Showing papers in "Cancer Journal in 2013"

Molecular Pathology of Pancreatic Cancer

Abstract: Until recently, pancreatic cancer was a poorly understood disease. Research in the past decade has shown conclusively, however, that pancreatic cancer is primarily genetic in nature. Inactivation with a variety of tumor-suppressor genes such as p16, DPC4, and p53, coupled with activation of oncogenes such as K-ras, are a few of the mutations that trigger the growth of cancerous cells. Understanding these mutations is critical to a better understanding of familial pancreatic cancer and to the development of gene-based screening tests and therapies. In this article, we review the genetic alterations identified in pancreatic cancer and provide examples of how this information can be applied to patient care.

Basic mechanisms of therapeutic resistance to radiation and chemotherapy in lung cancer.

Abstract: In recent years, there have been multiple breakthroughs in our understanding of lung cancer biology. Despite significant advances in molecular targeted therapies, DNA-damaging cytotoxic therapies will remain the mainstay of lung cancer management for the near future. Similar to the concept of personalized targeted therapies, there is mounting evidence that perturbations in DNA repair pathways are common in lung cancers, altering the resistance of the affected tumors to many chemotherapeutics as well as radiation. Defects in DNA repair may be due to a multitude of mechanisms including gene mutations, epigenetic events, and alterations in signal transduction pathways such as epidermal growth factor receptor and phosphoinositide 3-kinase/AKT. Functional biomarkers that assess the subcellular localization of central repair proteins in response to DNA damage may prove useful for individualization of cytotoxic therapies including poly(adenosine diphosphate-ribose) polymerase inhibitors. A better mechanistic understanding of cellular sensitivity and resistance to DNA damaging agents should facilitate the development of novel, individualized treatment approaches. Absolute resistance to radiation therapy, however, does not exist. To some extent, radiation therapy will always have to remain unselective and indiscriminant to eradicate persistent, drug-resistant tumor stem cell pools.

Androgen receptor antagonists in castration-resistant prostate cancer.

Abstract: Persistent androgen receptor (AR) signaling despite low levels of serum androgens has been identified as a critical target for drug discovery in castration-resistant prostate cancer (CRPC). As proof of principle that the AR remains relevant in CRPC, 2 AR-targeted agents recently approved by the Food and Drug Administration-abiraterone and enzalutamide-have increased overall survival for patients with CRPC in the setting of prior chemotherapy. This review focuses on the AR and 2 direct antagonists, enzalutamide and ARN-509. These next-generation AR antagonists offer great promise for patients with advanced disease. Relative to conventional antiandrogens such as bicalutamide, they bind to the receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity in preclinical models. The success of these AR-targeted agents in the clinic has changed the landscape of therapy for patients with CRPC, and further therapeutic options building on this platform are currently in development.

Robotic surgery: colon and rectum.

Abstract: Although robotic technology aims to obviate some of the limitations of conventional laparoscopic surgery, the role of robotics in colorectal surgery is still largely undefined and different with respect to its application in abdominal versus pelvic surgery. This review aims to elucidate current developments in colorectal robotic surgery.In colon surgery, robotic techniques are associated with longer operative times and higher costs compared with laparoscopic surgery. However, robotics provides a stable camera platform and articulated instruments that are not subject to human tremors. Because of these advantages, robotic systems can play a role in complex procedures such as the dissection of lymph nodes around major vessels. In addition robot-assisted hand-sewn intracorporeal anastomoses can be easily performed by the surgeon, without a substantial need for a competent assistant. At present, although the short-term outcomes and oncological adequacy of robotic colon resection have been observed to be acceptable, the long-term outcomes of robotic colon resection remain unknown.In rectal surgery, robotic-assisted surgery for rectal cancer can be carried out safely and in accordance with current oncological principles. However, to date, the impact of robotic rectal surgery on the long-term oncological outcomes of minimally invasive total mesorectal excision remains undetermined. Robotic total mesorectal excision may allow for better preservation of urinary and sexual functions, and robotic surgery may attenuate the learning curve for laparoscopic rectal resection. However, a major drawback to robotic rectal surgery is the high cost involved.Large-scale prospective randomized clinical trials such as the international randomized trial ROLARR are required to establish the benefits of robotic rectal surgery.

PBRM1 and BAP1 as novel targets for renal cell carcinoma

Abstract: Technological advances in genome sequencing have led to the identification of novel driver genes mutated in renal cancer. Hitherto, 1 gene was known to be frequently mutated in renal cell carcinoma of clear cell type (ccRCC), the von Hippel-Lindau (VHL) gene. VHL was identified by positional cloning as the gene responsible for a familial syndrome with renal cancer predisposition, von Hippel-Lindau. Subsequently, VHL was found to be inactivated in approximately 90% of sporadic ccRCC. The discovery of VHL, together with the elucidation of its function, transformed the treatment of ccRCC leading to the introduction of 5 new drugs into the clinic. However, no other familial ccRCC predisposing genes are frequently mutated in sporadic ccRCC. With the development of massively parallel sequencing, a plethora of somatically mutated genes has been identified. Most genes are mutated at low frequencies, but 3 genes are mutated in more than 10% of ccRCC, PBRM1 (mutated in ~50%), BAP1 (~15%), and SETD2 (~15%). Like VHL, all 3 genes are 2-hit tumor suppressor genes. Furthermore, these 3 genes are within a 50-Mb region on the short arm of chromosome 3p that encompasses VHL and is deleted in ~90% of ccRCC. We discovered that PBRM1 mutations tend to anticorrelate with BAP1 mutations in ccRCC and that PBRM1- and BAP1-mutated tumors exhibit different biology and are associated with markedly different outcomes. This established the foundation for the first molecular genetic classification of sporadic ccRCC. Herein, I review the evidence that implicated PBRM1 and BAP1 as renal cancer driver genes, provide an update on the function of the gene products, and speculate on how mutations in these genes may be exploited therapeutically.

An inflammatory mediator, prostaglandin e2, in colorectal cancer

Abstract: It is widely accepted that intake of dietary fats and chronic inflammation are risk factors for developing colorectal cancer. Arachidonic acid is a major component of animal fats, and the bioactive lipids produced from this substrate play critical roles in a variety of biologic processes, including cancer. Cyclooxygenase-derived prostaglandin E2 is a known proinflammatory lipid mediator that promotes tumor progression. Metabolism of arachidonic acid by the cyclooxygenase pathway provides one mechanism for the contribution of dietary fats and chronic inflammation to carcinogenesis. In this review, we highlight recent advances in our understanding of how a proinflammatory mediator prostaglandin E2 promotes colorectal cancer immune evasion. These findings may provide a rationale for the development of new therapeutic approaches to subvert tumor-induced immunosuppression.

Future of robotic surgery.

Abstract: In just over a decade, robotic surgery has penetrated almost every surgical subspecialty and has even replaced some of the most commonly performed open oncologic procedures. The initial reports on patient outcomes yielded mixed results, but as more medical centers develop high-volume robotics programs, outcomes appear comparable if not improved for some applications. There are limitations to the current commercially available system, and new robotic platforms, some designed to compete in the current market and some to address niche surgical considerations, are being developed that will change the robotic landscape in the next decade. Adoption of these new systems will be dependent on overcoming barriers to true telesurgery that range from legal to logistical. As additional surgical disciplines embrace robotics and open surgery continues to be replaced by robotic approaches, it will be imperative that adequate education and training keep pace with technology. Methods to enhance surgical performance in robotics through the use of simulation and telementoring promise to accelerate learning curves and perhaps even improve surgical readiness through brief virtual-reality warm-ups and presurgical rehearsal. All these advances will need to be carefully and rigorously validated through not only patient outcomes, but also cost efficiency.

Bone-targeting radiopharmaceuticals including radium-223

Abstract: Bone-seeking radionuclides including samarium-153 ethylene diamine tetramethylene phosphonate and strontium-89 have been used for decades in the palliation of pain from bone metastases especially from prostate cancer. Emerging evidence of improved survival in metastatic castration-resistant prostate cancer (CRPC) with the first-in-class α-radionuclide, radium-223 (Ra) has rekindled interest in the role of bone-seeking radionuclide therapy.We review the literature for randomized controlled trials of bone-seeking radionuclides and explore some of the issues regarding the optimal use of these agents. In particular, we discuss dose, dose rate, radiobiology, and quality of radiation and postulate on potential future directions in particular combination schedules. β-Emitting, bone-seeking radionuclides have proven ability to control pain in prostate cancer metastatic to bone with pain response rates in the order of 60% to 70% when used as single agents. Most of the published trials were underpowered to detect differences in survival; however, there is evidence of the potential for disease modification when these agents are used in combination with chemotherapy or in multiple cycles.Data from the recent phase III ALSYMPCA trial that compared Ra to placebo in symptomatic CRPC demonstrate a significant improvement in median overall survival of 3.6 months for patients with symptomatic CRPC metastatic to bone treated with 6 cycles of the α-emitting radionuclide Ra compared with placebo. The success of Ra in improving survival in CRPC will lead this agent to become part of the treatment paradigm for this disease, and with such an excellent safety profile, Ra has huge potential in combination strategies as well as for use earlier in the natural history of metastatic prostate cancer.

Hampering immune suppressors: therapeutic targeting of myeloid-derived suppressor cells in cancer.

Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with suppressive properties that preferentially expand in cancer. Myeloid-derived suppressor cells mainly suppress T-cell proliferation and cytotoxicity, inhibit natural killer cell activation, and induce the differentiation and expansion of regulatory T cells. The wide spectrum of MDSC suppressive activity in cancer and its role in tumor progression have rendered these cells a promising target for effective cancer immunotherapy. In this review we briefly discuss the origin of MDSCs and their main mechanisms of suppression and focus more on the approaches developed up to date targeting of MDSCs in tumor-bearing animals and cancer patients.

Cancer immunosurveillance and immunoediting by natural killer cells.

Abstract: Cancer immunosurveillance eradicates certain neoplasms, but the selective pressure exerted by this active surveillance leads to the emergence of immune evasive tumor clones in a process called cancer immunoediting. Natural killer (NK) cells are potent effectors of cancer immunoediting and can destroy tumors directly via exocytosis of cytotoxic granules or indirectly by producing interferon γ to activate M1 and TH1 immune responses. This review gathers current knowledge of NK immunosurveillance of primary tumors induced in mice and highlights the importance of NK immunosurveillance for human cancers. Evidence of NK immunoediting, as revealed by studies using NK-deficient models, demonstrates how exposure to NK cells engenders modification of cancer immunogenicity to permit survival and progression of the tumor clone in an immunocompetent environment.

Robotic thyroidectomy and neck dissection: past, present, and future.

Abstract: The advantages of endoscopic thyroidectomy and neck dissection include reduced hyperesthesia or paresthesia in the neck and favorable cosmetic outcomes. However, endoscopic thyroidectomy with neck dissection has a long learning curve, as well as technical limitations associated with a 2-dimensional view and a reduced dexterity of movement, particularly when operating in deep and narrow spaces such as the neck area. A robotic approach has been developed to overcome these limitations, facilitating manipulation and shortening the learning curve. This system enables the surgeon to control the 3-dimensional high-definition camera, reducing physiological tremors and enabling free dexterity of movement using articulated instruments. Therefore, robotic surgery has been found to eliminate many problems encountered with conventional endoscopic techniques.Recently, robotic thyroidectomy with neck dissection via a gasless transaxillary approach was shown to yield similar oncologic outcomes as conventional open procedures, as determined by postoperative radioactive iodine scans, serum thyroglobulin concentrations, and number of retrieved cervical lymph nodes. We also found that the robotic technique was safe and feasible in thyroid cancer patients, yielding excellent cosmetic results, reduced pain, improved sensory changes and decreased postoperative voice changes and swallowing discomfort. For surgeons, the use of a robot offers a shorter operation time and the need for a shorter learning curve than conventional endoscopic thyroidectomy. Robotic thyroidectomy also causes less musculoskeletal discomfort to surgeons than open or endoscopic thyroidectomy. The advantages of robotic surgery over open or endoscopic surgery suggest that robotic thyroidectomy with neck dissection may become the preferred surgical option for patients with thyroid cancer. Further analyses of surgeons' experience, assessments of long-term outcomes, and randomized controlled trials remain important.

Integrating palliative care in oncology: the oncologist as a primary palliative care provider.

Abstract: The provision of comprehensive cancer care in an increasingly complex landscape necessitates that oncology providers familiarize themselves with the application of palliative care. Palliative care is a learnable skill. Recent endeavors in this arena have demonstrated that providing palliative care is part and parcel with providing compassionate and high-quality cancer care, specifically as it pertains to physical and emotional outcomes for patients and their caregivers alike. The basic tenets of providing palliative care emphasize: frequent and honest communication, routine and systematic symptom assessment, integration of spiritual assessments, and early integration of specialized hospice and palliative care resources as a patient's circumstances evolve. This article will endeavor to review and synthesize recent developments in the palliative care literature, specifically as they pertain to the oncologist as a primary palliative care provider.

Symptoms and symptom management in long-term cancer survivors.

Abstract: It is estimated that there are 13 million cancer survivors in the United States, and more than 65% of them are 5 or more years beyond their diagnosis. The majority are "cancer-free and free of cancer," although some survivors have late or long-term effects of treatment or develop second or secondary cancers. Late and long-term effects for survivors of childhood cancers have been well studied, but less is known about the "seasons of survivorship" for adult cancer survivors. Symptoms during diagnosis, treatment, and then extending through the first several years of survivorship were reported in more than half of a large and heterogeneous group of cancer survivors. The incidence of late and/or long-term symptoms and health problems of long-term cancer survivors is less well characterized. These persistent symptoms are related to survivors' cancer diagnosis and the treatment they received, as well as age and other comorbidities. Health-related quality of life generally is stable for many years, although some cancer survivors experience a significant drop in health-related quality of life years after treatment, although the etiology is not clear yet. This article provides an overview of the natural history of cancer survivorship ("The seasons of survivorship"), disease-specific toxicities, and changes in symptoms in cancer survivors over time. Several common symptoms are used as examples including pain, fatigue, and cognitive dysfunction.

Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics.

Abstract: To move forward with immunotherapy, it is important to understand how the tumor microenvironment generates systemic immunosuppression in patients with renal cell carcinoma (RCC) as well as in patients with other types of solid tumors. Even though antigen discovery in RCC has lagged behind melanoma, recent clinical trials have finally authenticated that RCC is susceptible to vaccine-based therapy. Furthermore, judicious coadministration of cytokines and chemotherapy can potentiate therapeutic responses to vaccine in RCC and prolong survival, as has already proved possible for melanoma. Although high-dose interleukin 2 immunotherapy has been superseded as first-line therapy for RCC by promiscuous receptor tyrosine kinase inhibitors (rTKIs) such as sunitinib, sunitinib itself is a potent immunoadjunct in animal tumor models. A reasonable therapeutic goal is to unite antiangiogenic strategies with immunotherapy as first-line therapy for RCC. This strategy is equally appropriate for testing in all solid tumors in which the microenvironment generates immunosuppression. A common element of RCC and pancreatic, colon, breast, and other solid tumors is large numbers of circulating myeloid-derived suppressor cells (MDSCs), and because MDSCs elicit regulatory T cells rather than vice versa, gaining control over MDSCs is an important initial step in any immunotherapy. Although rTKIs like sunitinib have a remarkable capacity to deplete MDSCs and restore normal T-cell function in peripheral body compartments such as the bloodstream and the spleen, such rTKIs are effective only against MDSCs, which are engaged in phospho-STAT3-dependent programming (pSTAT3+). Unfortunately, rTKI-resistant pSTAT3- MDSCs are especially apt to arise within the tumor microenvironment itself, necessitating strategies that do not rely exclusively on STAT3 disruption. The most utilitarian strategy to gain control of both pSTAT3+ and pSTAT3- MDSCs may be to exploit the natural differentiation pathway, which permits MDSCs to mature into tumoricidal macrophages (TM1) via such stimuli as Toll-like receptor agonists, interferon γ, and CD40 ligation. Overall, this review highlights the mechanisms of immune suppression used by the different regulatory cell types operative in RCC as well as other tumors. It also describes the different therapeutic strategies to overcome the suppressive nature of the tumor microenvironment.

Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma.

Abstract: The product of a proto-oncogene, the c-Met protein is a transmembrane receptor tyrosine kinase Its only known ligand, hepatocyte growth factor/scatter factor, regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis Dysregulation of c-Met and hepatocyte growth factor have been observed in both clear cell and non-clear cell renal cell carcinomas (RCCs), although only papillary RCCs harbor activating mutations in the MET gene In clear cell RCC, there is evidence of a direct link between loss of von Hippel-Lindau and up-regulation of c-Met As in other cancers, high expression of c-Met correlates with worse outcomes in RCC In vitro and in vivo preclinical RCC models demonstrate cancer control with small molecule and antibodies against c-Met Given these findings, the c-Met pathway is a logical therapeutic target in RCC, and several agents are in clinical testing with early signs of efficacy

Targeting the apoptosis pathway in prostate cancer.

Abstract: Important inroads have been made in the understanding and treatment of metastatic prostate cancer in recent years. However, the need for agents targeting novel pathways remains ever present. One such area with promise is through apoptosis or programmed cell death. Many perturbations within the apoptotic process have been associated with treatment resistance and progression in castration-resistant prostate cancer; thus, therapeutic potential exists with agents that can restore an effective apoptotic response to cellular stressors. This article focuses on agents in clinical development targeting apoptosis through the intrinsic and extrinsic pathways. We review the current status of agents that intervene at the Bcl2 checkpoints, humanized antibodies to death receptors, agents that target the inhibitors of apoptosis proteins, mimetics of small mitochondria-derived activator of caspases, and antisense therapies targeting cytoprotective chaperones. Although single-agent activity has been demonstrated with some of these agents, the clinical development path forward will see them coupled with standard hormonal therapy and chemotherapy. OGX-011 (custirsen), which inhibits expression of the cytoprotective chaperone protein clusterin, is the most mature of these agents and is being tested in combination with chemotherapy in phase III clinical trials for castration-resistant prostate cancer, and results are eagerly awaited.

Dendritic cells, inflammation, and breast cancer.

Abstract: Solid tumors are well known for their genomic heterogeneity. Although some aspects of this derive from so-called driver mutations, it is now clear that tumor cells possess a seemingly limitless capacity to evade cell death pathway activation, maintain essential survival programming, and initiate resistance networks that block efficacy of cytotoxic and targeted therapy. Given this amazing survival capability, how then to design approaches for effective eradication of malignant cells? Also present within all solid tumors is a diverse assemblage of genomically stable immune cell types. Whereas some of these possess documented activities that foster tumor progression, others possess inherent activities that when favored lead to rapid tumor cell elimination. This review focuses on aspects of dendritic cell biology in solid tumors, especially breast cancers, which point to dendritic cells as a tractable tool to exploit for immune-based therapies.

Tubulin-targeted agents including docetaxel and cabazitaxel.

Abstract: Microtubules are dynamic filamentous cytoskeletal proteins that are responsible for cellular integrity and architecture, mitosis, intracellular transport, cell signaling, and gene expression. Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. Cabazitaxel, an antitubulin agent, which demonstrates activity in multidrug- and docetaxel-resistant cancer cell lines, demonstrates a survival benefit over mitoxantrone and prednisone in patients who have failed docetaxel-based chemotherapy. This article reviews the use of antitubulin agents in patients with castration-resistant prostate cancer.

The changing natural history of metastatic prostate cancer.

Abstract: Since 1941, the understanding of prostate cancer pathogenesis and therapy has undergone a significant transformation. Rigorous translational research has identified multiple mechanisms underlying castration resistance, the fatal clinical state of the disease. Therapeutic approaches targeting these mechanisms in metastatic castration-resistant prostate cancer have now been clinically validated in the clinic including high-potency androgen signaling inhibition, novel cytotoxic chemotherapy, and bone-targeted therapies. Despite these advances, cure remains an elusive goal. The natural history of metastatic prostate cancer has evolved particularly in the last 2 decades in step with improved management of age-associated comorbidities, improved imaging, and the expansion of novel therapies, thus providing new opportunities and challenges. It is also important to note that the advent of prostate-specific antigen testing caused a stage shift in the disease spectrum, thus leading to earlier interventions and potentially positively impacting survival. The optimal sequencing and combinations of available therapies, predictive biomarkers, and better understanding of mechanisms of resistance remain high priority. Further refinement of the clinical niche for novel therapies in hormone-sensitive and castration-resistant disease through rationally designed clinical trials incorporating molecular, clinical, and imaging biomarkers and quality-of-life correlatives is of paramount importance.

Robotic surgical simulation.

Abstract: Robotic surgery has undergone exponential growth and has ever developing utilization. The explosion of new technologies and regulation have led to challenges in training surgeons who desire this skill set. We review the current state of robotic simulation and incorporation of simulation into surgical training curricula. In addition to the literature review, results of a questionnaire survey study of 21 expert and novice surgeons attending a Urologic Robotic Oncology conference using 3 different robotic skill simulation devices are discussed. An increasing number of robotic surgery simulators have had some degree of validation study of their use in surgical education curricula and proficiency testing. Although simulators are advantageous, confirmation of construct and predictive validity of robotic simulators and their reliability as a training tool will be necessary before they are integrated into the surgical credentialing process.

Personal growth during the experience of advanced cancer: a systematic review.

Abstract: Over the past decade, research has documented the positive consequences individuals attribute to the experience of traumatic, life-threatening events, including enhanced life appreciation, improved social relationships, and a deepened sense of self and meaning. Despite evidence that individuals with cancer frequently perceive growth as a result of their experience, personal growth in the context of advanced cancer has received markedly less attention. In light of the unique challenges accompanying the experience of advanced cancer, the phenomenon of perceiving positive consequences and making meaning of the cancer experience (i.e., personal growth) may be distinct in patients with life-limiting disease as compared with more commonly studied early-stage cancer survivor samples. The purpose of this article was to review studies examining personal growth in adults diagnosed with advanced cancer to encourage medical professionals to consider and respond to their concerns around meaning within palliative care. We conducted a systematic review of the PubMed and PsycINFO electronic databases for studies examining personal growth in patients with advanced cancer published between January 1960 and January 2013. Of the 197 studies reviewed, 12 quantitative studies and 10 qualitative studies met criteria for inclusion. The review revealed that many patients with advanced cancer both cite finding meaning at the end of life as important and perceive positive consequences as a result of their experience. In comparison to early-stage cancer or benign disease, advanced cancer may serve to prompt higher levels of personal growth. However, these findings are mixed and may indicate a complex, nonlinear relationship between cancer prognosis and personal growth. The most promising candidates for promoting personal growth during advanced disease include younger adult age, spirituality, and psychosocial resources (optimism, marriage, and social support from close others and health care providers). Importantly, a co-occurrence of personal growth with both distress and well-being in advanced cancer suggests that personal growth in this unique context is characterized by perceived positive consequences in the face of considerable demands, which may be reflected by greater negative and positive markers of adjustment. Understanding and awareness of personal growth in individuals with advanced cancer may facilitate health care providers' ability to consider and respond to concerns around meaning and personal growth within palliative care, given the growing literature on psychosocial interventions for patients with advanced cancer. Integration of the existing research base with intervention development is an opportunity for future research.

Complex Roles of Inflammasomes in Carcinogenesis

Abstract: The central role of chronic inflammation in the promotion of tumor growth is supported by a broad range of experimental and clinical evidence. However, the molecular mechanisms converting transient inflammatory tissue reactions into a tumor-promoting microenvironment remain largely elusive. Because inflammasomes have been shown to regulate the proinflammatory cytokines interleukin 1β (IL-1β) and IL-18, they have been implicated in the relationship between tumor genesis/progression and inflammation. For instance, many cancers have been directly linked to inflammasome-mediated sterile inflammation, where a blockade of IL-1β and IL-18 has been shown to inhibit tumor growth. On the other hand, inflammasome activation also has potent antitumorigenic effects, where malignant precursor cells are eliminated through pyroptotic cell death. Indeed, inflammasome activity can even increase the efficacy of certain chemotherapies. Here, we review the current understanding on the complex and sometimes contradictory role of inflammasomes in carcinogenesis.

Robotic surgery: gynecologic oncology.

Abstract: In the field of gynecologic oncology, robotic-assisted surgery has emerged as an invaluable minimally invasive approach to comprehensive surgical staging and the treatment of cervical and endometrial cancer. This review focuses on operative indications for robotic surgery in several gynecologic disease sites and summarizes the available literature on perioperative outcomes for robotics compared with conventional methods and evolving common practice patterns among gynecologic oncologists. Areas of controversy surrounding this technology and justification of widespread use are also discussed, including the paucity of randomized controlled trials, long-term efficacy data, and cost-effectiveness research.

USP-11 as a predictive and prognostic factor following neoadjuvant therapy in women with breast cancer.

Abstract: PURPOSE USP-11, a member of the ubiquitin-specific protease family, has emerged as an essential regulator of double-strand break repair. Few studies have shown that silencing USP-11 led to hypersensitivity to poly(ADP-ribose) polymerase inhibition, ionizing radiation, and DNA-damaging agents. We sought to examine the predictive and prognostic relevance of USP-11 in patients treated with neoadjuvant systemic therapy (NST) for breast cancer. METHODS Fifty-six women who were treated with NST for breast cancer between 1999 and 2004 were included in the study. The Kaplan-Meier product-limit method was used to estimate disease-free survival and overall survival rates. Logistic regression models were fit to determine the associations between USP-11 status, pathological complete response (pCR), and survival. RESULTS Sixteen patients (29%) had high-USP-11-expressing tumors, and 40 (71%) patients had low-USP-11-expressing tumors. No significant differences were observed in pCR rates with respect to USP-11 status. At a median follow-up of 7.4 years, 33 patients (59%) experienced a disease recurrence or death. Patients with high-USP-11-expressing tumors had a higher risk of recurrence (odds ratio [OR], 3.87; 95% confidence interval [CI], 1.51-9.93; P = 0.005) and death (OR, 6.03; 95% CI, 2.00-18.17; P = 0.001) than those with low-USP-11-expressing tumors. Patients who did not achieve a pCR had an increased risk of recurrence (OR, 5.16; 95% CI, 1.16-23.07; P = 0.03). CONCLUSIONS Our data indicate that USP-11 is not a predictor of a pCR after anthracycline-taxane-containing NST for breast cancer. Low USP-11 expression was independently correlated with better survival outcomes.

Spirituality in cancer care at the end of life.

Abstract: There is a compelling need to integrate spirituality into the provision of quality palliative care by oncology professionals. Patients and families report the importance of spiritual, existential, and religious concerns throughout the cancer trajectory. Leading palliative care organizations have developed guidelines that define spiritual care and offer recommendations to guide the delivery of spiritual services. There is growing recognition that all team members require the skills to provide generalist spiritual support. Attention to person-centered, family-focused oncology care requires the development of a health care environment that is prepared to support the religious, spiritual, and cultural practices preferred by patients and their families. These existential concerns become especially critical at end of life and following the death for family survivors. Oncology professionals require education to prepare them to appropriately screen, assess, refer, and/or intervene for spiritual distress.

Targeting MET and vascular endothelial growth factor receptor signaling in castration-resistant prostate cancer.

Abstract: Effective management of bone metastases in men with castration-resistant prostate cancer (CRPC) remains an important unmet medical need. MET and vascular endothelial growth factor receptor (VEGFR) are rational targets for intervention in CRPC. Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival. Cabozantinib is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and VEGFR-2. A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans, bone turnover markers, and pain response, but with significant adverse events leading to dose reduction and treatment discontinuation. Lower doses of cabozantinib retain high levels of activity with less toxicity. Ongoing phase III clinical trials will define the role of cabozantinib in CRPC. We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date.

Management of normal tissue toxicity associated with chemoradiation (primary skin, esophagus, and lung).

Abstract: Nearly one quarter of patients with lung cancer present with locally advanced disease where concurrent chemoradiotherapy is the current standard of care for patients with good performance status. Cisplatin-based concurrent chemoradiotherapy consistently showed an improvement in survival compared with sequential chemoradiotherapy, at the expense of an increase in the toxicity profile. Over the past decades, several encouraging biomarkers such as transforming growth factor-beta and radioprotective agents such as amifostine were studied but without reaching approval for patient care. We reviewed the prevalence and risk factors for different adverse effects associated with the combined chemoradiotherapy modality, especially dermatitis, mucositis, esophagitis, and pneumonitis. These adverse effects can further be divided into acute, subacute, and chronic. Dermatitis is usually rare and responds well to topical steroids and usual skin care. Acute esophagitis occurs in 30% of patients and is treated with proton pump inhibitors, promotility agents, local anesthetic, and dietary changes. Radiation pneumonitis is a subacute complication seen in 15% of patients and is usually managed with steroids. Chronic adverse effects such as radiation fibrosis and esophageal stricture occur approximately 6 months after completion of radiation therapy and are usually permanent. In this review, complications of chemoradiotherapy for patients with locally advanced lung cancer are delineated, and approaches to their management are described. Given that treatment interruption is associated with a worse outcome, patients are aggressively treated with a curative intent. Therefore, planning for treatment adverse effects improves patient tolerance, compliance, and outcome.

Bone targeted therapies in metastatic castration-resistant prostate cancer.

Abstract: Prostate cancer is the most common male cancer. About 90% of metastatic patients will develop bone metastases. Bone disease is responsible of pain, deterioration of quality of life and serious bone complications. Proliferation of prostate cancer cells in the bone marrow induces osteoclast activation and osteolysis. Targeting the bone microenvironment reduces morbidity. Relevant preclinical and clinical studies of bone-targeted therapies in castration-resistant prostate cancer were identified in PubMed and clinical trial databases. Different drugs are available or in development that target bone resorption (bisphosphonates, RANK ligand inhibitors), bone formation (endothelin 1 inhibitors), cancer cell migration (SRC-family kinase inhibitors, vascular endothelial growth factor-MET inhibitors), and survival (radiopharmaceuticals). In phase III trials, zoledronic acid, denosumab, and radium-223 were shown to significantly delay skeletal-related events. Radium-223 was also shown to improve overall survival. Biomarkers of bone resorption (urinary N-telopeptide) and bone making (alkaline phosphatase) have an independent prognostic impact. Targeting the bone microenvironment is an important component of castration-resistant prostate cancer management to reduce bone complications and improve overall survival. Biomarkers of bone turnover have an independent prognostic impact.

Role of radiotherapy in adrenocortical carcinoma.

Abstract: Purpose Adrenocortical carcinoma (ACC) is a rare and highly malignant tumor usually diagnosed in an advanced stage. Radiation therapy has been a poorly studied and underutilized therapeutic option. Methods This retrospective analysis reviewed treatment courses for 14 patients with pathologically confirmed ACC treated between 1997 and 2012. Two patients were treated adjuvantly following surgery, and 12 were treated with palliative intent. Patients presented with stage II (n = 4), stage III (n = 7), and stage IV (n = 3) disease. Patients had a mean age of 51.5 years. Ten patients received chemotherapy before radiotherapy (RT), and 12 patients received surgery before RT, before receiving radiation at a mean of 17.8 months after diagnosis. Results In total, 20 sites were treated, 2 of which were in an adjuvant setting, and 18 of which were for palliative indications in 12 patients as follows: (1) pain/neuropathy (n = 10), (2) prophylactic treatment of asymptomatic recurrences (n = 3), and (3) prevention of imminent metastatic complications (n = 2), hemoptysis (n = 1), severe mass effect (n = 1), and brain metastasis (n = 1). Sites were treated to a median dose of 36.3 Gy (range, 17.5-60 Gy) in a median of 2.5 Gy/fraction (range, 1.8-4 Gy). At a mean follow-up of 22.0 months for the 2 patients given adjuvant RT, 1 patient did not have a local recurrence during a 14.3-month period of follow-up, and the other had a local recurrence 14.5 months after RT. At a mean follow-up of 11.3 months for the 12 patients receiving palliative RT, 10 patients had either a clinical or radiographic response. Of the courses of palliative RT that had adequate radiographic follow-up, 4 treatments (27%) resulted in a partial response. Eleven treatments (73%) that were able to be evaluated resulted in clinical improvement. Acute Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicities observed in 7 patients included 3 grade 1, 4 grade 2, and 1 grade 3. No patient had acute toxicity of grade 4 or greater or any Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late toxicity of grade 1 or greater. Discussion This report is one of the largest to date examining the role of modern radiation techniques in the management of ACC. We conclude that radiation can be effective in the management of metastatic ACC, palliating local symptoms, and preventing complications from large metastases. Radiation should be considered as an option in multimodality management of ACC patients.

Robotic surgery: review of prostate and bladder cancer.

Abstract: Minimally invasive laparoscopic surgery has become to replace many of the open procedures in urology because of the obvious benefits in perioperative morbidity. However, because of the technical challenges and steep learning curve, the adoption of laparoscopy has been limited to only highly skilled laparoscopic surgeons. The introduction of the da Vinci surgical system (Intuitive Surgical Inc, Sunnyvale, Calif) has offered significant technical advantages over laparoscopic surgery. Because of the wide acceptance of robotic-assisted radical prostatectomy over the past decade, it has paved the way for urologists to tackle other complex operations, such as a radical cystectomy to decrease the morbidity of the operation. The goal of this article was to review the history and discuss the application and current status of the robot in both prostate and bladder cancer management. We present our technique of performing a robotic-assisted radical prostatectomy and the application of the robust prostate experience to robotic cystectomy.