European Journal of Clinical & Medical Oncology

Functional imaging by (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) is being increasingly incorporated into the evaluation of patients with aggressive non-Hodgkin lymphoma (NHL). Its use for the initial staging in combination with computed tomography has now become standard. PET has recently been included in consensus criteria for response after therapy for Hodgkin lymphoma and aggressive NHL. At the end of therapy, PET has a high positive and negative predictive value (PPV, NPV) for relapse in the pre-rituximab era. However, in the rituximab era, there appears to be a higher rate of false-positive PET scans, making the PPV lower, while the NPV remains high. Interim PET scans are an attractive concept for early evaluation of response, and possibly to guide intensification or de-escalation of therapy. Similar to the end-of-therapy scans, the PPV for mid-therapy scans appears to be low in the rituximab era. Trials testing the modification of therapy based on an interim PET scan are ongoing. For surveillance of patients in remission from aggressive NHL, there is as yet no convincing data that monitoring with PET is superior to traditional surveillance. The evidence to date suggests that a positive PET scan during or after rituximab-based therapy for aggressive NHL should be confirmed by a biopsy if major treatment decisions will be made using the results.
Families with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome. While some environmental factors (such as farming related exposures and occupational chemicals) may increase risk of CLL, results of epidemiological studies have been generally inconsistent inconsistent and well-defined extrinsic risk factors are unknown. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions including non-Hodgkin lymphomas, especially other indolent lymphomas. The precursor condition, monoclonal B-cell lymphocytosis (MBL) also aggregates in CLL families. However because the baseline population risks for CLL and other indolent lymphomas are low, the absolute risk to a first-degree relative for developing CLL or a related disease is also low. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated several genes as being important in CLL but more studies are needed to verify these findings. Results from whole genome association are promising. The ability to conduct large scale genomic studies will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate etiologic pathways.
Published Phase I-III clinical research trials investigating the efficacy of yoga for treating insomnia and sleep quality impairment. 
Many cancer patients and survivors, between 15 to 90%, report some form of insomnia or sleep quality impairment during and post-treatment, such as excessive daytime napping, difficulty falling asleep, difficulty staying asleep, and waking up too early. Insomnia and sleep quality impairment are among the most prevalent and distressing problems reported by cancer patients and survivors, and can be severe enough to increase cancer mortality. Despite the ubiquity of insomnia and sleep quality impairment, they are under-diagnosed and under-treated in cancer patients and survivors. When sleep problems are present, providers and patients are often hesitant to prescribe or take pharmaceuticals for sleep problems due to poly pharmacy concerns, and cognitive behavioral therapy for insomnia can be very difficult and impractical for patients to adhere to throughout the cancer experience. Research suggests yoga is a well-tolerated exercise intervention with promising evidence for its efficacy in improving insomnia and sleep quality impairment among survivors. This article provides a systematic review of existing clinical research on the effectiveness of yoga for treating insomnia and sleep quality impairment among cancer patients and survivors.
Malignant peritoneal mesothelioma (MPM) is a rare and aggressive neoplasm that is largely resistant to traditional anti-cancer therapies. For years it has been considered a terminal condition and once diagnosed, patients generally survived less than a year despite aggressive treatment. Although rare, the worldwide incidence of MPM continues to rise, in part due to its association with asbestos exposure. Patients usually present with non-specific symptoms of abdominal distension and pain making the diagnosis challenging. In recent years, aggressive cytoreductive surgery with the administration of hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival in patients with MPM treated at multiple centers worldwide. This review article briefly highlights the presentation, diagnosis, and natural history of MPM. We then explore the available treatment options with primary focus on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Therapy-related acute myeloid leukemia (t-AML) has been widely accepted for decades as the most serious long-term complication of treatment for early breast cancer. However, in contrast to epidemiological studies which consistently report an elevated risk of acute myeloid leukemia (AML) after breast cancer compared with the age-matched population, the findings of clinical trials organizations and institutions with a large breast cancer experience have been inconsistent in identifying the existence of an elevated risk and the contribution of plausible factors to an increased risk such as drug dose and dose intensity, newer vs older agents, and the contribution of radiation therapy and growth factor support. Epidemiological studies have also provided inferential evidence that host factors contribute to an elevated risk of AML after a breast cancer diagnosis. This evidence includes an increased risk of AML in the preadjuvant chemotherapy era, the absence of a rising risk of AML following the widespread application of adjuvant chemotherapy in clinical practice, an increased risk of AML after a diagnosis of other cancers, and an increased risk of other cancers after a breast cancer diagnosis. Inherited polymorphisms of genes involved in cancer risk and behavior could plausibly explain host susceptibility to AML and breast cancer, and a focus of current research is the investigation of polymorphic variation of genes involved in DNA repair pathways and drug metabolism. Although numerous studies have reported associations, all lack the genomic breadth and statistical depth to accurately quantify the effect of low-penetrance genetic variation on AML risk after breast cancer. Until definitive data are available to determine whether AML is therapy related or associated with susceptibility factors independent of therapy, women with early breast cancer should be fully informed of both their elevated long-term risk of AML and the potential contribution of adjuvant chemotherapy to this risk.
(A) Event-free survival probability (pEFS) and (B) cumulative incidence of subsequent relapse (CIR) in patients with first (n577) or second (n514) relapse of ALL by MRD status of , vs $10 24 leukemic cells before allogeneic SCT. MRD $10 24 leukemic cells: n545; censored, n514; deaths, n57; relapses, n524; pEFS (5 years)50.27¡0.07; CIR (5 years)50.57¡0.08. MRD ,10 24 leukemic cells: n546; censored, n529; deaths, n512; relapses, n55; pEFS (5 years)50.60¡0.08; CIR (5 years)50.13¡0.06. EFS, log-rank, P,0.004. CIR, Gray, P,0.001. Taken from [50], copyright consent for publication of Figure 1 was given by the Journal of Clinical Oncology: License date: October 6, 2009; License number: 2283030338406
Kaplan-Meier analysis of event-free survival (EFS) according to chimerism status. CC/LL-MC, complete chimerism/low-level mixed chimerism; de-MC, decreasing mixed chimerism; in-MC, increasing mixed chimerism. Taken from [58], copyright consent for publication of Figure 2 was given by the Journal of Clinical Oncology: License date: October 6, 2009; License number: 2283021063229
(A) Kaplan-Meier analysis of event-free survival (EFS) in patients with increasing mixed chimerism (MC; n546). (B) Patients with increasing MC (inMC) who received additional therapy (n531) and patients with increasing MC who did not receive additional treatment (n515). Taken from [58], copyright consent for publication of Figure 3 was given by the Journal of Clinical Oncology: License date: October 6, 2009; License number: 2283021063229
Relapse is still the principal cause of treatment failure after allogeneic stem cell transplantation (SCT) for high-risk childhood acute lymphoblastic leukemia (ALL). Specific methods aimed at preventing relapse comprise the use of intensive treatment prior to transplant, optimal transplant preparative regimens, and post-transplant interventions with targeted or immunological therapies. Diagnostic tools such as minimal residual disease (MRD) and chimerism monitoring peritransplant can identify patients facing the highest risk for relapse, and provide a basis for therapeutic intervention to prevent relapse. Patients with increasing mixed chimerism or MRD burden have been shown to benefit from pre-emptive therapy. A variety of targeted immunological therapies are emerging, which could have an impact on relapse and improve the survival of children with ALL after transplantation.
Summary of Prospective, Randomized Trials evaluating Adjuvant Treatment of Patients with Resected Pancreatic Adenocarcinoma 
Pancreatic adenocarcinoma is an aggressive cancer with an overall 5-year survival of 5% or less. In patients who have resectable tumors, resection can lead to an improvement in overall survival, but local and distant recurrence rates remain high. Adjuvant therapy has demonstrated mixed results in clinical trials; thus the optimal adjuvant treatment of resected pancreatic cancer remains unclear. The purpose of this article is to review and assess the pertinent literature and try to determine an acceptable and uniform approach to adjuvant therapy in patients with resected adenocarcinoma of the pancreas. We focus on adjuvant chemotherapy and chemoradiation, and their impact on overall survival in this subgroup of patients.
Lung cancer is the leading cause of cancer-related mortality in the developed world. The majority of patients with non-small cell lung cancer (NSCLC) present with advanced disease. Even in the one-third of patients presenting with early-stage disease, there is a high rate of relapse despite complete surgical resection. As most patients recur with distant metastases, it is hypothesized that micrometastases may be present at the time of surgery, suggesting a potential role for adjuvant chemotherapy. Postoperative cisplatin-based chemotherapy has been established as the standard of care in resected stage II–III NSCLC, improving 5-year survival by 8–15%. This review explores the evolution of adjuvant chemotherapy trials since the 1970s, charts what progress has been made to date, and analyzes the evidence leading to current standards of care. We also review some of the retrospective studies evaluating potential biomarkers in NSCLC and evaluate whether these may contribute to the heterogeneity of the chemotherapy response and assist in tailoring treatment. In addition, we review current studies of targeted therapy in the adjuvant setting and offer potential future directions for research.
Based on results from randomized phase III studies adjuvant cisplatin-based chemotherapy represents the current standard of care in patients with resected stage IB-III non-small cell lung cancer. A pooled analysis of the five largest cisplatin-based adjuvant chemotherapy trials conducted after 1995 showed an absolute overall survival benefit of 5.4% at five years. Even though almost 50 % of non-small cell lung cancers occur in patients older than 70, this group of patients were under-represented in these studies with less than 10 % falling into this category. We herein review the studies which investigated this subgroup of patients.
Endometrial cancer is a common malignancy affecting women. The majority of patients are diagnosed with endometrial cancer early and treated curatively with surgery and adjuvant therapy. The platinums, taxanes, and anthracyclines are the most active agents in endometrial cancer and therefore form the basis of first-line chemotherapy regimens. Challenges arise in the context of women who suffer from disease that is refractory to first-line chemotherapy or recurrent after receiving treatment. Second-line therapies are currently being investigated. The most effective to date is paclitaxel; however, the response is temporary, patients ultimately progress, and survival is poor. Other therapies have failed to show improved response or survival compared with paclitaxel in the second-line setting. Because paclitaxel is part of first-line therapy, there are many patients who are paclitaxel resistant but require second-line therapy. Ixabepilone is a novel semi-synthetic member of the epothilones that acts as a microtubule-stabilizing drug similar to paclitaxel. However, ixabepilone has shown activity in cell lines that are paclitaxel resistant, and has shown activity in clinical trials against a variety of malignancies. Current investigations into ixabepilone for endometrial cancer are ongoing and will further define ixabepilone’s role in treatment for endometrial cancer.
Epithelial ovarian carcinoma is considered to be one of the most lethal genital cancer types. Incomplete surgery, even far away from a basic staging procedure such as simple adnexectomy, hysterectomy, or even only cystectomy operation, is in question. Presently, there are no data on the role of reoperation and re-debulking in such previously incompletely operated advanced-stage patients.
Metastatic esophageal cancer is incurable with 5-year survival rates of under 5% using currently available therapeutic strategies. Palliative chemotherapy with cisplatin- and 5-fluorouracil (5FU)-based regimens remains the standard of care for patients with recurrent unresectable or metastatic esophageal cancer. Upfront cisplatin-based regimens are poorly tolerated in some patient groups and, for patients with recurrent disease after platinum-based therapies, there is a need for an alternate efficacious regimen without significant toxicities. The combination of docetaxel and irinotecan is an active regimen in this disease and has been investigated in several phase II trials. Weekly dosing of chemotherapy is preferred over a once every 3 weeks regimen on account of comparable efficacy and improved toxicity profile. Future directions include investigation of pharmacogenomic treatment assignment, particularly as irinotecan appears to be active in tumors with high ERCC1 expression, which tend to be resistant to cisplatin. Combinations with biologics such as bevacizumab and cetuximab, which have shown additive benefit with other cytotoxic combinations, are also of interest for future study.
Early tumors are independent of blood supply. Vascularization promotes growth and metastasis of tumors.  
VEGF and VEGF receptors and down stream signaling pathways as potential targets for therapy.
Different TKIs in Production Pipeline
Molecularly targeted therapies are becoming increasingly important in clinical oncology practice. Several critical molecular pathways have been identified, and novel therapeutic agents targeting these pathways are now approved and administered routinely in different solid malignancies. Angiogenesis, and in particular the vascular endothelial growth factor (VEGF) pathway, plays a central role in the development and progression of solid malignancies including non-small cell lung cancer (NSCLC). Agents designed to target this pathway include both antibodies targeting VEGF and small molecule tyrosine kinase inhibitors that can inhibit signaling through the VEGF receptors. A number of agents targeting the VEGF pathway have shown promising results in the treatment of NSCLC, and some, such as bevacizumab, have even been approved and are available for routine administration in combination with chemotherapy for patients with NSCLC. This is a concise review of the major angiogenic pathways and the targeted agents designed to block these pathways. The review will focus on the benefits of antiangiogenic agents that are in advanced clinical development in NSCLC, as well as the future direction of this field.
Immunohistochemical profile of ALK-positive DLBCL. (A) Characteristic granular cytoplasmic expression of ALK. (B) Strong expression of MUM1. (C) Expression of epithelial membrane antigen. (D) Lack of expression of CD20  
Immunohistochemical and Molecular Features of 77 Cases of ALK- positive DLBCL Number studied Number positive Percentage
Kaplan–Meier survival estimates for patients with ALK-positive DLBCL. (A) Overall survival (OS) for the entire group. (B) OS according to clinical stage. (C) OS according to age at diagnosis. (D) OS according to CD4 expression. (E) OS according to site of involvement. (F) OS according to chemotherapy received  
Clinical Features of 77 cases of ALK-positive DLBCL Reported in the Literature
Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-positive DLBCL) is a rare subtype of DLBCL. In this review, the authors discuss the potential lymphomagenetic role of ALK gene rearrangements, address the distinct clinical and pathological characteristics, and evaluate potential prognostic factors for survival of 77 cases of ALK-positive DLBCL reported in the literature. Pathologically, ALK-positive DLBCL shows a plasmablastic appearance and CD20 negativity in the tumor cells, making this lymphoma a challenging diagnosis. ALK-positive DLBCL can be seen at any age but shows a bimodal incidence. ALK-positive DLBCL is also characterized by a clinical aggressive behavior and poor response to both standard and highly intensive therapies, with a 5-year overall survival of 27%. Finally, advanced clinical stage, age older than 18 years, and extranodal disease are associated with worse survival.
Bone density loss is a common complication in allogeneic stem cell recipients and known to have an adverse affect on the quality of life, especially for long-term survivors of allogeneic stem cell transplantation (SCT). The risk factors predicting bone loss after allogeneic SCT include chemotherapeutic agents, immunosuppressants, immobilization, and hypogonadism. Although prophylactic treatment with bisphosphonate remains a controversial issue based on published data, bisphosphonate treatment may be beneficial for all allogeneic SCT recipients, or at least for those recipients with a high risk of developing severe bone loss after SCT. It has already been suggested that zoledronic acid (ZA) may play a role in preventing bone loss after SCT and can be comfortably used in an SCT setting. The long-term use of ZA may also offer benefits in terms of maintaining bone density, especially in patients with chronic graft-vs-host disease (GVHD). Thus, early post-transplant administration of ZA is recommended and may need to continue until 1 or 2 years after SCT depending on the status of the recipient, for example, the GVHD severity, GVHD treatment intensity, and other clinical parameters.
Protocols for Total Dose Iron Infusion of Low-Molecular-Weight Iron Dextran used at Salford Royal Foundation Trust Hospital A: Standard protocol 
Anemia is common in oncology patients and is associated with poor outcomes and reduced quality of life. Anemia can be treated with blood transfusions and/or erythropoietin-stimulating agents (ESAs) in combination with iron. ESAs have been widely used by nephrologists for the management of anemia in patients with chronic kidney disease (CKD). Iron supplementation has been shown to improve hemoglobin response to ESAs, reduce ESA requirement, and improve quality of life in patients with CKD and cancer. Despite these findings, intravenous iron is underutilized in cancer patients. This review will discuss the role of intravenous iron in the management of oncology patients, as well as discussing methods of administration including the use of total-dose infusion regimens. Studies have shown that intravenous iron can be administered as a total-dose infusion with equal safety and efficacy to multiple low-dose infusions. Total-dose infusion may thereby improve patient convenience as well as reduce the hospital costs of administering IV iron.
Treatment with cytotoxic chemotherapy has reached a therapeutic plateau in advanced-stage non-small cell lung cancer (NSCLC), and the development of anti-angiogenesis therapy has become an area of intense investigation. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is approved in combination with platinum-based therapy for the treatment of patients with non-squamous advanced-stage NSCLC in Europe and the United States. Patients with brain metastases were previously considered ineligible for treatment with bevacizumab, but a recent phase II trial has demonstrated a low rate of central nervous system hemorrhage, and treated brain metastases are no longer considered a contraindication to bevacizumab. Oral multitargeted tyrosine kinase inhibitors that target the VEGF receptors are also in development. To date, the common toxicities observed with these agents include nausea/vomiting, hypertension, diarrhea, fatigue, and rash, including hand–foot syndrome. Three phase III trials have been performed to investigate the activity of vandetanib, an oral inhibitor of VEGF receptors and epidermal growth factor receptor (EGFR). A higher response rate, longer progression-free survival (PFS; the primary endpoint), and improved time to deterioration of symptoms was observed in the vandetanib and docetaxel combination arm compared to docetaxel in patients who were receiving second-line therapy; a statistically significant improvement in overall survival was not observed. A significant difference in PFS was not observed in the two other phase III trials investigating vandetanib. This agent is not commercially available in Europe or the United States. Phase III trials of sorafenib, sunitinib, BIBF 1120, and cediranib in advanced NSCLC are ongoing.
Patient and Tumor Characteristics
Variables Differentiating between Tumors Responsive and Resistant to Letrozole by SAM
Ontology of Genes Predictive of Neoadjuvant Response to Letrozole Biological process 22277 annotated probe sets on the chip, 31 annotated probe sets in the list
RNA expression profiles from breast cancer biopsies taken before and after 10–14 days of neoadjuvant treatment with the aromatase inhibitor, letrozole, together with change in expression between the time points were compared in tumors classified as clinically responsive or resistant to treatment. Statistical analysis for microarrays identified 31 expression variables (six pretreatment, four on-treatment, and 21 change parameters) that were significantly different (P<0.001) between 37 responsive tumors and 15 resistant cases. Notably, 18 of 21 change variables coded for ribosomal proteins. Gene ontology terms corresponding to the 31total variables were highly statistically enriched for “translation” and “structural components of ribosomes”. These data highlight the importance of changes in the expression of ribosomal proteins as early markers distinguishing between breast cancers clinically responsive and resistant to neoadjuvant letrozole.
Peripheral T/NK-cell lymphomas (PTCL) comprise a rare and heterogeneous group of malignancies that are characterized by an aggressive course. So far, no standard therapy has been defined. With the exception of anaplastic large cell lymphoma (ALCL) expressing the anaplastic lymphoma kinase (ALK), conventional (anthracycline-based) polychemotherapy leads to dismal outcome, with sustaining complete remissions achievable in only a minority of patients. High-dose therapy supported by autologous stem cell transplantation (HDT-ASCT) is a well-defined and widely used therapeutic approach in different hematological malignancies (e.g., relapsed aggressive B-cell lymphomas, relapsed Hodgkin’s disease, multiple myeloma), and has also shown efficacy in relapsed PTCL. However, on account of the lack of randomized PTCL-restricted studies, the impact of HDT-ASCT as first-line therapy in PTCL is unclear. Retrospective studies in this setting have shown good feasibility with a low therapy-associated morbidity and mortality not exceeding toxicity in high-dose studies on aggressive B-cell lymphomas. To date, five larger prospective PTCL-restricted trials have addressed this strategy, varying in terms of inclusion criteria, induction therapy, high-dose protocols, etc. The outcome shows promising results with an overall survival of about 50% at 3 years. Patients achieving complete remission (CR) at transplantation seem to benefit most from this strategy. Therefore, induction therapy needs to be further improved to increase the transplantation rate. With the limited data available, upfront HDT-ASCT seems a reasonable approach in eligible patients, especially in patients achieving CR after induction therapy. This approach should be urgently evaluated in randomized trials, as planned by the German High-Grade Non-Hodgkin Lymphoma Study Group.
Two skin lesions on the leg of patient 1 (769.5 cm and 363 cm). Muscle fibers covered with fibrin are visible  
Introduction: The combination of cetuximab, bevacizumab, and chemotherapy is under evaluation in different tumor types. Manageable acneiform eruptions, nail and hair changes are the most common skin reactions. Materials and methods: We conducted a phase II trial evaluating the combination of cetuximab, bevacizumab, and irinotecan in 32 patients with recurrent glioblastoma multiforme. Three cases of severe and unexpected skin toxicity developed. A detailed report is presented. Results: Multiple deep and large necrotic wounds extending to the muscle fascia developed 2–12 weeks after the initiation of therapy. All patients received high-dose systemic corticosteroids. A biopsy from the lesions of one patient showed leukocytoclastic vasculitis. Cetuximab treatment was discontinued. The lesions healed in one case while on bevacizumab and irinotecan. One patient underwent reconstructive flap surgery with complete healing. In one case, the lesions became chronic. Conclusion: Caution is recommended when combining epidermal growth factor receptor (EGFR) and angiogenesis inhibitors in patients receiving high-dose systemic corticosteroids.
The development of biomarkers to determine prognosis and predict response to therapy is an active area of research and represents an important part of the ongoing effort to individualize cancer care. Circulating tumor cells (CTCs) have demonstrated promise in several malignancies including prostate, breast, and colon cancer, and are being investigated prospectively as a correlative endpoint in clinical trials. Circulating tumor cells are also detectable in patients with advanced bladder cancer. The current review summarizes the recent technological advances in the detection and characterization of CTCs as well as their potential as a clinically useful biomarker in the management of patients with bladder cancer.
Neuron-specific enolase (NSE) has been the tumor marker of choice in small cell lung cancer (SCLC). It is considered specific for this malignancy and for neuroendocrine tumors, and it is useful in the diagnosis, prognosis, and follow-up of these patients. However, its low sensitivity, mainly in patients with limited disease (LD), has led to its use in combination with other tumor markers not as specific for SCLC. ProGRP, the precursor form of gastrin-releasing peptide (GRP), the mammalian counterpart of amphibian bombesin, is a useful tumor marker in SCLC. Abnormal ProGRP (>50 pg/mL) may be found only in a small subset of patients with benign (0.4%) or malignant disease (24%, 99% with concentrations <100 pg/mL), excluding SCLC and neuroendocrine tumors. Renal failure is the most important source of false positive results with ProGRP, possibly due to difficulties in the clearance of the tumor marker. ProGRP serum levels >150 pg/mL are indicative of SCLC with a probability of 93.7%. The ProGRP sensitivity in SCLC, the absence of false positive results in samples with hemolysis, the greater differences between normal ranges and the levels found in SCLC patients, and the higher specificity in other malignancies support ProGRP as the tumor marker of choice for SCLC. However, ProGRP and NSE are complementary tumor markers, and the use of both tumor markers simultaneously increases the sensitivity achieved with ProGRP by 15%. Tumor markers may be useful in the histological differentiation of non-small cell lung cancer (NSCLC) and SCLC. Patients with squamous cell carcinoma antigen (SCC) serum levels >2 ng/mL were always NSCLC, whereas those with SCC <2 ng/mL, ProGRP >100 pg/mL, and NSE >35 ng/mL were all SCLC patients. Using the criteria specified in Table 2, the sensitivity was 76.7% and 79.5% and the specificity was 97.2% and 99.6% in the differentiation of NSCLC and SCLC, respectively, with a positive predictive value of 98.6% and 98.6% and a negative predictive value of 60.7% and 92.9%. Tumor marker determination in patients with suspicious signs of lung cancer reveals the histological diagnosis in the majority of lung cancer patients in a few hours.
Bone health has become increasingly important in the management of early breast cancer. The reasons for this include the general recognition of post-menopausal osteoporosis as an important health issue, the long survival of most women diagnosed with breast cancer, and the impact of treatments, especially the aromatase inhibitors, on bone density. Algorithms and guidelines for managing these issues have mainly focused on detecting low bone mineral density and treating it. New evidence has emerged suggesting that secondary causes of low bone mineral density are common and a significant problem for breast cancer survivors. This article reviews recent studies and suggests ways of incorporating these new data into practice.
Lymphedema is a chronic debilitating condition affecting many long-term breast cancer survivors. The incidence of lymphedema is reported to range from 6% to 70% after axillary surgery for breast cancer; however, its true incidence has been difficult to quantify because of the lack of standard diagnostic and universal assessment criteria. Extent of nodal dissection, axillary radiation, injury, and infection in the ipsilateral upper extremity remain significant risk factors for the development of lymphedema. Current changes in axillary management, including the adoption of sentinel node biopsy, the selective omission of completion axillary dissection after a positive sentinel node, and the elimination of axillary staging, have been proposed to further reduce axillary morbidity. Early research on lymphedema risk reduction focuses on supervised weight training after axillary surgery, axillary reverse mapping to avoid removal of lymph nodes draining the upper extremity, and incorporation of fused single photon emission computed tomography (SPECT)-CT axillary nodal images to better plan adjuvant radiation treatments.
Radiation-Induced Dermatitis Scales used in Various Cohort Studies
Breast IMRT using multiple field-in-field segment compensation. The breast is treated by two opposite beams, and the figure represents only the medial beam. During radiation delivery, the beam is progressively shut by a multileaf collimator to avoid the creation of hotspots  
The majority of early-stage breast cancers are treated with breast-conserving surgery followed by adjuvant radiation treatment on the whole breast. Acute dermatitis is a frequent side-effect of adjuvant breast radiotherapy, and this treatment can also impair the long-term cosmetic result. Breast intensity-modulated radiation therapy (IMRT) is a technique that improves the radiation dose distribution in the breast, allowing the avoidance of “hotspots”. To review current evidence that breast IMRT provides a patient benefit, a MedLine search was done to identify articles reporting on this technique. A total of 63 manuscripts reporting on breast IMRT were identified. Fifty-six articles present original research data; the majority (80%) reported on physics or dosimetry, a smaller number on clinical outcomes (15%), and on health sciences or radiobiology (5%). Eight articles reported clinical outcomes, with six being single-institution retrospective or prospective cohort from three centers in the USA, and two reporting prospective randomized controlled trials were from the UK and Canada. Combining all these data, the clinical outcomes of nearly 780 patients receiving breast IMRT have been reported and compared with 767 patients receiving standard wedged radiotherapy. There is level 1 evidence that breast IMRT reduces acute dermatitis from a Canadian, multicenter, randomized, double-blinded, clinical trial, and there is level 1 evidence that breast IMRT improves the long-term cosmetic results from a UK randomized clinical trial.
Although the advent of trastuzumab and lapatinib has improved clinical outcomes for patients with HER-2/neu overexpressing breast cancer, many patients still progress and ultimately die from their cancers; thus, additional treatment approaches are needed. HER-2/neu vaccines have demonstrated promise in generating HER-2/neu-specific antitumor immune responses in patients with both early-stage and advanced breast cancer. Currently studied vaccines have achieved success in overcoming immune tolerance to self-antigens, broadening immune responses via epitope spreading, generating durable immunologic memory, and expanding the applicability of vaccination to multiple human leukocyte antigen (HLA) subtypes. In addition, HER-2/neu vaccines appear safe when administered with common adjuvant breast cancer therapies. Notably, vaccines have not resulted in additional cardiac toxicity when co-administered with trastuzumab; in fact, this combination may prove immunologically synergistic. HER-2/neu vaccines merit further investigation in the clinical setting, particularly as combination immunotherapy alongside standard treatment modalities.
Ovarian cancer remains a leading cause of cancer death among women, with an estimated 125000 deaths worldwide. Newly diagnosed ovarian cancer is very responsive to first-line platinum-based therapy, but the majority of patients will have disease recurrence. Patients in whom disease recurs more than 6 months after completing prior platinum-based treatment are considered to have platinum-sensitive disease, and questions remain regarding the optimal management of their disease. Many options exist for these patients, including systemic chemotherapy, and in specific circumstances, secondary cytoreductive surgery or radioablative techniques can be considered for patients with localized recurrences and long disease-free intervals. For patients receiving systemic chemotherapy, data from clinical trials suggest that combination platinum-based chemotherapy should be considered in this setting for patients in whom the toxicities would be acceptable, although the optimal regimen remains unclear. Ongoing investigations seek to address the role of secondary cytoreductive surgery, the optimal therapy for recurrent platinum-sensitive disease, the therapeutic potential of non-platinum-based therapies, and the role of biological therapy in this setting.
Although lung cancer is predominantly caused by tobacco consumption, lung cancer among never smokers is an important health problem that is rapidly gaining recognition. The main causes of lung cancer in never smokers are still unknown, but second hand smoke exposure, radon exposure, occupational or environmental exposures, and viruses have been implicated. Lung cancer in never smokers has specific epidemiological and clinical characteristics; specifically, the disease occurs more frequently in women, particularly of Asian descent, and the main histology is adenocarcinoma. Specific molecular characteristics of the disease, compared with lung cancer in smokers, have also been identified including mutations in epidermal growth factor receptor (EGFR), EML4-ALK, K-ras, p53, and certain chromosomal abnormalities. Never smokers with lung cancer also have a better response to many treatments and a better survival than smokers. All these characteristics suggest that lung cancer in never smokers is distinct from lung cancer in smokers. This article will review the epidemiological and molecular findings, and the possible risk factors for lung cancer in never smokers.
Number of indications for chemotherapy and cumulative rise over time in head and neck cancers
The management of head and neck cancer is complex and requires a multidisciplinary approach to optimize the balance between the goals of organ preservation and long-term cure. The role of chemotherapy in head and neck cancers has recently expanded as a result of increasing evidence in the induction and postoperative setting. Several evidence-based clinical practice guidelines have been published by reputable cancer organizations to facilitate the translation of evidence from clinical trials to patient care. There is a high concordance in the recommendations for chemotherapy between the various clinical practice guidelines in head and neck cancers. The quality of evidence for recommendations for induction, concurrent and postoperative chemotherapy is high, but remains poor in the palliative setting. The main limitations of current guideline recommendations are the lack of guidance in addressing the impact of performance status and comorbidities in their recommendations for chemotherapy. Population-based studies suggest that the compliance with guideline recommendations for chemotherapy may be lagging behind newer evidence, and that opportunities for improvement in care exist.
(A) Two-dimensional display of the MS peak with the smallest P-value (P52.82610 25 ) in representative patients with severe AE (right) and without AE (left). (B) A representative haptoglobin-derived MS peak in 47 triplicate LC-MS runs (22 without AEs (blue) and 25 with severe AEs (red)) aligned along the RT of LC (top). Columns represent the mean intensity of triplicates (bottom). LC, liquid chromatography; RT, retention time. Originally published by the American Society of Clinical Oncology [30]  
(A) Category classification of hematologic toxicities based on the worst CTC AE grades of neutropenia and thrombocytopenia during the first two cycles of gemcitabine monotherapy. (B–D) Plasma haptoglobin levels according to the hematologic toxicity Categories in the modeling (B), V1 (C), and V2 (D) cohorts. Horizontal lines represent mean levels of haptoglobin. LLN, lower limit of normal. Originally published by the American Society of Clinical Oncology [30]  
Severe hematologic toxicity generally requires dose reduction or postponement strategies, which often compromise treatment efficacy and survival outcome. At present, there is no established predictive tool to identify patients at risk of a severe adverse event after any type of chemotherapy regimen. We have carried out a proteomics study using plasma samples from pancreatic cancer patients who had received the same gemcitabine treatment to identify new biomarkers that might be useful for prediction of gemcitabine-induced neutropenia and thrombocytopenia. We found that the baseline plasma level of haptoglobin showed a correlation with the severity of neutropenia and thrombocytopenia. In this short review, we summarize the available evidence regarding the prediction of hematologic adverse events after cytotoxic chemotherapy. Knowledge of predictive factors for toxicity should be incorporated into more intelligent selection of chemotherapy regimen and dosing to get closer to the ideal of personalized therapy.
Chronic lymphocytic leukemia (CLL), a disease affecting neoplastic B cells, primarily presents in individuals between the ages of 65 and 70 years. It is characterized by progressive immunodeficiency, which manifests as an increased likelihood of developing infections. In patients with CLL, an increased susceptibility to infection can be the result of disease-related immunosuppression or develop as a result of treatment. The introduction of nucleoside analogues and monoclonal antibodies such as rituximab has improved response rates, but at the expense of increased infection rates. Despite a lack of prospective randomized trials evaluating the efficacy of prophylactic antibiotic use in this patient population, this remains the primary modality for managing infectious complications in patients with CLL. Patients receiving treatment for CLL appear to be at the greatest risk of infection and should be considered for antibacterial prophylaxis. In patients receiving purine analogues or alemtuzumab, prophylaxis against infections such as herpes zoster, hepatitis B virus, and fungal infections is also recommended. Hypogammaglobulinemia is considered the most important factor in patient susceptibility to infection. Intravenous immunoglobulin (IVIG) is a fractionated blood product that is derived from plasma and primarily contains immunoglobulin G (IgG). Available data from clinical trials indicate that selected patients with CLL who are at risk for infection can be protected from this complication by the regular administration of IVIG. Clinical trial data indicate that IVIG (400 mg/kg every three weeks for 12 months) significantly reduces bacterial infections (P = 0.001), including serious bacterial infections (P<0.03), and significantly reduces hospital admissions (P = 0.005) and febrile episodes (P = 0.004). IVIG-related adverse events occur in approximately 1–15% of patients; however, in general practice, <5% of patients experience clinically significant reactions. Although the routine administration of IVIG may not be warranted, the available data consistently indicate that prophylactic IVIG reduces bacterial infections in selected patients with CLL.
WHO's 2000 System of Classification for Neuroendocrine Tumors
Grading System According to TNM Staging System by Rindi et al [15]
Trial Evaluating Target Therapies in the Treatment of Pancreatic Neuroendocrine Tumors (PNETs)
Study Evaluating Different Chemotherapy Regimens in Well-to Moderately Differentiated Pancreatic Neuroendocrine Tumors
Although their incidence has been rising over the last decades, pancreatic neuroendocrine tumors (PNETs) are relatively uncommon, accounting for less than 5% of all primary pancreatic malignancies. They are classified based on morphological and biological characteristics. The World Health Organization (WHO) classification from 2000 subcategorizes gastroenteropancreatic neuroendocrine tumors into well-differentiated tumors, well-differentiated carcinomas, and poorly differentiated carcinomas; the TNM staging system from 2006 considers three “G” groups based on the Ki-67 level and three “T” groups related to the size. Retrospective analyses confirmed the prognostic relevance of both WHO and TNM staging systems for PNETs. As for treatment, chemotherapy, somatostatin analogs, interferon, and peptide radioreceptor therapy can have a role in PNETs. Over the last decade several molecular targeted agents have been studied. Among them sunitinib and everolimus are in the most advanced phase of clinical investigation. This is a literature review, based on a Medline search for pancreatic neuroendocrine tumor and carcinoma, which will focus on the clinical importance of classifications and the advances of molecular targeted therapies in PNETs.
Patient Characteristics
RTOG 0415 and Restrictive Dose Constraints
Dose Comparisons for Organs at Risk for Both Types of IMRT Plans for the ''Average'' Patient, including all Patients
Planning Target Volume (PTV) Dose Comparison between the Two Types of IMRT Plans for the ''Average'' Patient, including the Middle Six Patients
Purpose: Intensity Modulated Radiation Therapy (IMRT) is considered by many to be the standard of care in the delivery of external beam radiotherapy treatments to the prostate. The purpose of this study is to determine if using criteria stricter than that used in the current randomized trials will provide dosimetric improvement. Materials and Methods: Treatment plans were produced for ten patients utilizing the dose constraints recommended by the large randomized RTOG 0415 protocol and more restrictive restraints similar to those employed by a large cancer center. Results: The restrictive plans show consistently lower doses to the rectal and bladder volumes of interest. They also show a significant reduction in dose to the penile bulb. PTV coverage was more homogeneous for the protocol based plans. Conclusions : It is clear from our analysis that general constraints, while easily met, don’t result in the maximal benefits of Intensity Modulated Radiation Therapy in sparing the rectum. The trade off is with more homogeneity in the target volume. Further research is needed to identify the ideal balance between reducing toxicity and sacrificing tumor coverage.
Vitamin D synthesis and metabolism in humans  
Vitamin D has long been recognized as a fundamental mediator of calcium and skeletal homeostasis. More recently, however, the important role that vitamin D plays in a wide variety of other cellular processes, including inhibition of carcinogenesis by induction of differentiation, inhibition of cellular proliferation and angiogenesis, and promotion of apoptosis, has been appreciated. Multiple myeloma, a severely debilitating, incurable, and uniformly fatal neoplastic disease of B cell origin, is frequently complicated by severe skeletal complications related to lytic bone destruction. The role that vitamin D may play in myeloma bone disease and/or multiple myeloma itself, however, has remained unknown. Here, we review our recent study of 148 subjects who had their vitamin D status determined within 2 weeks of a new clinical diagnosis of multiple myeloma. The prevalence of vitamin D deficiency (defined as a serum 25-hydroxyvitamin D level <20 ng/mL (50 nmol/L)) increased in parallel with International Staging System categorization, indicating that subjects with worse clinical prognosis were more likely to have vitamin D deficiency. However, vitamin D levels were not predictive of skeletal morbidity. These data provide the first data demonstrating an inverse association between vitamin D status and clinical prognosis in patients with multiple myeloma. Further, these data suggest that assessment of vitamin D status may be an important adjunctive aspect of providing care for patients with myeloma, and that larger prospective studies to assess the role of vitamin D in multiple myeloma disease progression, overall survival, and quality of life may be warranted.
H&E staining of GBM. Top: cortical infiltration with tumor cells. Bottom: some of the characteristic histological features including pseudopalisading necrosis and glomeruloid vascular proliferation (arrow). T, tumor; CX, cortex; N, necrosis
Typical magnetic resonance spectroscopy profile of a patient with glioblastoma multiforme. (A) DWI of glioblastoma multiforme. (B) and (C) Voxel of interest in cystic mass showing lactate peak at 1.3 ppm with inversion at a different sequence. (D) Axial T1-weighted MRI with contrast. (E) MRS with voxel placement in different areas (1, within mass; 2 and 3, enhancing rim; 4, contralateral brain). Characteristic peaks (x, choline; y, creatine/phosphocreatine; z, Nacetyl aspartate). Modified with permission from [81]
Kaplan-Meier survival curve of overall survival in patients with methylated MGMT promoter vs patients with unmethylated MGMT promoter, randomized to radiotherapy and temozolomide. Reprinted with permission from [61]
Significant copy number aberrations in GBM. Both gene amplifications as well as deletions were detected by comparative genomic hybridization. DNA samples from 206 GBM specimens analyzed as part of the study by the Cancer Genome Atlas Research Network. Reproduced with permission from [71]
Glioblastoma multiforme (GBM) is the most common of all primary brain tumors and has the worst prognosis. Increased understanding of glioma biology and pathophysiology has translated into interesting advances in the diagnostic approach for patients bearing these tumors. This review explores the clinical, radiographic, and histological features of GBM that aid in its identification, with an emphasis on the application of emerging technologies. The use of novel imaging modalities including magnetic resonance imaging (MRI) spectroscopy, positron emission tomography, and perfusion MRI are discussed along with a review of tumor genetics and epigenetics from the perspective of their diagnostic and prognostic relevance.
Hepatic resection is the potential curative therapy for select hepatic malignancies, but inadequate future liver remnant (FLR) following resection may limit the performance of adequate surgical resection. As a result, portal vein embolization (PVE) has been developed to induce hypertrophy in the FLR to facilitate safe hepatic resection. Here, we performed a systematic review of the literature to provide an outline and summary of the current status of PVE and to identify current developments and controversies regarding its application in hepatic surgery. Although data from randomized controlled trials may be lacking, current reports indicate safe and effective application of PVE. However, a consensus on standard technique and appropriate patient selection has not been established. Furthermore, the potential effects of PVE on tumor growth and proliferation remain to be fully elucidated. Nevertheless, PVE appears to be a safe technique that effectively decreases the risk of fulminant hepatic failure in patients requiring major hepatic resection. Future studies are necessary to address appropriate patient selection for this technique and its optimal role in the multidisciplinary management of hepatic malignancies.
Multimodal imaging in patients with malignant gliomas. Routine MRI of one patient with a previously diagnosed left occipital glioblastoma showed typical contrast enhancement of a recurrent tumor (A). This was supported by FET-PET analysis (B) and confirmed by histology from a reoperation. Another patient who also had a contrast-enhancing lesion on follow-up MRI after tumor resection and radiochemotherapy followed by adjuvant TMZ (C) did not have elevated activity in FET-PET performed at the same time point (D), which suggests pseudoprogression.  
Possible Genetic Pathways in Glioblastomas. 
The standard treatment for patients with newly-diagnosed glioblastoma multiforme includes microsurgical tumor resection, external beam radiation in combination with temozolomide (TMZ) chemotherapy, and then adjuvant chemotherapy with TMZ alone. In addition, there are new drugs targeting different key players in tumorigenesis and angiogenesis in malignant gliomas that are currently being tested in clinical trials. Thus, more sophisticated molecular and genetic profiling will be necessary to determine which patients are most likely to benefit from the specific treatment options. In cases of unavoidable tumor recurrence, no clear standard of therapy exists, and there is no expert consensus on how to treat these patients. Re-resection, re-radiation, or changes in chemotherapeutic schedule or drug are general options, but each has to be considered on a case-by-case basis. In addition, institutions often have some mostly experimental local or systemic approaches that are considered in recurrent glioblastomas. This has led to growing uncertainty as to how to treat patients with glioblastomas and recurrent disease and when to use which therapeutic option. Decision-making also depends on the time point of therapy onset, and therefore also the correct detection of real tumor progression. Magnetic resonance imaging (MRI) has been demonstrated to have diagnostic limitations in cases of “pseudoprogression” after multimodal therapy and in patients treated with antiangiogenic drugs. Thus, new imaging techniques such as MR spectroscopy, MR FLAIR sequences, ADC maps, and nuclear medicine imaging with O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography (FET-PET) or other tracers will be of almost as much importance in the treatment of glioblastoma as the different tumor therapies in due time.
Soft tissue sarcomas (STSs) are a heterogeneous group of solid tumors generally associated with a poor prognosis. Even with optimal treatment for localized disease, approximately 30–50% of patients will develop metastases within two to three years from diagnosis. Chemotherapy is the mainstay of treatment in patients with unresectable advanced or metastatic disease. While significant efforts have been made in recent years to identify new effective therapies, doxorubicin and ifosfamide have remained the most commonly administered agents until recently. For patients who are refractory to these agents, no standard of care exists. Furthermore, patients refractory to first-line treatment generally have a poor response to second-line therapy. The limited treatment options available for advanced or metastatic STS have prompted investigation of alternative chemotherapeutic agents. One of these agents is the antineoplastic agent trabectedin (Yondelis®; ET-743), which was initially derived from the Caribbean marine tunicate Ecteinascidia turbinata and is now produced synthetically. Trabectedin is the only approved drug for the treatment of relapsed STS, and it is recommended by the European guidelines for the treatment of advanced or metastatic STS with particular efficacy against leiomyosarcoma and liposarcoma. In phase II clinical trials, trabectedin provided disease control and/or clinical benefit in more than 50% of patients and was accompanied by a median overall survival (OS) rate of up to 14 months. The combination of trabectedin and doxorubicin extends the OS rate to 15 months. These encouraging results support the role of trabectedin in the treatment of STS. The results of ongoing clinical trials investigating the activity of trabectedin in combination with other chemotherapeutic agents and in specific histological subtypes of STS should further define the place of this emerging agent in the management of this difficult-to-treat population.
(A) Overall survival was significantly greater among patients positive for CD26 than negative for CD26 (P,0.00001 by log-rank test). (B) Diseasefree survival was significantly greater among patients positive for CD26 than negative for CD26 (P,0.00001). Reprinted with permission from [15]. Copyright 2008, American Society of Clinical Oncology  
Gastrointestinal stromal tumor (GIST) is a recently established tumor entity that originates from interstitial cells of Cajal (ICC), and comprises the majority of mesenchymal tumors in the gastrointestinal tract. Frequent overexpression and mutation of the KIT proto-oncogene or the platelet-derived growth factor receptor α (PDGFRA) has resulted in the introduction of imatinib mesylate as a model for molecule-based treatment of solid tumors. GIST has a wide spectrum of morphological and clinical features, ranging from bland to frankly malignant tumors of spindled, epithelioid, or mixed appearance. Traditionally, several key prognostic factors, such as mitotic rate, Ki-67 (MIB-1) index, tumor size, and tumor site, have been developed, and the combination of these factors has been confirmed to have relatively high accuracy in predicting the outcomes of GIST. Over the last decade, advances in gene expression array technology have enabled the simultaneous examination of the expression of numerous genes. Many investigators have applied this technology to a series of GIST cases in an effort to understand the basic biology of this tumor in order to better predict tumor outcome and clarify tumor pathogenesis. Data from these studies suggest that gene expression profiling and the development of signature pattern recognition may provide a powerful tool in understanding the biology and identifying the prognosis of GIST. Such studies have confirmed that CD26, a type II, cell surface glycoprotein known as dipeptidyl peptidase IV (DPP4), is not only a biomarker for predicting the outcome of gastric GIST, but may also play an important role in malignant progression, and that its inhibitors are drug candidates.
Integrins are cell surface molecules that are important for the interaction of cells with the extracellular environment. Crucial for cell survival and migration, integrins have been recognized as a unique target for central nervous system cancers. In the most malignant of these, glioblastoma multiforme (GBM), integrins have key roles in supporting robust tumor angiogenesis as well as facilitating the survival, migration and infiltration of transformed tumor cells into the brain itself. The anti-integrin activity of several compounds that target the tumor and its environment has been tested in early phase clinical trials in patients with malignant brain cancer. This review outlines the function of integrins and the current state of clinical investigation.
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas with disparate responses to standard chemotherapy regimens. Although there have been significant advances in B-cell lymphoma management, the treatment of PTCL remains a challenge, especially for relapsed or refractory disease. Furthermore, there are limited data focusing on the issue of salvage treatment strategies in the setting of PTCL. This review addresses the recent advances in salvage treatments, including autologous and allogeneic stem cell transplantation, and discusses novel approaches currently under investigation.
Summary of Published Phase I Trials 
Summary of Published Phase II Trials 
Triapine is a ribonucleotide reductase inhibitor, which has been investigated in a variety of tumor cell lines in the preclinical setting. Phase I trials have reported encouraging results in the treatment of hematological malignancies, whereas the results have been disappointing for solid tumors. This article offers a review of preclinical data and clinical outcomes with future directions.
Thrombocytopenia in patients with solid malignancy can be caused by bone marrow involvement or toxicity from anticancer therapy; however, it could rarely be the first presentation of a tumor such as breast cancer or lymphoma. Hematological paraneoplastic syndromes such as paraneoplastic thrombocytopenia and/or immune thrombocytopenic purpura (ITP) are well described as secondary findings simultaneously with malignancies such as breast cancer and lymphoma. Other hematological conditions such as severe amegakaryocytic thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), and myelodysplastic syndromes (MDS) have also rarely been described as a possible paraneoplastic process complicating solid tumors. On the one hand, occult disseminated malignancy may mimic ITP and TTP, leading to diagnostic and therapeutic problems. On the other hand, thrombocytopenia could be the first manifestation of cancer.
Stage 1a1 has been established to define a subset of cervical cancer patients who may desire future fertility and are eligible for conservative surgery. Recently, however, a number of stage 1a1 cases with lymph node metastasis have been reported. Some of these cases had positive lymphovascular space invasion (LVSI), which some studies have identified as a negative prognostic factor. There is still, however, disagreement between International Federation of Gynecology and Obstetrics and Society of Gynecologic Oncologists regarding whether LVSI may be used as a staging criterion. Although stage 1a1 cases may still be managed conservatively, gynecologic oncologists must consider the possibility of lymph node metastasis, particularly in patients with positive LVSI, and counsel patients accordingly. Here, we summarized case series of stage 1a1 cervical cancer with extensive LVSI and pelvic lymph node metastasis and review the relevant literature.
The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved agents and the clinical perspectives of these new weapons against metastatic melanoma.
Fulvestrant, an estradiol analog that binds directly to the estrogen receptor (ER) and anastrozole, an inhibitor of the aromatase enzyme are two antiestrogen agents that are currently used in the endocrine treatment of postmenopausal women with breast cancer. This article reviews the clinical efficacy and safety data for both agents, which led to their approval as monotherapies for the first- or second-line treatment of advanced breast cancer. The use of both agents in combination will also be discussed. Although first approved at a dose of 25o mg, fulvestrant 500 mg has recently been shown to be associated with a clinically meaningful benefit over fulvestrant 250 mg in the second-line setting. While fulvestrant is currently recommended following failure on prior endocrine treatment, suboptimal suppression of the ER at the originally approved 250 mg dose led to further speculation that fulvestrant 500 mg may have increased efficacy in the treatment of advanced disease. Results from the phase III CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer) study show that fulvestrant 500 mg is superior to 250 mg in terms of the primary endpoint of time to progression (TTP). In addition, the phase II Fulvestrant FIRst-Line Study Comparing Endocrine Treatments (FIRST) showed that fulvestrant 500 mg had a similar clinical benefit rate and longer TTP than anastrozole 1 mg as first-line therapy for advanced breast cancer. With their distinct modes of action, both anastrozole and fulvestrant have a critical role to play in the management of hormone receptor-positive advanced breast cancer.
The Ki-67 monoclonal antibody recognizes a nuclear antigen that is present in all phases of the cell growth cycle but is absent in resting cells. The Ki-67 proliferation index is used to measure the growth fraction of malignant cells. In the major types of lymphoma, its range is very wide. Mean Ki-67 expression is low in indolent lymphomas and high in aggressive lymphomas; a cutoff index value of 45% can help clinicians to differentiate indolent from aggressive lymphoma. In follicular lymphoma, the Ki-67 proliferation index increases with increased follicular grade. In diffuse large B-cell lymphoma (DLBCL), most studies found that a high Ki-67 proliferation index (>60-70%) was a predictor of poor survival. The most extensive data exist on mantle cell lymphoma, for which multivariate analyses confirmed the central prognostic role of cell proliferation and the superiority of the Ki-67 proliferation index over all other histomorphological and clinical criteria. The stratification of patients with mantle cell lymphoma according to Ki-67 expression can be expected to have a profound impact on therapeutic options in risk-adapted strategies. For the prognostication of peripheral T-cell lymphoma, the Ki-67 proliferation index was integrated into a new predictive score. Thus, overall, the Ki-67 proliferation index is an important tool for determining lymphoma grade, and in many subtypes, it has prognostic significance. At the same time, it should be borne in mind that Ki-67 staining is still associated with poor reproducibility among laboratories, and each laboratory should determine its own cutoff values.
A 57-year-old woman presented with urinary symptoms. Imaging demonstrated a left-sided hydronephrosis and filling defect of the left distal ureter. A laparoscopic left nephroureterectomy with open removal of the bladder cuff was subsequently performed. Pathology demonstrated a grade 1 endometrioid endometrial adenocarcinoma arising within the context of intra-ureteric endometriosis. Malignancy arising from endometriosis, although uncommon, is well recognised. This is the first reported case of endometrial cancer arising on a background of predominantly intrinsic ureteric endometriosis following total abdominal hysterectomy and bilateral salpingo-oophorectomy 27 years previously for extensive endometriosis.
Methotreaxate (MTX) is a folat inhibitor that inhibits DNA, RNA, and protein synthesis. MTX has a lot of side effects especially on the gastrointestinal system such as mucositis, ulcerative stomatit, nausea, vomiting, diarrhea, and hepatic toxicity. Here we reported a 13-yearold girl patient in association with T-cell lymphoblastic non-Hodgkin lymphoma who developed an excessive intra-abdominal and intrathorasic hemorrhage unresponsive to fresh frozen plasma and thrombocyte transfusions followed by high-dose MTX treatment. Also discussed is the off-label use of rFVIIa in the patients with excessive bleeding unresponsive to conventional treatment. This patient received rFVIIa in a dose of 50 mg/kg every 2 h for three doses (total 300 mg/kg). We suggest that the rFVIIa treatment is effective for excessive bleeding unresponsive to conventional treatment caused by high-dose MTX treatment and the off-label use of rFVIIa may be thought of in the treatment of excessive hemorrhages followed by MTX treatment.
Human DAB2IP (hDAB2IP), a novel GTPase-activating protein modulating Ras-mediated signaling, is a candidate tumor suppressor gene. However, promoter methylation of hDAB2IP in colorectal cancer (CRC) is poorly understood. To ascertain the mechanism of gene promoter hypermethylation in CRC cells, we investigated the promoter methylation status of hDAB2IP genes in four CRC cell lines using a methylation specific polymerase chain reaction (MS-PCR). The frequency of DNA methylation was detected in three of the four CRC cell lines. The hDAB2IP gene expression was examined and determined using a reverse transcription-PCR (RT-PCR) and immunoblot analysis in CRC cell lines. Gene expression was silenced or down-regulated in SW-480 with methylated hDAB2IP, but could be restored by treatment with 5-aza-2?-deoxycytidine, a DNA methyl-transferase inhibitor. The frequency of DNA methylation was detected in 10 of 25 colon tumors (40%), compared with 0 of 25 (0%) corresponding adjacent normal colon tissues (pB0.005). These results suggest that hDAB2IP methylation is frequently present in colon cancer, and gene silencing may play an important role in colorectal carcinogenesis.
Top-cited authors
Edward A. Levine
  • Wake Forest School of Medicine
Aaron Blackham
  • University of South Florida
Peter Bader
  • Goethe-Universität Frankfurt am Main
Hermann Kreyenberg
  • University Hospital Frankfurt
Andre Willasch
  • Goethe-Universität Frankfurt am Main