in UV-visible spectrum. FESEM and TEM images showed the existence of nanoparticles with sizes of 20-40 nm. FTIR measurements were carried out to identify the possible biomolecules responsible for capping and efficient stabilization of the nanoparticles. The purity and the crystalline properties were confirmed by EDX diffraction analysis, which showed strong signals with energy peaks in the range of 2-2.4 keV, indicating the existence of gold atoms. The synthesized AuNPs showed significant neurite extension on PC-12 cells. Nerve growth factor 50 ng/mL was used as a positive control. Treatment with different concentrations (nanograms) of AuNPs resulted in neuronal differentiation and neuronal elongation. AuNPs induced maximum neurite outgrowth of 13% at 600 ng/mL concentration. CONCLUSION: In this study, the AuNPs synthesis was achieved by a simple, low-cost, and rapid bioreduction approach. AuNPs were shown to have potential neuronal differentiation and stimulated neurite outgrowth. The water-soluble bioconstituents could be responsible for the neuroactivity. This is the first report for the biosynthesis of AuNPs using the hot aqueous extract of H. erinaceus.

Osthole attenuates doxorubicin-induced apoptosis in PC12 cells through inhibition of mitochondrial dysfunction and ROS production.

Doxorubicin (DOX) is a potent, broad-spectrum chemotherapeutic drug used for treatment of several types of cancers. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent prooxidant activity. It has been reported that DOX has toxic effects on normal tissues, including brain tissue. In the current study, we investigated the protective effect of osthole isolated from Prangos ferulacea (L.) Lindl. on oxidative stress and apoptosis induced by DOX in PC12 as a neuronal model cell line. PC12 cells were pretreated with osthole 2 h after treatment with different concentrations of DOX. 24 h later, the cell viability, mitochondrial membrane potential (MMP), the activity of caspase-3, the expression ratio of Bax/Bcl-2, and the generation of intracellular ROS were detected. We found that pretreatment with osthole on PC12 cells significantly reduced the loss of cell viability, the activity of caspase-3, the increase in Bax/Bcl-2 ratio, and the generation of intracellular ROS induced by DOX. Moreover, pretreatment with osthole led to an increase in MMP in PC12 cells. In conclusion, our results indicated that pretreatment with nontoxic concentrations of osthole protected PC12 cells from DOX-mediated apoptosis by inhibition of ROS production.

Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol: a pilot study.

BACKGROUND: Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly population has an 'adrenal incidentaloma', up to 20% of these show low-grade autonomous cortisol secretion and 60% of patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible. METHODOLOGY/PRINCIPAL FINDINGS: In a prospective open-label pilot study, six individuals with adrenal incidentalomas and autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03), lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in insulin AUC >7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by the Helsinki heart study). CONCLUSIONS: Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT00721201.

Triterpene saponins from the roots of Dipsacus asper and their protective effects against the Aß(25-35) induced cytotoxicity in PC12 cells.

Three new triterpene saponins, named asperosaponin A-C (1-3), together with seven known triterpene saponins (4-10) were isolated from the roots of Dipsacus asper. The structures of compounds 1-3 were elucidated on the basis of detailed spectroscopic analysis and chemical methods. Compounds 1-3, 6-10 had significantly protective effects in PC12 cells against the Aß(25-35) induced cytotoxicity. All the compounds isolated showed no cytotoxic activity against three human cancer cell lines, A-549, Bel-7402 and BGC-823.

Long-term response and postsurgical complete remissions after treatment with sunitinib malate, an oral multitargeted receptor tyrosine kinase inhibitor, in patients with metastatic renal cell carcinoma.

Receptor tyrosine kinase (RTK) inhibitors have revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and significantly extended survival in these patients. Sunitinib is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs-1, -2, and -3), platelet-derived growth factor receptors (PDGFRs-α and -ß), stem-cell factor receptor (KIT), FMS-like tyrosine kinase 3 (FLT3), colony-stimulating factor 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (REarranged during Transfection; RET). Sunitinib is approved multinationally for the treatment of advanced RCC, and is considered the reference standard of care for first-line treatment. In clinical trials, sunitinib has been associated with a consistent, distinct profile of adverse events. Here we describe three cases that show that it is possible to manage adverse events occurring during sunitinib therapy, and thus allow patients with mRCC to receive an effective dose of sunitinib in order to achieve long-term disease control. These cases also show that surgical resection, performed whenever possible, can help to improve control of metastatic disease and so avoid the unnecessary toxicity and high costs of prolonged antiangiogenic therapy.

Pharmacologic modulation of serine/threonine phosphorylation highly sensitizes PHEO in a MPC cell and mouse model to conventional chemotherapy.

BACKGROUND: The failure of cytotoxic cancer regimens to cure the most drug-resistant, well-differentiated solid tumors has been attributed to the heterogeneity of cell types that differ in their capacities for growth, differentiation, and metastases. We investigated the effect of LB1, a small molecule inhibitor of serine/threonine protein phosphatase 2A (PP2A), on its ability to inhibit a low growth fraction and highly drug-resistant solid neuroendocrine tumor, such as metastatic pheochromocytoma (PHEO). Subsequently, we evaluated the increased efficacy of chemotherapy combined with LB1. METHODOLOGY/PRINCIPAL FINDINGS: The effect of LB1 and temozolomide (TMZ), a standard chemotherapeutic agent that alone only transiently suppressed the growth and regression of metastatic PHEO, was evaluated in vitro on a single PHEO cell line and in vivo on mouse model of metastatic PHEO. In the present study, we show that metastatic PHEO, for which there is currently no cure, can be eliminated by combining LB1, thereby inhibiting PP2A, with TMZ. This new treatment approach resulted in long term, disease-free survival of up to 40% of animals bearing multiple intrahepatic metastases, a disease state that the majority of patients die from. Inhibition of PP2A was associated with prevention of G1/S phase arrest by p53 and of mitotic arrest mediated by polo-like kinase 1 (Plk-1). CONCLUSIONS/SIGNIFICANCE: The elimination of DNA damage-induced defense mechanisms, through transient pharmacologic inhibition of PP2A, is proposed as a new approach for enhancing the efficacy of non-specific cancer chemotherapy regimens against a broad spectrum of low growth fraction tumors very commonly resistant to cytotoxic drugs.

Painless acute pancreatitis associated with sorafenib treatment: a case report.

Sorafenib is a multikinase inhibitor that is used for the treatment of metastatic renal-cell carcinoma. We report the case of a patient with painless acute pancreatitis associated with sorafenib treatment. The patient was a 71-year-old man who had undergone surgery for left renal carcinoma and tumor thrombus in the inferior vena cava and right atrium (IVC-RA). After a follow-up period of 3 years, he developed right adrenal metastasis and received interferon (IFN)-alpha treatment. One year later, progression of the adrenal metastasis was observed, and he was admitted to a hospital for treatment with sorafenib, which was administered at a dose of 800 mg/day. Two weeks later, he developed painless acute pancreatitis associated with sorafenib treatment. Thereafter, sorafenib treatment was discontinued, and he was treated with conservative therapy. Three weeks later, he was discharged. Even though painless acute pancreatitis associated with sorafenib treatment is rare, the possible development of painless acute pancreatitis in patients undergoing sorafenib treatment must be kept in mind.

Increased uptake of [¹²³I]meta-iodobenzylguanidine, [¹8F]fluorodopamine, and [³H]norepinephrine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors.

[¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [¹²³I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P<0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [(123)I]MIBG was significantly increased in liver metastases 9.5 ± 1.1% compared to 3.19 ± 0.4% in untreated control liver metastases (P<0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [(131)I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma.

Evaluation of response in malignant tumors treated with the multitargeted tyrosine kinase inhibitor sorafenib: a multitechnique imaging assessment.

OBJECTIVE: The purpose of this article is to illustrate the characteristic changes induced in different tumor types by the multitargeted tyrosine kinase inhibitor sorafenib. CONCLUSION: Sorafenib reduces tumor perfusion and thereby induces necrosis and often hemorrhage. Malignant tumors treated with sorafenib undergo both morphologic and functional changes; however, the morphologic changes are less frequent and inadequate for early evaluation of response. Therefore, imaging tools accurately assessing hemorrhage and decrease in tumor perfusion with subsequent necrosis should be the mainstay in monitoring targeted therapy agents.

Weekly clodronate treatment prevents bone loss and vertebral fractures in women with subclinical Cushing's syndrome.

INTRODUCTION: Chronic mild endogenous glucocorticoid excess has been shown to cause bone loss and to increase fracture risk in both post-menopausal and premenopausal women. Currently, it is unclear if patients with subclinical Cushing's syndrome (SCS) with osteoporosis or osteopenia may benefit from antiresorptive treatment and the type of therapy to be given. OBJECTIVE: This pilot randomized study was aimed at evaluating the effects of 12-month im administration of clodronate (100 mg every week) on vertebral and femoral bone mineral density (BMD), bone turnover markers and on subjective pain in premenopausal women with SCS due to adrenal incidentalomas. METHODS: Forty-six women (age, 43.1+/-7.7 yr) with SCS due to adrenal incidentaloma and osteoporosis/osteopenia were randomized to receive clodronate plus supplement of Calcium (500 mg daily) and Vitamin D3 (800 mg daily) (group 1, no.=23) or supplements only (group 2, no.=23). Both groups were similar in terms of age, body mass index, cortisol levels, BMD values, and bone turnover markers. All of the women were re-evaluated after 12 months. RESULTS: After 12 months of treatment, in group 1, a significant increase in lumbar BMD occurred (p=0.04), while bone turnover markers decreased by about one third (p<0.05). In group 2, bone turnover markers did not change and BMD values slightly decreased (p=ns). The differences in bone turnover markers and in lumbar BMD between the two groups were significant (p<0.05, all). No new vertebral fracture occurred in group 1, while in group 2 the spine radiographies revealed 2 new fractures and a worsening of two pre-existent fractures. An improvement in subjective back pain, assessed by visual analogue scale pain score was observed in group 1 (from 4.3+/-2.7 to 2.9+/-2.0; p<0.05) but not in group 2 (from 4.4+/-3.1 to 4.2+/-3.4; p=ns). No significant changes occurred in cortisol secretion or clinical picture of the SCS during the study. CONCLUSIONS: Intramuscular administration of clodronate effectively increased lumbar BMD values, preserved bone mass at the femoral neck, stabilized vertebral fracture index, and decreased subjective back pain in pre-menopausal women with SCS. Since the untreated group continued to lose bone, antiresorptive treatment should be considered in patients with SCS, according to the prevision of surgical treatment, prevalent fractures, BMD values, age, concomitant morbidities, and desire for pregnancy.

Hepatoblastoma presenting with focal nodular hyperplasia after treatment of neuroblastoma.

Focal nodular hyperplasia (FNH) is a benign, poorly understood hepatic tumor that is rare in children. Although there is no evidence for malignant degeneration, FNH can occur adjacent to a malignancy. Here, the case of a 4-year-old boy with a hepatic mass and history of stage IV neuroblastoma is presented. Initial imaging and core-needle biopsy were consistent with FNH. However, after left lateral segmentectomy, pathologic examination revealed a malignant tumor most consistent with small cell undifferentiated hepatoblastoma as well as 3 foci of FNH in the surrounding parenchyma.

Adrenal metastasis of breast cancer with involvement of the inferior vena cava.

Tumour thrombosis of the inferior cava vein is usually associated with primary renal cell cancer. To our knowledge, this is the first case reported of adrenal metastasis of breast cancer extending into the inferior vena cava. There are few references in the literature documenting this extension with positron emission tomography (PET) and enhanced computed tomography (CT). The authors focus on the role of combined PET-CT imaging in the accurate detection of malignant thrombus.

[The effect of retinoic acid on primary cultures of human pheochromocytoma cells]. / Wplyw kwasu retinowego na komórki pheochromocytoma.

INTRODUCTION: Retinoic acid is a regulator of gene expression which, by binding to its nuclear receptor, determines the degree of differentiation in multiple cancer cell types. On the basis of this capability it was introduced, e.g. in the therapy of neuroblastoma. In cells derived from neural crest, such as neuroblastoma cells, retinoic acid initiates differentiation into neurons. This substance acts in a similar way on a rat pheochromocytoma cell line PC12. The aim of our work was to examine the influence of retinoic acid on the phenotype of human pheochromocytoma cells in primary culture. MATERIAL AND METHODS: Observations were made on two primary cultures isolated from human pheochromocytoma. Cells were grown in RPMI1640 medium supplemented with 10% foetal bovine serum. Subsequently, the cultures were treated with 100 mMol retinoic acid for three-days. An evaluation of the phenotype change was performed by estimating the expression levels of F-actin, MAP-2 protein, and chromogranin, with the use of a confocal microscopy. RESULTS: The introduction of retinoic acid into the culture caused an increase in the F-actin level and its redistribution in the form of stress fibers. Simultaneously, the cells changed their shape, generating more processes. No change was detected in the expression level of neuroendocrine markers: MAP-2 and chromogranin. CONCLUSIONS: Retinoic acid appears to have an influence on some phenotype parameters of human pheochromocytoma cells. Further work is needed to determine the molecular mechanisms of this process, and to evaluate thoroughly the benefits of introducing retinoic acid into therapy of pheochromocytoma tumors.

Growth hormone deficiency after localized ganglioneuroblastoma: A case report.

Growth hormone deficiency (GHD) related to standard dose chemotherapy has rarely been described. We report on a case of localized ganglioneuroblastoma treated by carboplatin/etoposide for 2 courses and surgery, which developed a serious GHD after 56 months. At present, the child is growing on by GH replacement therapy. We discuss about the hypothesis that GHD may be related to chemotherapy and we report a review of previous published cases.