Central hepatectomy: The golden mean for treating central liver tumors?

The treatment of patients with central liver tumors involving segments 4, 5 and 8 is a difficult clinical problem. These tumors often straddle Cantlie's line and involve parts of both lobes of the liver. The traditional management of such tumors is to perform either an extended right or an extended left hepatectomy. However, extended hepatectomies are associated with greater morbidity and mortality, mainly due to increased risk of postoperative liver failure. Central hepatectomy (or mesohepatectomy) may be superior to extended hepatectomy, because it conserves more liver parenchyma. However, the operation can be tedious and may result in increased blood loss, and was therefore infrequently used. Recommendations for its application for centrally located tumors are not clear. The aim of our study is to evaluate the evidence supporting central hepatectomy as a safe procedure for the management of central hepatic tumors, and to describe the effectiveness of central hepatectomy compared to extended hepatectomy. We present herein two patients who underwent central hepatectomy and systematically review the English literature until December 2006. We found 13 studies of multisegmental (> or = 2 segments) central liver resection that included at least four patients. Only three retrospective non-randomized studies have looked at central hepatectomy in comparison to lobar or extended hepatectomy, and no clear consensus emerges. To date, there is insufficient evidence to categorically state that central hepatectomy is superior to extended hepatectomy, thus the use of all approaches can be justified. However, if central hepatectomy can be performed without excessive blood loss, then it should be preferred, as it is less extensive and results in greater functional remnant liver. Additionally, it would clearly be superior in patients with cirrhosis.     

Social cognition in patients with intracranial tumors: do we forget something in the routine neuropsychological examination?

Journal of Neuro-Oncology - Social cognitive functions are of high clinical relevance. To date, little is known about social cognition in neurooncological patients and this domain is usually not...     

Do autochthonous tumors interfere with effector T cell responses?

The assumption that autochthonous tumors interfere with the effector T cell (T(E)) response implies that they first induce functional T cells. However, if T(E) are generated, they usually remain functional, persist life-long as memory cells and prevent tumors. This holds true for some virus-induced tumors and is associated with evolutionary pressure. In contrast, models that allow monitoring of tumor antigen-specific T cells suggest that spontaneous autochthonous tumors either sneak through or induce T(E) too late when the tumor has developed resistance to T(E) or induce tolerance. This can be explained by the absence of evolutionary pressure.     

Manufacturing CAR-NK against tumors: Who is the ideal supplier?

Chimeric antigen receptor-natural killer(CAR-NK) cells have emerged as another prominent player in the realm of tumor immunotherapy following CAR-T cells. The unique features of CAR-NK cells make it possible to compensate for deficiencies in CAR-T therapy, such as the complexity of the manufacturing process, clinical adverse events, and solid tumor challenges. To date, CAR-NK products from different allogeneic sources have exhibited remarkable anti-tumor effects on preclinical studies and have g...     

Adrenocortical tumors and insulin resistance: What is the first step?

The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin‐like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF‐1 and IGF‐2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF‐1 receptors. Interestingly, apparently non‐functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors.     

Do children with optic pathway tumors have an increased frequency of other central nervous system tumors?

We questioned whether children with optic pathway tumors (OPTs) have an increased frequency of other CNS tumors on the basis of experience with a number of such children treated at our institution. The medical records of all patients with OPTs treated at Golisano Children's Hospital at Strong at the University of Rochester from 1957 to 2000 were reviewed to determine the incidence of additional CNS tumors in these children and whether the occurrence of these other CNS tumors is associated with any risk factors. Twenty-six children had OPTs. Twelve of the 26 children had biopsy-proved tumors; the remaining 14 were diagnosed on the basis of CT or MRI scans. Eight of the 26 patients (31%) had a total of 11 additional CNS tumors. (One child had 2 additional CNS neoplasms, and a second child had 3.) Nine were biopsy proved (3 glioblastoma, 3 anaplastic astrocytoma, 3 low-grade astrocytoma), and 2 were diagnosed by imaging studies alone (acoustic neuromas). Eight of the 11 tumors occurred at a median of 5 years (0.8-25 years) subsequent to the diagnosis of the OPTs; 3 were diagnosed simultaneously with the OPT. Of the 17 children with neurofibromatosis (NF) and OPTs, 8 (47%) had additional CNS tumors, while none of the 9 children (0%) without NF had other CNS tumors (P = 0.023). There was no association between radiation treatment of the primary OPT and subsequent development of other CNS tumors in the group as a whole, or when the analysis was confined to children with NF. Despite this lack of statistical association, all 7 CNS tumors that occurred following radiation arose in irradiated areas. The risk of simultaneous or subsequent CNS tumors in children with NF and OPTs is high. These children should be closely monitored for the simultaneous or subsequent occurrence of other CNS tumors.     

Health Care Costs: How Do We Decide Value? When Do We Decide? How Do We Particularize the Decisions?

The role of cost-effectiveness analyses in medical decision making is examined.How do oncologists and patients make heath care decisions? Do we use a “shared decision-making” model? Has paternalism become a thing of the past? Do we rely on the latest randomized trial data and then apply it in the same way that the trial eligibility criteria were determined? When we counsel someone about cancer care (screening, prevention, and treatment), do we include financial risks in the discussion? Costs for cancer care are rising throughout the world. This is especially noted in high-income countries [1]. Contributors to increasing costs include demographic, technological, regulatory, industrial, and governmental factors as well as individual patient and physician behaviors. Lack of knowledge of “costs” and limited reporting of “true” benefits of medical care are impediments to meaningful discussions of providing individual care and reforming health care. Individual and societal expectations are also driving the “cost curve” of health care. Financial considerations, overuse, for example, are perceived to be placing more pressure on the practice of medicine in the U.S. than in the past. Costs of new treatment development through the clinical trial process, individual and group expenditures, and public/governmental monetary outlays for cancer treatment drugs continue to rise. The research focus on “targeted therapy,” like trastuzumab, and personalized cancer treatment based on the molecular characteristics of an individual''s cancer may also increase the costs of new treatment development and patient care.There is a great deal of angst regarding the future of medicine and the care of the sick based on the perception that we will not be able to afford care. The recent emphasis on “end-of-life” care has precipitated worry of “rationing,” an act undertaken by policy makers, and financial means testing for medical care. Reports of personal bankruptcy resulting from critical or life-threatening medical illnesses fill the news [2]. There is also a perception of inequality in access and distribution of health interventions known to be of value, not rationing but an access to care concern and a distributive justice issue nonetheless. It is incumbent on the oncology community that we discuss, review, and assess the best means of providing care for the benefit of all citizens. The costs of cancer care have been the subject of ethical review, and the question has been asked: “How much is life worth?” [3] Evidence-based medicine, based on analysis of randomized controlled trials (RCTs), and comparative effectiveness research provide two methods that have been proposed to assist in decision making for health care. Whereas evidence-based medicine has, as a component, the patient''s values and participation in the decision, comparative effectiveness research (CER) does not “particularize” an individual treatment decision. CER is defined as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care.” This is intended to provide assistance in health care decisions for the public, policy makers, and individuals with the goal of improving health care [4]. Other clinical decision aids, such as number needed to treat and number needed to harm, and clinical efficacy reports from RCTs have their proponents. It has been suggested that RCTs lack the necessary details for use in clinical practice [5]. Each method has supporters and detractors and no “surefire” best method is available to practicing physicians and patients to aid in clinical decision making. Countries such as the U.K. have developed formal processes for the evaluation of technologies and drug therapies to guide health care financial coverage decisions. The U.K. National Institute for Clinical Excellence provides an explicit methodology for analysis of technologies and therapeutics and includes cost-effective analysis (CEA) in the process. This method uses decision analysis methodology and data from RCTs to reach a decision on the relative benefits and costs of interventions. The analysis generally is described as a measure of life-years gained (LYG) or quality-adjusted life years (QALYs) for reporting purposes. Comparing two or more interventions can provide a measure of the “incremental cost-effectiveness,” often expressed as a ratio, of the differing strategies for treatment, as an example, chemotherapy for human epidermal growth factor receptor (HER)-2⁺ breast cancer with and without trastuzumab [4, 6–8]. Other countries, including Australia and Canada, also use cost-effectiveness measures for approving the use of drugs and technologies. In the U.S., a consensus panel defined the use of CEA and stated that “the information it provides is critical to informing decisions about the allocation of health care” [9, 10]. CER and CEA have been used effectively not only for policy decision but also to enhance individual informed decision making for clinicians and patients. In the U.S., costs have not been part of the approval decision process for the U.S. Food and Drug Administration (FDA). They require safety and effectiveness determinations for making drug approval decisions. The approval is generally for an “indication,” but once approved an agent may be used as desired by practicing clinicians. Although some insurers, including the Centers for Medicare and Medicaid Services, have restrictions, the development of approved compendia based on guidelines for care make chemotherapy agent use more liberal than the FDA may have intended. Many clinicians may not be aware of drug costs in relation to benefit derived for their patients, or perhaps think these “should not be” a consideration.It is clear that some rational process for addressing costs of care and benefit for individuals and society must be developed and generally agreed upon if we are to sustain cancer care advances. In the U.S., we have an opportunity to enhance and implement a rational approach to care decisions, but we will need leadership to develop the national will to proceed. Physician organizations, the American Society for Clinical Oncology for example, are best suited to bring this to the public and provide the necessary background and imperatives for change.The recently enacted Patient Protection and Affordable Care Act will expand health care coverage to an estimated 32 million currently uninsured individuals by 2019. This increase in health care need comes as the “baby boomer” generation will be reaching Medicare benefits age. These two coincident occurrences are expected to have the potential to further strain heath care budgets and access unless adequate, rational policy relief is forthcoming. Physicians must play a leadership role in attempting to curtail costs while providing value in health care. In this issue of The Oncologist, Hedden and colleagues provide a thoughtful assessment of trastuzumab use in the treatment of primary and metastatic breast cancer [11]. Their intent was not only to review clinical efficacy addressing the usual parameters of disease-free survival and overall survival but also to examine, in a formal, systematic critical way, QALYs and LYG in relation to economic parameters. They provide a range of costs for trastuzumab use and accept that it is cost-effective [12]. They chose to examine cost–benefit in a “real-world” scenario and relied on previously published RCT data for assessing the impact of trastuzumab over a projected 28-year time frame even though there are limited data for trastuzumab benefits beyond 5 years. Data for recurrence estimates were derived from results of published RCTs in similar populations of patients with primary and metastatic breast cancer. Cost data were obtained from the British Columbia Cancer Agency database. The use of Markov methodology allowed for decision modeling over time, and a variety of clinical outcomes states were considered. Transitions to differing health states were then applied to a hypothetical population of women with primary and metastatic breast cancer using previously published clinical trial data to inform the scenarios and transitions of the Markov model. Expert “opinion” for the modeling was minimized. A variety of sensitivity analyses confirmed the initial QALY and LYG data for trastuzumab use in patients with HER-2⁺ breast cancer.The clinician may rightly ask “What monetary value is used to declare something cost-effective?” And who decides? The “floor” for defining “cost-effective” monetarily is not universally standardized. It is encouraging that trastuzumab, a lifesaving treatment, is deemed cost-effective.This is not the first CEA of trastuzumab use for breast cancer and it is unlikely to be the final version. Other reports include studies from North America, Europe, Australia, and China and a systematic review from Taiwan [12–24]. An estimate of recurrences avoided in relation to cardiac events has also been reported [14]. These have used methods to assess QALYs and LYG, as well as “societal costs.” Generally, analyses do not include all costs, indirect and direct. Markov modeling has been the most common method of assessing outcomes, and differing choices for state transitions do not allow for crosscomparison of cost-effectiveness outcomes. With the exception of an analysis from the U.K., all reports conclude that trastuzumab use, especially in the adjuvant setting, is cost-effective for for the treatment of patients with HER-2⁺ breast cancer [25].The U.K. report concluded that the cost-effectiveness of trastuzumab remains “uncertain” and requires further research on the “duration of treatment effect” and “late toxicities.” These data would be useful for most RCTs. Often, RCTs lack sufficient data for supporting clinical decision making [5].For the Canadian system, drug prices are negotiated with pharmaceutical companies based not only on price but also on volume of drug use; therefore, it is likely that trastuzumab acquisition costs are less in Canada than in the U.S. Drug pricing, especially for new cancer agents, is a focus in the U.S. Tradeoffs for health care based on price are likely to occur [3]. CER may help in decisions about cancer care but only if an alternative treatment option is available. Until we have such data, unique expensive agents for treating patients with cancer should be reviewed with formal, critical systematic analyses of cost-effectiveness based on survival or quality of life as a measure of patient benefit. Oncologists need to become part of the ethical decision process to assure appropriate care is provided for all.Hedden and colleagues are to be commended, not only for providing a meaningful analysis supporting a beneficial treatment for breast cancer patients, but also for reminding all practitioners of the need for critical thinking regarding the costs of cancer care.Recent publications have emphasized the need for “high-value, cost-conscious care” [26]. Physician involvement in these efforts must be considered carefully and critically, and practice efforts must be aligned with these efforts to change our practice.The recent update of the American College of Physicians Ethics Manual succinctly states our responsibilities: “parsimonious care that utilizes the most efficient means to effectively diagnose a condition and treat a patient respects the need to use resources wisely and to help ensure that sources are equitably distributed.” This is a matter of ethics, beneficence, and justice [27].Until better or the “best” treatment for HER-2/Neu⁺ breast cancer is developed, trastuzumab is the most and only demonstrated cost-effective treatment. When new treatments become available through research, CER will be needed to further guide treatment choices and inform patients and physicians.Physicians can begin to change now by asking the “high-value” questions [28].As we strive to eliminate cancer and its attendant suffering for our patients in daily practice, have cost, access, and availability become part of our thinking?See the accompanying article on pages 164–171 of this issue.     

Laparoscopic glissonean approach: Making complex something easy or making suitable the unsuitable?

BackgroundThe use of laparoscopic glissonean approach has many potential benefits such as shorter operative times, lower blood loss with low morbidity.MethodsThe aim with this study was to perform an evaluation of 12 years of our experience with laparoscopic glissonean approach in liver surgery, from a technical standpoint using a prospective database. Anatomical laparoscopic liver resections using hilar dissection and non-anatomical resections were excluded from this study.Results327 patients (170 females and 157 males) with mean age of 56 years were included. 196 (60%) of procedures were major resections. 65% of procedures were performed in the last 5 years. 208 patients were operated on for secondary lesions. In 38 patients the liver was cirrhotic. Morbidity was 37.3% and 90-day mortality occurred in 2 patients (0.6%). Blood transfusion was necessary in 10.7% of patients. Median hospital stay was 4 days.ConclusionsLaparoscopic glissonean approach is a safe and feasible technique. It may be preferred in some clinical situations as it is associated with shorter operative times, lower blood loss, and low morbidity. It is superior to standard laparoscopic hepatectomy when an anatomical resection, especially if a segment or section is to be removed. However, application of this technique requires accurate preoperative tumor localization, identification of potential anatomic pedicle variations, as well as surgeon expertise.     

Do FHIT gene alterations play a role in human solid tumors?

The fragile histidine triad (FHIT) gene encloses an active common chromosomal fragile site, FRA3B. This gene is known to be associated with genomic instability, apoptosis and DNA damage. FHIT disturbances have been related to carcinogenesis in different types of human tumor. Despite this, there are some controversies about the exact role of the FHIT gene in relation to tumor biology. Several pieces of evidence support the hypothesis that FHIT acts as a tumor suppressor gene. A loss or decrease in the Fhit protein expression appears to be related to tumor progression, poor prognostic factors and lower survival rates. The most frequent causes of FHIT expression changes are gene mutations, epigenetic alteration and loss of heterozygosity. This literature review aims to clarify the involvement of the FHIT gene in carcinogenesis, tumor progression and clinical outcome in prevalent solid malignancies, such as breast, lung, cervical, esophageal, gastric and colorectal cancers.     

Isolated hepatic perfusion for the treatment of liver tumors: sunset or sunrise?

Experience with isolated hepatic perfusion (IHP) is limited to a few centers in the world because of the technical difficulties, surgery-related morbidity, and unproved efficacy in randomized trials. Experimental animal IHP models have led to exploring new ways of improving efficacy, reducing technical difficulties, and minimizing regional and systemic toxicity. Future research should be directed to the identification of suitable biologic or chemotherapeutic agents, defining clinical indications, and development of technical modifications to make it more generally applicable and even repeatable.     

Breast cancer stem cells: something out of notching?

We and others have established that the developmental Notch receptor signaling pathway is active in breast cancer cell lines, as well as in preinvasive and invasive primary samples. Recently, a role for Notch in regulating the hierarchy of stem and progenitor cells in both normal and cancer epithelium has been elucidated. Because inhibiting the Notch receptor signaling pathway is a possible future breast cancer therapy, here, we review the expression and activity of the different ligands and receptors and summarize the various ways in which the pathway's activity can be inhibited, and the likely effects of inhibition on different tumor cell subpopulations.