Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010–2014)

Background

The spectrum of lung neuroendocrine tumors (NETs) encompasses low grade typical carcinoid (TC), intermediate grade atypical carcionid (AC) and high grade, both large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC), with extreme differences in management and survival.

Tolerability of the synthetic retinoid fenretinide® (HPR)

Fenretinide®, N-(4-hydroxyphenyl)retinamide (HPR), is a synthetic retinoid which has been proven effective in inducing cell differentiation and in inhibiting carcinogen induced mammary tumors in rodents. Because of its efficacy and low toxicity in animals, HPR has been proposed for chemopreventive evaluation in humans. Thus, a randomized trial has been conducted to select a dose which can be administered over a lengthy period of time and with acceptable toxicity. The retinoid was administered orally to patients already operated on for breast cancer in daily doses of 100, 200 and 300 mg for 6 months and subsequently at 200 mg for another 6 months. No acute toxicity was found. Dermatological toxicity was minimal and no liver function abnormalities were observed. Nausea and headaches were infrequent and always mild. Menstrual irregularities were recorded with similar frequency in the treatment and placebo groups and appeared to be more age related than drug dependent. After 6 months of treatment one of 25 patients taking 300 mg HPR daily experienced impaired night vision, confirmed by the electroretinogram, and resolved by interruption of treatment. Because the 300 mg daily dose is possibly associated with impaired dark adaptation, the recommended dose for chemoprevention trials of HPR is 200 mg per day.     

Fulvestrant ('Faslodex'): extending the reach of endocrine therapy?

An effective option for estrogen receptor-positive breast cancer, endocrine therapy has had a significant role in improving the survival of women with postmenopausal breast cancer for more than 20 years. However, acquired resistance to disease by cancer cells is the repeated cause of relapse for patients. This supplement explores current thinking on resistance to endocrine therapy and, in particular, the potential role for fulvestrant ('Faslodex'), a novel endocrine therapy that possesses a unique mechanism of action.     

Cysteine cathepsins (proteases)--on the main stage of cancer?

Cysteine cathepsins are involved in degradation of extracellular matrix, facilitating growth, invasion, and metastasis of tumor cells, in tumor angiogenesis, in apoptosis, and in events of inflammatory and immune responses. In this issue of Cancer Cell, demonstrate association of increased cathepsins activity with angiogenic vasculature and invasive fronts of carcinomas during tumorigenesis in transgenic mouse models using activity-based chemical probes and in vivo imaging. Moreover, this study shows that a broad-spectrum cysteine cathepsin inhibitor effectively blocks several stages of tumorigenesis in the RIP1-Tag2 transgenic mouse model, offering new therapeutic opportunities in cancer treatment.     

Hydroxyurea potentiation of the antineoplastic activity of cyclophosphamide and 4′-(9-acridinylamino)methanesulfon-M-anisidide (AMSA) in the brown Norway rat myelocytic leukemia model

Summary The activities of hydroxyurea (HU), 4-(9-acridinylamino) methanesulfon-M-anisidide (AMSA) and cyclophosphamide (CY) were examined in the brown Norway rat myelocytic leukemia model in experiments designed to determine the synergy, optimal drug sequencing, and therapeutic index of combinations of these agents. A single dose of CY or four consecutive daily doses of AMSA produced increased survival in leukemic rats, with a positive-slope dose-response curve up to the maximum tolerated dose (MTD). HU at 1/2 MTD produced a minimal antileukemic effect but significantly potentiated the antineoplastic activity of 1/2 MTD of CY or AMSA with no significant toxic death rate. Drug-sequence experiments demonstrated that maximal synergy was achieved when HU was given immediately after CY but immediately before or during AMSA administration. No significant cure rate was seen with any CY/HU or HU/AMSA sequence. The three drugs given in the sequence of CY followed 3 days later by HU and AMSA simultaneously, however, was curative in the majority of rats with advanced leukemia, whereas other sequences were more toxic or less effective. Each of the drugs in these experiments was given at 1/2 of its single-agent MTD. HU significantly potentiates the antineoplastic effect of CY and AMSA in a drug-sequence-dependent manner in this model, apparently with an improved therapeutic index.Supported by the State of Nebraska Cancer and Smoking Disease Research Program Grant #87-10R     

Expression of somatostatin receptors in oncocytic (Hürthle cell) neoplasia of the thyroid

Ten consecutive patients with Hürthle cell lesions of the thyroid (nodule/adenoma/carcinoma) were studied by (111)In-DTPA-D-Phe1-octreotide scintigraphy. Octreotide scintigraphy localized the primary Hürthle cell tumour in eight patients as distinct areas of increased uptake of radionuclide. Two patients with Hürthle cell carcinoma, previously thyroidectomized, had their metastases visualized by octreotide scintigraphy. Northern analyses showed expression of multiple somatostain receptor subtypes. Visualization of the Hürthle cell tumour may be due to a higher expression of somatostatin receptors in the lesions than in surrounding normal thyroid tissue. The tissue/blood (111)In concentration ratios for tumour samples from five patients showed clearly higher values than observed for normal connective tissue, muscle or lymph nodes. A relatively high uptake of (111)In was also observed in goiter tissue, which may lead to misinterpretations. The main indication for octreotide scintigraphy in patients with Hürthle cell carcinoma is suspicion of metastatic disease.     

High-precision conformal radiotherapy (HPCRT) of prostate cancer—a new technique for exact positioning of the prostate at the time of treatment

Purpose: Biopsies taken 2 years after radiotherapy of localized prostate cancer indicate residual tumor cells in 20–60% of cases, and the prognosis for these patients is unfavorable. More precise methods of localization of the prostate are desirable to increase the dose to the prostate tumor and minimize the volume of adjacent sensitive tissues that are currently included in the planning target volume. We have sought a method to more accurately locate the prostate at the time of treatment, allowing a reduction of the volume of rectum and bladder included in the high dose region during dose escalation.Methods and Results: We have developed a new technique using a special urethral catheter (patent pending), containing markers that can be visualized by the radiotherapy machine for accurate positioning of the prostate. The catheter is used throughout the treatment planning procedure and the isocenter is placed on one of the markers. On the treatment couch the markers are visualized on port-films and with portal imaging immediately before dose delivery. A beam-center-marker on the accelerator makes it possible to adjust the isocenter position to within 1 mm, giving very high precision, independent of external fixation. The technique involves a simple patient setup. The method has been tested in five patients with conventional dose level (70 Gy) and in 24 patients in the first Scandinavian dose escalation study with external beam radiotherapy. No increase in acute side-effects was observed.Conclusion: With the new high precision conformal radiotherapy (HPCRT) technique we have developed a technique that allows us to increase the dose to the prostate without excessive side effects. The method reduces the uncertainties in prostate localization, is easy to handle, and feasible in routine treatment.     

SU11248 (sunitinib) directly inhibits the activity of mammalian 5′-AMP-activated protein kinase (AMPK)

AMPK has been termed the fuel sensor of mammalian cells because it directly responds to the depletion of the fuel molecule ATP. In previous work, we found that AMPK is strongly activated by tumor-like hypoxia and glucose deprivation, independently of the oxygen response system associated with HIF-1. We also observed high levels of AMPK activity in tumor cells in vivo, using different model tumors. These findings suggested the hypothesis that modulation of AMPK activity could have therapeutic value for the treatment of solid tumors. To investigate this hypothesis, we have been conducting a SAR study of potential small-molecule modulators of AMPK activity. Here we report that the chemotherapeutic drug SU11248 (sunitinib) is at least as potent an inhibitor of AMPK as compound C, which is a commonly used experimental direct inhibitor of the enzyme. We also provide a computational model of the binding pose of SU11248 to an AMPKα subunit, which suggests a structural basis for the affinity of the drug for the ATP site of the catalytic domain. The ability of SU11248 to inhibit AMPK has potential clinical significance—there may be populations of SU11248-treated patients in which AMPK activity is inhibited in normal as well as in tumor tissue.Key words: AMPK, compound C, SU11248, sunitinib, type II inhibitor     

Borderline tumours of the ovary: A cohort study of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group

BackgroundBorderline ovarian tumours (BOTs) are recognised as a unique entity of ovarian tumours that do not exert infiltrative destructive growth or stromal invasion. Prognosis of BOT is much better compared to the more common invasive epithelial ovarian cancer. Information regarding prognostic factors is inconclusive and no prospective studies exist that evaluate therapeutic strategies. We therefore started a retrospective–prospective cohort study to better understand BOT and identify scenarios in which future studies could be developed.MethodsConsecutive patients with BOT treated between 1998 and 2008 in 24 German centres were analysed. The retrospective part of the study retrieved patients’ data from hospital records and clinical tumour registries while active follow-up and an independent central pathology review were carried out prospectively.FindingsBOT was confirmed in 950 patients, two thirds had serous BOT and 30.5% mucinous BOT. Most were diagnosed in stage I (82.3%); 7.6% and 10.1% had stages II and III, respectively. Overall, 74 patients (7.8%) experienced relapse and 43 (4.5%) died within the observation period. Multivariate analysis revealed higher stage, incomplete staging, tumour residuals, and organ preservation as independent prognostic factors for disease recurrence. Neither microinvasion nor micropapillary growth pattern showed any significant impact. Of 74 relapsed patients, 30% had malignant transformation to invasive ovarian cancer with five-year progression-free survival and overall survival of 12% and 50%, respectively.InterpretationPrognosis of BOT correlates with tumour-related as well as surgery-related factors. The balance between recurrence risk and organ preservation and fertility-sparing surgery is an important issue deserving further research.     

How does Epstein–Barr virus (EBV) complement the activation of Myc in the pathogenesis of Burkitt's lymphoma?

A defining characteristic of the aggressive B cell tumour Burkitt's lymphoma (BL) is a reciprocal chromosomal translocation that activates the Myc oncogene by juxtaposing it to one of the immunoglobulin gene loci. The consequences of activating Myc include cell growth and proliferation that can lead to lymphomagenesis; however, as part of a fail-safe mechanism that has evolved in metazoans to reduce the likelihood of neoplastic disease, activated oncogenes such as Myc may also induce cell death by apoptosis and/or an irreversible block to proliferation called senescence. For lymphoma to develop it is necessary that these latter processes are repressed. More than 95% of a subset of BL – known as endemic (e)BL because they are largely restricted to regions of equatorial Africa and similar geographical regions – carry latent Epstein–Barr virus (EBV) in the form of nuclear extra-chromosomal episomes. Although EBV is not generally regarded as a driving force of BL cell proliferation, it plays an important role in the pathogenesis of eBL. Latency-associated EBV gene products can inhibit a variety of pathways that lead to apoptosis and senescence; therefore EBV probably counteracts the proliferation-restricting activities of deregulated Myc and so facilitates the development of BL.     

Role of non-receptor and receptor tyrosine kinases (TKs) in the antitumor action of α-difluoromethylornithine (DFMO) in breast cancer cells

We have shown that administration of α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis, reduces the invasive and metastatic properties of MDA-MB−435 breast cancer cells while activating multiple signal transduction pathways, including MAPK, Stat3, Stat1, and JNK. Since the activity of these signaling mechanisms is frequently regulated by upstream tyrosine kinases (TKs), we tested whether non-receptor and receptor TKs may be involved in the signaling and biological effects of DFMO in MDA-MB−435 cells. Treatment with DFMO (1 mM for 48 h) did not affect Src phosphorylation (Tyr 416). Administration of the Src-family members inhibitor PP-1 (1 μM), blocked Src phosphorylation in the absence and in the presence of DFMO, but did not block the signaling effects of DFMO (increased phosphorylation of Stat3, Stat1, ERK and JNK). PP-1 treatment, on the other hand, inhibited the invasiveness of MDA-MB−435 cells in matrigel and potentiated the anti-invasive effect of DFMO. Next, we focused on the role of receptor TK. Western analysis of cell lysates from MDA-MB−435 cells failed to show the presence of EGF-R and HER-2neu but demonstrated the expression of c-Met, the receptor for hepatocyte growth factor (HGF). Therefore, we tested the effect of DFMO on the HGF/c-Met pathway which is strongly implicated in the progression of human breast cancer. We found that DFMO treatment blocked HGF-induced c-Met phosphorylation in MDA-MB−435 cells, suggesting that its anti-invasion action may be mediated, at least in part, by blocking c-Met signaling. Next, we showed that 1 mM DFMO suppressed HGF induced invasiveness of MDA-MB−435 cells in matrigel. Combination administration of DFMO with suboptimal doses of PHA-665752, a specific c-Met inhibitor, reduced invasiveness to an even greater extent than the individual treatment. These findings indicate that Src-family members, while not involved in DFMO action, promote invasiveness of breast cancer cells and their inhibition may enhance the antitumor effect of PA depletion. Our data also point to inhibition of HGF/c-Met pathway as a possible novel approach to enhancing the antitumor action of DFMO.     

Delayed initiation of radiotherapy for glioblastoma: how important is it to push to the front (or the back) of the line?

The most effective chemotherapeutic for glioblastoma (GBM) is the DNA alkylating agent temozolomide (TMZ). In a recent study by Hegi et al. benefit from TMZ was significantly associated with methylation of the promoter of the O6-methylguanine-DNA methyltransferase (MGMT) gene; however, the correlation was imperfect. Some patients with methylated tumors were short survivors and others with unmethylated tumors were long survivors. These exceptions have raised the possibility that TMZ response might be influenced by non-MGMT mechanisms. The effect of p53 status on response to TMZ was explored in traditional glioma cell lines (U87MG, U251MG, U343MG, U373MG, SF767, LN443 and LNZ308) and brain tumor initiating cells (BTICs—BT012, BT025, BT042, BT048, BT060 and BT069) in two ways: (1) inhibition of p53 by RNAi and (2) sensitivity in relation to intrinsic p53 status, either wild-type or mutant. Traditional glioma cell lines that did not express a functional p53 were significantly more sensitive to TMZ than cell lines with functionally intact wild-type p53 expression. Altered p53 expression or function had only minor effects on TMZ sensitivity in BTICs and tended to decrease sensitivity to TMZ. RNAi specific for p53 had little effect on sensitivity in p53 null glioma cells. Absence of a functional p53 increases TMZ sensitivity in traditional glioma cell lines, an effect that is independent of MGMT status, and not seen in BTICs. P53 status may influence response to TMZ in differentiated cells in a GBM with a negligible affect on its initiating cells.     

Positron Emission Tomography (PET) radiotracers in oncology – utility of 18F-Fluoro-deoxy-glucose (FDG)-PET in the management of patients with non-small-cell lung cancer (NSCLC)

PET (Positron Emission Tomography) is a nuclear medicine imaging method, frequently used in oncology during the last years. It is a non-invasive technique that provides quantitative in vivo assessment of physiological and biological phenomena. PET has found its application in common practice for the management of various cancers.Lung cancer is the most common cause of death for cancer in western countries.This review focuses on radiotracers used for PET scan with particular attention to Non Small Cell Lung Cancer diagnosis, staging, response to treatment and follow-up     

The biology and physiology of ‘Nolvadex’ (tamoxifen) in the treatment of breast cancer

Summary After more than a quarter of a million patient years experience with tamoxifen in the clinic, it is perhaps appropriate to re-examine the working hypothesis for the activity of this drug. This hypothesis states that tamoxifen is an anti-oestrogen which exerts its anti-tumour activity by competing for and binding to cytoplasmic oestrogen receptor protein in the tumour.The evidence that tamoxifen is an anti-oestrogen in animals and man is seen to vary from species to species and between target organs within a species. The balance of the evidence supports the conclusion that this drug acts as an oestrogen antagonist in man.If the activity of this drug were confined to an effect mediated by the oestrogen receptor (ER), there should be a clear correlation between the anti-tumour effect of tamoxifen and the presence of ER. The clinical and pre-clinical data are reviewed. Whilst the majority of the evidence points to an effect in advanced breast cancer mediated through the ER, there are data that show the correlation is not absolute. The data are examined and the evidence for non-receptor mediated anti-tumour activity is reviewed.We conclude that whilst the majority of the activity of tamoxifen is that of an anti-oestrogen mediated through the ER, compelling evidence exists that this may not be its only anti-tumour activity at normal clinical doses. These findings might explain tamoxifen's activity in some ER negative tumours.Nolvadex is a trade mark, the property of Imperial Chemical Industries PLC.     

Progress Report of a Phase I Study of the Intracerebral Microinfusion of a Recombinant Chimeric Protein Composed of Transforming Growth Factor (TGF)-α and a Mutated form of the Pseudomonas Exotoxin Termed PE-38 (TP-38) for the Treatment of Malignant Brain Tumors

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF- and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25ng/mL to 100 with a 40mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.     

Neuregulins 1–4 are expressed in the cytoplasm or nuclei of ductal carcinoma (in situ) of the human breast

Summary A new family of epidermal growth factor-like proteins, the Neuregulins (NRGs), have recently been identified and are expressed in a range of normal tissues and in some forms of cancer including breast cancer. In this study we examined using immunohistochemical staining expression of NRG1alpha, NRG1beta, NRG2alpha, NRG2beta, NRG3 and NRG4 in sixty cases of pre-invasive ductal carcinoma in situ of the breast representing different degrees of differentiation. Each protein was expressed in a high proportion of these cases showing a predominantly homogenous cytoplasmic staining pattern. Nuclear expression of NRG1alpha, NRG1beta, and NRG3 was however also observed in a significant fraction of cases. High levels of expression of NRG2beta and NRG4 were associated with high-grade tumours (p≤0.005), NRG2beta staining was associated with tumour size >25 mm (p=0.005) while NRG3 nuclear staining was present more often in low-grade tumours (p=0.039). This data demonstrates that each member of the NRG family of ligands is present in pre-invasive ductal breast cancer and that they may be involved in regulating cell behaviour. The significance of intranuclear expression remains to be determined but suggests a novel mechanism of action for some of these proteins.