Treatment Of Disseminated Disease Research Articles

Active bone marrow S-values for the low-energy electron emitter terbium-161 compared to S-values for lutetium-177 and yttrium-90

BackgroundBased on theoretical and preclinical results, terbium-161 may be a valid alternative to lutetium-177 and yttrium-90 in radionuclide therapies. The large low-energy electron emission from terbium-161 is a favorable feature in the treatment of disseminated disease, but its impact on the radiosensitive bone marrow needs to be evaluated. Using voxel-based skeletal dosimetry models in which active bone marrow is defined as regions containing stem cells and progenitor cells of the hematopoietic lineage, we generated S-values (absorbed dose per decay) for terbium-161 and evaluated its distribution-dependence in bone marrow cavities.MethodsS-values in the active bone marrow were calculated for terbium-161, lutetium-177, and yttrium-90 irradiation using two (male/female) image-based bone marrow dosimetry models. The radionuclides were distributed to one of the three structures that define the spongiosa bone region in the skeletal models: (i) active bone marrow, (ii) inactive bone marrow, or (iii) surface or whole volume of the trabecular bone. Decay data from ICRP 107 were combined with specific absorbed fractions to calculate S-values for 13 skeletal sites. To increase the utility, the skeletal site-specific S-values were averaged to produce whole-body average S-values and spongiosa average S-values.ResultsFor yttrium-90, the high-energy β particles irradiate the active marrow regardless of the source compartment, consistently generating the highest S-values (65–90% higher). Between terbium-161 and lutetium-177, the largest differences in S-values were with an active marrow source (50%), such as self-irradiation, due to the contribution of the short-ranged conversion and Auger electrons from terbium-161. Their influence decreased as the source moved to inactive marrow or the surface or volume of the trabecular bone, reducing the S-values and the differences between terbium-161 and lutetium-177 (15–35%).ConclusionThe S-values of terbium-161 for active bone marrow and, consequently, the bone marrow toxicity profile were more dependent on the radionuclide distribution within the bone marrow cavity than the S-values of lutetium-177 and yttrium-90. This effect was attributed to the considerable low-energy electron emission of terbium-161. Therefore, it will be critical to investigate the bone marrow distribution of a particular radiopharmaceutical for accurate estimation of the active bone marrow dose.

Metastatic uveal melanoma: The final frontier.

Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10-13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95-100% and 83-100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.

Transplant-associated penile Kaposi sarcoma managed with single agent paclitaxel chemotherapy: a case report

BackgroundKaposi’s sarcoma is an uncommon complication in renal transplant patients, and typically presents with cutaneous lesions on the lower extremities. Penile involvement has been reported only rarely. Management of cutaneous-limited disease is primarily reduction of immunosuppression and conversion to an mTOR-inhibitor, whereas the treatment of disseminated disease in transplant patients is more variable.Case presentationA 75-year-old male, originally from Somalia, received a deceased-donor kidney transplant for diabetic and hypertensive nephropathy. Seven months post-transplant he presented with lower limb lesions, oedema and bilateral deep vein thromboses. He then developed a fast-growing painful lesion on his penile shaft. A biopsy of this lesion confirmed KS, and a PET scan demonstrated disseminated disease in the lower extremities, penis and thoracic lymph nodes. His tacrolimus was converted to sirolimus, and his other immunosuppression was reduced. He was treated with single agent paclitaxel chemotherapy in view of his rapidly progressing, widespread disease. The penile lesion completely resolved, and the lower extremity lesions regressed significantly. His kidney allograft function remained stable throughout treatment.ConclusionThis case illustrates a rare presentation of an uncommon post-transplant complication and highlights the need for a high index of suspicion of KS in transplant patients presenting with atypical cutaneous lesions. It serves to demonstrate that the use of single agent paclitaxel chemotherapy, switch to an mTORi and reduction in immunosuppression where possible produces excellent short-term outcomes, adding to the body of evidence for this management strategy in disseminated Kaposi’s sarcoma.

Prognostic value of Bax expression in the primary colon tumor of patients with metastatic colorectal cancer receiving first-line treatment with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil

Objective: to evaluate the prognostic value of Bax expression in the primary colon tumor of patients with metastatic colorectal cancer (mCRC) receiving first-line treatment with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil. Materials and methods . The study included patients with mCRC (morphologically (histologically) verified diagnosis of colonic adenocarcinoma) that have never received treatment for disseminated disease. Study participants received a new first-line treatment regimen with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil. We evaluated both short-term and long-term treatment outcomes. We also assessed the level of Bax expression in primary tumor samples (biopsy/surgery specimens) collected prior to initiation of first-line treatment using immunohistochemical methods. We analyzed the correlation between the levels of Bax expression and short-term/long-term treatment outcomes. Results. Seventeen out of 20 mCRC patients included in the study were tested for Bax expression in the primary tumor using immunohistochemical staining. The analysis of correlation between Bax expression in tumor tissue and time-to-progression in patients with mCRC receiving first-line treatment with a triple combination of drugs demonstrated that high Bax expression was a favorable prognostic factor associated with longer time-to-progression. Median time-to-progression was significantly longer in patients with Bax overexpression than in those with low levels of Bax expression or no expression: 15.7 15,7 ± 3.38 months vs 8.6 15,7 ± 0.6 months, р = 0.012. When analyzing the impact of Bax expression on the overall survival (OS) in patients with mCRC, we found that patients with Bax overexpression demonstrated better OS (median follow-up time 17.3 15,7 ± 2.54; OS was not reached; mean value 31.26 15,7 ± 2.85 months) than patients with low Bax expression or no expression (median OS 13.60 15,7 ± 3.03 months), p = 0.021. Conclusion. Our results suggest that Bax overexpression in the primary colon tumor is a favorable prognostic factor associated with longer progression-free survival and OS in mCRC patients receiving first-line treatment with a triple combination of drugs.

Sexual Function and Quality of Life in a National Cohort of Survivors of Bilateral Testicular Cancer

BackgroundSexual function and quality of life remain unexplored among long-term survivors of bilateral testicular cancer (TC). ObjectiveTo investigate sexual function, fatigue, anxiety, and depression among long-term survivors of bilateral TC (unilateral TC with contralateral germ cell neoplasia in situ [TC+GCNIS] or bilateral TC [BTC]). Design, setting, and participantsThis was a cross-sectional study of 2479 long-term TC survivors, of whom 126 were treated with contralateral radiotherapy for GCNIS, 93 were treated with bilateral orchiectomy for BTC, and 2260 had unilateral TC (reference group). Outcome measurements and statistical analysisOutcomes were assessed using validated questionnaires at a median time since diagnosis of 17 yr (interquartile range 12–23). Results for survivors of TC+GCNIS and of BTC were compared with those for the reference group. Adjustment was made for age and treatment for disseminated disease. Results and limitationsThe age-adjusted risk of anxiety was significantly higher among BTC survivors (odds ratio 1.7, 95% confidence interval [CI] 1.1–2.8; p=0.002) than in the reference group. Apart from a higher risk of reduced motivation among survivors of TC+GCNIS (β=0.067, 95% CI 0.0013–0.13; p=0.046) there were no significant differences between the groups. Limitations include the low number of cases with symptoms of depression. ConclusionsSurvivors of BTC had a higher risk of anxiety but did not experience impairment of other aspects of quality of life when compared to survivors of unilateral TC. These results are of importance for evidence-based information on late effects for bilateral TC patients. Patient summaryWe evaluated quality of life and sexual function among long-term survivors of bilateral testicular cancer. Reassuringly, we did not find impaired quality of life apart from a higher risk of anxiety when comparing survivors of bilateral testicular cancer with survivors of unilateral testicular cancer.

Impact of topoisomerase IIα overexpression in the primary colon tumor on the prognosis of metastatic colorectal cancer

Background.The evaluation of clinical and morphological characteristics is not sufficient to predict the prognosis of metastatic colorectal cancer (mRCC). Tumor aggressiveness may vary significantly even in patients with similar clinical and morphological disease characteristics. These differences are believed to be associated with molecular tumor characteristics and can be used as additional prognostic factors for patient survival.Objective:to evaluate the effect of topoisomerase IIα overexpression (topoIIα) in primary colon tumor on the mRCC prognosis.Materials and methods. The study cohort included patients with mRCC that have not previously received treatment for disseminated disease. All participants had a morphologically verified diagnosis of colon adenocarcinoma and received first-line chemotherapy with oxaliplatin and capecitabine. We evaluated both short-term and long-term treatment outcomes. We also assessed the expression of topoIIα in primary colon tumors (biopsy/surgical specimens obtained prior to initiation of first-line treatment) using immunohistochemical methods. We aimed to evaluate the association between the level of topoIIα expression and short-term/long-term treatment outcomes. We analyzed the impact of topoIIα expression in the primary tumor on the efficacy of first-line chemotherapy, progression-free survival (PFS) and overall survival (OS) in patients with mRCC.Results. Immunohistochemical evaluation of topoIIα expression in the primary tumor was conducted for 39 patients with mRCC. We found no correlation between topoIIα expression and PFS, i.e. median PFS did not differ significantly between patients with topoIIα-positive and topoIIα-negative tumors (p >0.05). Individuals with low levels of topoIIα expression in the primary tumor and those with topoIIα-negative cancer demonstrated significantly higher OS than patients with topoIIα overexpression (median OS 16.30 ± 2.0 months; 95 % confidence interval 12.32–20.28 vs 7.7 ± 4.98 months; 95 % confidence interval 0.00–17.46; p = 0.007).Conclusion.Overexpression of topoIIα is a factor of poor prognosis associated with poorer OS in patients with mRCC that received first-line chemotherapy with oxaliplatin and capecitabine.

Plasma as adjuvant in melanoma treatment via mitochondrial targeting

Cutaneous melanoma is a highly aggressive malignancy and has rapidly increased over the past several decades [1]. Although the clinical biology and pathogenesis of melanoma are well understood, the prognosis remains poor with limited therapeutic options in the metastatic stage of the disease [2]. Reactive oxygen species (ROS) may be drivers of carcinogenesis and may cause oxidative damage to several cellular components, so it is generally considered to be deleterious [3]. However, ROS, as well as the products generated during redox reactions can act as second messengers and participates of signaling pathways, activating redox-sensitive transcription factors and gene expressions leading to cell proliferation, metastasis, and therapy resistance [4]. Although antioxidants can prevent the onset of melanoma [5], studies have shown that a systemic pro oxidant status is necessary to prevent distant metastases [6]. Consequently, some therapies aim at the generation of ROS as a mechanism of death [7]. Despite advances in chemotherapy, immunotherapy, and radiotherapy, the success in drug treatment of disseminated disease remains limited. The large number of side effects and resistance to treatment are the main causes of unsuccessful therapy. Thus, it is necessary to search for new strategies that can increase patient survival and quality of life. Cold plasma is a partially ionized gas proved its effectiveness for different applications in health care and medicine. It has been shown to exert various biologic effects to living tissue and cells ranging from cytoprotective to cytotoxic potency depending on the applied technique [8]. The gas generates reactive oxygen and nitrogen species [9] that are being deposited in cell culture media [10]. Such oxidant-enriched media selectively kills cancer cells in vitro by targeting the mitochondrial network [11], but the exact mechanism is still unclear. We aim at therapeutic strategies combining chemotherapy/radiotherapy with cold plasma as a strategy against melanoma. In addition, we studied the mitochondrial action mechanism of plasma, elucidating its possible target.

Adenocarcinoma de uraco: ¿qué tanto sabemos?

BackgroundThe urachus is an embryonic remnant of the allantois. Urachal carcinoma is a rare entity, with only 400 cases described in the literature. The incidence of this tumor is not known due to its low frequency, and its study protocol and ideal treatment are not strictly defined. AimsOur aim was to show and compare the results of 5 published series on adenocarcinoma of the urachus in order to understand the best diagnostic course and optimum treatment for these tumors. At present, very little is known of this pathology, except that partial cystectomy with complete exeresis of the urachus is recommended as the initial surgical strategy. We therefore decided to carry out a review of the literature in order to know the etiopathogenesis, clinical manifestations, and best therapeutic approach with respect to this rare tumor. MethodsA search of the PubMed and MDConsult databases covering the last 10 years was carried out for series that have analyzed adenocarcinoma of the urachus. Studies in Spanish, English, and French were selected, excluding case reports. A total of 5 series were selected and reviewed. ResultsThe majority of urachal tumors are adenocarcinomas. The definitive diagnosis is made through histopathologic analysis, with tomography and ultrasound being useful complementary studies. Clinical symptoms are characterized by haematuria and a palpable pelvic mass in the majority of patients. The most widely used staging system is that proposed by Sheldon. The majority of cases are diagnosed in late stages because the manifestations do not appear until then.The treatment of choice is partial cystectomy with en bloc resection of the urachus and umbilicus. Radiotherapy may be used in cases of locally advanced disease, with results in 30% of the patients. Chemotherapy based on cisplatin and 5-fluorouracile can be used as neoadjuvant and/or adjuvant therapy and as treatment for disseminated disease. Survival of the patient with metastatic disease is about one year. ConclusionsWhenever possible, complete exeresis of the tumor should be attempted through partial cystectomy and en bloc resection of the urachus and umbilectomy, together with extended lymph node dissection. Despite the search for different combinations, a definitive chemotherapy regimen has yet to be established.

Physical Biology in Cancer. 1. Cellular physics of cancer metastasis

One of the major challenges in cancer research today is developing new therapeutic strategies to control metastatic disease, the spread of cancer cells from a primary tumor to seed in a distant site. Advances in diagnosis and treatment options have increased the survival rate for most patients with local tumors; however, less progress has been made in treatment of disseminated disease. According to the SEER Cancer Statistics Review, 1975-2010, in the case of breast and prostate cancers, only one in four patients diagnosed with distant metastatic disease will survive more than five years. Current research efforts largely focus on identifying biological targets, such as specific genes and signaling pathways that drive two key steps of metastasis, invasion from the primary tumor and growth in the secondary site. On the other hand, there are phenotypic traits and dynamics in the metastatic process that are not encoded by single genes or signaling pathways but, rather, a larger system of events and biophysical characteristics. Connecting genomic and pathway investigations with quantitative physical phenotypic characteristics of cells, the physical microenvironment, and the physical spatiotemporal interactions of the metastatic process provides a stronger complementary understanding of the disease.

Disseminated Cryptococcosis Presenting as Obstructive Jaundice in an Imunocompetent Pregnant Female

Purpose: A 22-year-old, gravid three, para two at 36 weeks of gestation presented with a 1-month history of right upper quadrant pain and jaundice. Past medical history notable for choledocholithasis and cholecystectomy. No fever, weight loss, or night sweats. No smoking, illicit drug use, or alcohol intake. Exam revealed scleral icterus and right upper quadrant tenderness. Vitals were stable. Labs: leukocytosis, microcytic anemia, mild transaminitis, and obstructive jaundice. Autoimmune, viral hepatitis panels, and HIV were negative. She delivered a healthy baby. CT chest and abdomen showed extensive systemic lymphadenopathy. MRCP and ERCP showed irregularities and dilatation of the intra and extra-hepatic bile ducts with common bile duct stricture. Biliary stent failed to resolve cholestasis. Liver biopsy therefore done, showed centrilobular cholestasis, portal edema, and necrosis with rare granulomas and eosinophils. Blood cultures and lymph node biopsies were positive for numerous yeast form Cryptococcus neoformans. Serum cryptococcal antigen titers markedly elevated at 1:4096. CSF analysis and culture was negative. Following antifungal therapy, follow-up ERCP showed free flow of bile and patient's LFT's and lymphadenopathy improved. Cryptococcosis is an opportunistic fungus affecting immune-compromised patients with an affinity to the CNS, skin, and lungs. We present an extremely rare case of disseminated cryptococcemia involving the biliary tree in an immunocompetent patient. Treatment for disseminated disease in pregnancy is induction with amphotericin or LFAmB with or without flucytosine for 2-4 weeks, followed by fluconazole for consolidation and maintenance, started after delivery. Prompt identification and treatment is important to prevent bad obstetric outcomes and mortality in this group.Figure: ERCP.Figure: Lymph node biopsy.

Abstract 42: Biological significance of the lipogenic enzyme acetyl-CoA carboxylase in the control of metastatic properties of murine and human transformed cells

Abstract In recent years, it has been determined that the fatty acid synthesis pathway is upregulated in several types of cancers of epithelial origin at both transcriptional and translational levels. Unlike normal cells, cancer cells rely on this pathway to provide the fatty acid precursors needed for synthesizing lipids that preferentially segregate into the liquid ordered microdomains of the plasma membrane. Acetyl-CoA carboxylase (ACC) is the ATP dependent and rate limiting step of fatty acid synthesis and catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. Interestingly, overexpression of this enzyme increases with severity of breast cancer patient samples and cell lines, indicating a possible role for ACC in the metastatic process. Preliminary findings from our lab indicate that ACC is important for the proteolytic invasion and migration of transformed cells independently of cell death. Moreover, ACC is critical for formation of F-actin rich membrane structures known as podosomes, which have been implicated in the metastatic process in recent years. Restoration of podosomes in cells with ACC inhibition was achieved with the addition of the soluble fatty acid, C18:1 (oleate). In contrast, inhibition of the fatty acid synthetic enzyme, fatty acid synthase (FASN), or the Δ9 desaturase, stearoyl-CoA desaturase 1 (SCD-1), does not affect podosome formation. However, inhibition of FASN resulted in attenuated proteolytic invasion and migration of transformed cells with a phenotype similar to cells with ACC inhibition although not quite to the same degree. In addition to regulation at transcriptional and translational levels, ACC activity is also regulated by phosphorylation/dephosphorylation by AMP activated protein kinase (AMPK). Decreased ACC phosphorylation at serine 79 (S79) has been shown to correlate with increased disease severity and reduced disease free survival of lung adenocarcinoma patients. This indicates that the phosphorylation status of ACC may be an important mechanism that cancer cells manipulate to successfully achieve metastasis. Therefore, induction of phosphorylation, and inactivation of ACC, either by activation of AMPK or by direct mutation of S79 may be sufficient to reduce invasion and migration of cancer cells. Taken together, investigating ACC phosphorylation status and analyzing the resulting phenotype will advance the mechanistic understanding of how cancer cells metastasize and possibly provide new therapeutic avenues to explore in the treatment of disseminated disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 42.

Manifestations, Diagnosis, and Treatment of Strongyloides stercoralis Infection

To summarize current literature on the manifestations, diagnosis, and treatment of Strongyloides stercoralis infection. A search was conducted of PubMed (1970-August 2007). Search terms included Strongyloides stercoralis, hyperinfection, prevention, and treatment. Reviews, studies, and recent case reports were included. Additional references were obtained from article bibliographies. All studies or review articles published in English from 1970 to August 2007 and case reports of hyperinfection or disseminated disease published since 2000 were evaluated. Strongyloidiasis is a parasitic infection endemic to tropical, subtropical, and temperate areas including the Appalachian region of the southern US. Prevalence rates vary widely. Patients may present with infection decades after original exposure. Diagnosis can be achieved by identifying the larvae in the stool; usually, more than one sample is needed. Most patients are asymptomatic. However, in immunosuppressed patients, a hyperinfection syndrome or disseminated disease may occur due to the ability of the parasite to reproduce within the host. The most common risk factors for these complications are immunosuppression caused by corticosteroids and infection with human T lymphotropic virus type 1. Treatment options for uncomplicated disease include thiabendazole, ivermectin, and albendazole. Thiabendazole has been replaced by ivermectin as treatment of choice due to better tolerance. These antihelminthics have been used to treat hyperinfection or disseminated disease alone or in combination, but data are limited to case reports or case series. Prevention of disease is mainly achieved by wearing shoes in endemic areas to avoid contact with infected soil. Strongyloides is a unique parasite that can cause a hyperinfection syndrome and disseminated infection several years after exposure. Treatment options include ivermectin, thiabendazole, or albendazole. Information on the best treatment for disseminated disease and hyperinfection is limited.

Neoplasia endócrina múltipla tipo 2

The term multiple endocrine neoplasia (MEN) was introduced by Steiner et al. in 1968 to describe disorders that include a combination of endocrine tumors. The Wermer syndrome was designed as MEN 1 and the Sipple syndrome as MEN 2. Sizemore et al. (1974) completed that the MEN 2 category included 2 subgroups: patients with medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid disease and a normal appearance (MEN 2A) and other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B). MTC is usually the first tumor diagnosed. The diagnosis of MTC has several implications: disease extent should be evaluated, pheochromocytoma and hyperparathyroidism should be screened and whether the MTC is sporadic or hereditary should be determined by a direct analysis of the RET proto-oncogene. Here, the pathological characteristics, genetic abnormalities, and clinical features of MEN 2 are discussed. The diagnostic and therapeutic approaches used to patients with clinical disease and carriers identified through familiar screening are also described. Progresses related especially to genetic screening and earlier intervention have permitted an improvement in the long-term outcome. However, treatment for disseminated disease is still ineffective.

Current management of mucosal melanoma of the head and neck.

While mucosal-based melanomas of the head and neck region are uncommon lesions, when they do arise they usually follow an inexorably aggressive course. Experience with these tumors is, necessarily, limited; as such, well-worked out treatment protocols for the treatment of such lesions are in short supply. It appears as though mucosal melanomas (MuMs) develop more frequently in the nasal cavity and paranasal sinus region, and less often in the oral cavity. It seems that the incidence of nodal metastasis is significantly lower for sinonasal MuMs than it is for MuMs of the oral cavity; this observation may influence decisions about performing neck dissection as a function of location of the primary MuM. At present, surgical excision remains the mainstay of treatment; however, anatomical complexities within the region can hamper attempts at complete excision. Radiotherapy has not traditionally been relied on for routine treatment of MuM, although some recent reports have challenged this view. Chemotherapy is, at present, employed principally in the treatment of disseminated disease and for palliation. As a diagnostic matter, MuM belongs to the class of tumors that, on light microscopy, may with some regularity be confused with other malignancies (including sarcomas, plasmacytomas, and carcinomas); as a consequence, this is a diagnosis which is often best confirmed by way of ancillary testing via immunohistochemical studies. A better grasp of the best means of treating MuM will likely come only when large referral centers are able to pool their experiences with these uncommon yet virulent malignancies.

Treatment of Acute Disseminated Lyme Disease

Past studies of the treatment of Lyme disease (Borrelia burgdorferi infection) have grouped patients with localized disease with patients manifesting

Targeted adenoviral vectors for cancer gene therapy (Review)

In order to realise the full potential of gene therapy as a rational approach to the treatment of cancer, it will be necessary to achieve delivery of the therapeutic gene selectively to target tumour cells. Such cancer cell-specific gene delivery is mandated in the context of locoregional or compartmentalised carcinomas, and is also an absolute requirement for the treatment of disseminated disease. Moreover, underlying any cancer gene therapy approach is the need to achieve a high level of efficiency of gene transfer to the target cells. Of the existing viral and nonviral gene delivery vehicles, the adenoviral vector uniquely fulfils two requirements of an intravenously administered vector for cancer gene therapy: systemic stability and the ability to accomplish efficient transduction of cancer cells. However, it is necessary to modify native adenoviral tropism in order to achieve selective transduction of target tumour cells. A number of strategies have been developed for this purpose, involving genetic or immunological modifications to either of two adenoviral capsid proteins, the fibre and penton base. These strategies are designed to generate a targetable, injectable vector which would represent a major advance in the field of cancer gene therapy.

Treatment of advanced breast cancer

Metastatic breast cancer is a major and increasing public health problem. The 5-year survival for this disease is only 15%, and while hormonal and chemotherapeutic options have had a significant impact on long-term survival for patients with localized disease, treatment for disseminated disease remains essentially palliative. New treatment options are urgently needed to improve the prospects for patients with metastatic breast cancer, particularly for those with disease characteristics indicating a particularly poor prognosis. Docetaxel (Taxotere) is a promising new drug and has shown encouraging activity in patients with disease resistant to anthracyclines and in patients with visceral metastases, both of which indicate a poor prognosis. Although docetaxel is, at present, only licensed for use in patients with anthracycline-resistant disease, this highly active drug should now be developed for first-line treatment, and eventually for adjuvant use.

The role of clarithromycin in the prophylaxis of disseminated Mycobacterium avium-intracellulare infection in patients with AIDS.

Clarithromycin is a first-line agent in the treatment of disseminated disease due to Mycobacterium avium-intracellulare (dMAC) in patients with the acquired immunodeficiency syndrome, and its role in dMAC prophylaxis is nearing definition. Fifteen abstracts described clinical outcomes when clarithromycin was given in various dosages as monoprophylaxis or in combination with other agents. Patients totaled 1063, the majority of whom had CD4+ counts of 100 cells/mm3 or below. In one study, MAC disease occurred in 4.5% of 343 clarithromycin-treated patients compared with 12.6% of 341 receiving placebo (p < 0.001). The remaining studies combined to report only two positive blood cultures, one positive sputum culture, and one positive culture of unidentified origin during their respective study periods. Gastrointestinal intolerance caused discontinuation of therapy in 21 (2.9%) of 722 patients receiving clarithromycin. Clinical evaluations show that the drug decreases the risk of dMAC, prolongs survival, and is well tolerated. Controlled clinical trials continue.

Malignant melanoma.

Malignant melanoma is the most rapidly increasing cancer in Caucasians throughout the world. The increased incidence is due to greater sun exposure arising from changes in clothing habits and life-styles over the past fifty years. Most melanomas arise in preexisting moles in sun-exposed sites and may spread rapidly via the vascular system if not detected and removed early. Treatment of disseminated disease is unsatisfactory, with most patients dying of refractory brain metastases.

Progress review: intrathecal and intratumoral injection of radiolabelled monoclonal antibodies (MoAbs) for the treatment of central nervous system (CNS) malignancies.

The systemic administration of monoclonal antibodies (MoAbs) as delivery vehicles for targeted radiation therapy is associated with many problems. Most studies show that insufficient isotope is taken up into the tumour to elicit a tumoricidal effect. This has led several groups to explore the administration of radiolabelled MoAbs into body compartments, specifically for the treatment of minimal tumour deposits that present either as malignant ascites or small nodules on the lining of body cavities. The use of 131Iodine (131I) labelled MoAbs in the treatment of disseminated disease in the central nervous system (CNS) is described and the possibility of administering radiolabelled MoAbs to a cavity generated after debulking surgery for malignant glioma in order to overcome the problem of poor MoAb uptake into solid tumour deposits is discussed together with the rationale for substituting 90Yttrium (90Y) for 131I.