Abstract: The TGF-beta superfamily is the most versatile considering the ability of its members to regulate proliferation, growth arrest, differentiation, and apoptosis of prostatic stromal and epithelial cells as well as the formation of osteoblastic metastases. TGF-beta mediated action in prostate cells follows a complex signaling pathway from binding and phosphorylation of receptor type II to the TbetaRI kinase to Smad activation, resulting in ligand-induced transcription. TGF-beta as an indirect tumor suppressor, its role of regulating tumor induction, as well as tumor suppression depending on the tissue microenvironment merits further exploration. The rationale for targeting growth factors and their receptors for therapeutic intervention is based upon the fact that these proteins represent the most proximate component of the signal transduction cascade. The alternate targeting of intracellular effectors in the signal transduction may be thwarted by cross talk between signaling pathways (such as the Smads in a dynamic interplay with the androgen receptor). TGF-beta within the context of its well-documented apoptosis regulatory actions in the prostate and the significance its key receptor TbetaRII as a potential tumor suppressor, provides a highly attractive candidate for such targeting with high clinical significance for the treatment and diagnosis of prostate cancer.

Abstract: The arachnoid membrane and pia mater are the two membranous layers that comprise the leptomeninges. Cerebrospinal fluid is made within the ventricular system by cells of the choroid plexus and ependyma. This chapter describes in detail the normal anatomic structure and physiologic interactions of the cerebrospinal fluid and leptomeningeal space that are critical to our understanding and treatment of leptomeningeal metastases.

Abstract: Knowledge of the molecular events that govern human thyroid tumorigenesis has grown considerably in the past ten years. Key genetic alterations and new oncogenic pathways have been identified. Molecular genetic aberrations in thyroid carcinomas bear noteworthy resemblance to those in acute myelogenous leukemias. Thyroid carcinomas and myeloid leukemias both possess transcription factor gene rearrangements-PPARgamma-related translocations in thyroid carcinoma and RARalpha-related and CBF-related translocations (amongst others) in myeloid leukemia. PPARgamma and RARalpha are closely related members ofthe same nuclear receptor subfamily, and the PML-RARalpha and PAX8-PPARgamma fusion proteins both function as dominant negative inhibitors of their wild-type parent proteins. Thyroid carcinomas and myeloid leukemias also both harbor NRAS mutations (15-25% of both cancers) and receptor tyrosine kinase mutations--RET mutations in thyroid carcinomas and FLT3 mutations in myeloid leukemias. The NRAS and tyrosine receptor kinase mutations are not observed in the same thyroid carcinoma or leukemia patients, suggesting that multiple initiating pathways exist in both. Lastly, thyroid carcinomas and myeloid leukemias possess p53 mutations at relatively low frequency (10-15%) in patients who tend to be older and have more aggressive, therapy resistant disease. Such parallels are unlikely to occur by chance alone and argue that common mechanisms underlie these diverse epithelial and hematologic cancers. The comparison of thyroid carcinomas and myeloid leukemias may highlight areas of thyroid cancer investigation worthy of further focus. For example, few collaborating mutations have been defined in thyroid carcinomas even though they play a clear role in myeloid leukemias, as exemplified by RARalpha rearrangements and FLT3 mutations that together dictate the promyleocytic leukemia phenotype. Functional interactions between collaborating mutations are possible at multiple levels, and it is tempting to speculate that some thyroid carcinomas might develop through an unique combination or co-activation of RET and RAS and/or RET and PPARgamma (and/or other) signaling systems. In fact, the ELE1-RET (PTC3) fusion protein contains the ELE1 nuclear receptor co-activator domain and it appears to physically associate with and inhibit wild-type PPARgamma in some papillary carcinomas. The similarities of the fusion proteins in thyroid carcinoma and myeloid leukemia suggest that a more directed search for fusion genes in non-thyroid carcinomas is warranted. In fact, novel fusion genes have been identified recently in aggressive midline, secretory breast, and renal cell carcinomas, although the epithelial nature of the latter is not well-documented. Interestingly, these cancers all tend to present more frequently in adolescence and young adulthood in a manner similar to thyroid and myeloid malignancies that have fusion genes. The analyses of cancers that present earlier in life may enhance fusion gene recognition in other carcinoma types. Definition and biologic characterization of the precursor cells that give rise to thyroid carcinoma will also be important. Myeloid leukemias are thought to arise from stem/progenitor cells that acquire disturbed self-renewal and differentiation capacities but retain characteristics of the myeloid lineages. Although the presence of comparable stem/progenitor cells in the thyroid are not defined, distinct thyroid cancer lineages and patterns of differentiation exist and candidate stem/progenitor cells such as the p63-immunoreactive solid cell nests are apparent. A last important area is development of molecular-based therapies for thyroid carcinoma patients resistant to standard radio-iodine treatment. Treatments for such cancers are limited and pathways defined by thyroid cancer mutations are prime targets for pharmacologic interventions with molecular inhibitors. Tyrosine kinase inhibitors and nuclear receptor ligands have proven dramatically effective in some myeloid leukemia patients. Various molecular inhibitors are being investigated now in thyroid cancer models. Such developments predict that the thyroid cancer model will continue to provide biologic insights into human carcinoma biology and that improved pathologic diagnosis and treatment for thyroid cancer patients sit on the not too distant horizon.

Abstract: An essential prerequisite for a successful sentinel node biopsy (SNB) procedure is an accurate map of the pattern of lymphatic drainage from the primary tumor site. The role of lymphoscintigraphy(LS) in SNB is to provide such a map in each patient. This map should indicate not only the location of all sentinel nodes but also the number of SNs at each location. Such mapping can be achieved using 99mTc-labeled small particle radiocolloids, high-resolution collimators with minimal septal penetration, and imaging protocols that detect all SNs in every patient regardless of their location. This is especially important in melanoma patients, since high-quality LS can identify the actual lymphatic collecting vessels as they drain into each SN. The SN is not always found in the nearest node field and is best defined as “any lymph node receiving direct lymphatic drainage from a primary tumor site.”

Abstract: The great majority of cancer patients can initially be rendered free of detectable disease by surgery and/or chemotherapy. Adjuvant chemotherapy or radiation therapy are generally only minimally beneficial, so there is real need for additional methods of eliminating residual circulating cancer cells and micrometastases. This is the ideal setting for treatment with a cancer vaccine. The immune response induced is critically dependent on the antigenic epitope and vaccine design. For antibody induction there is one best vaccine design, conjugation of the antigen to an immunogenic protein such as KLH and the use of a potent adjuvant such as the saponins QS-21 and GPI-0100. This approach alone induced strong antibody responses against the glycolipids GM2, fucosyl GM1 and globo H and the mucin backbone MUC1, and cancer cells expressing these antigens. Other antigens required additional modifications to augment relevant immunogenicity. GD2 and GD3 lactones and N-propionylated polysialic acid were significantly more effective at inducing antibodies against tumor cells than the unmodified antigens. Tn, sTn and TF trimers (clusters) were significantly more effective than the monomers at inducing antibodies reactive with the cancer cell surface. The optimal approach for Le(Y), KSA, PSMA, and CA125 (MUC16) remains to be determined. Antibodies are ideally suited for eradicating pathogens from the bloodstream and from early tissue invasion. Passively administered and vaccine induced antibodies have accomplished this, eliminating circulating tumor cells and systemic or intraperitoneal micrometastases in a variety of preclinical models, so antibody-inducing vaccines offer real promise in the adjuvant setting. Polyvalent vaccines will probably be required due to tumor cell heterogeneity, heterogeneity of the human immune response and the correlation between overall antibody titer against tumor cells and antibody effector mechanisms. Over the next several years, Phase II clinical trials designed to determine the clinical impact of polyvalent conjugate vaccines will be initiated in the adjuvant setting in patients with SCLC and several epithelial cancers.

Abstract: Leptomeningeal metastases (LM) are increasingly recognized as a devastating complication of solid tumors. Improved treatment of primary malignancy and advances in diagnostic imaging have led to an apparent increase in the number of patients diagnosed with LM. Unfortunately, therapeutic options remain limited. Radiotherapy is used to treat bulky tumor and provide symptomatic relief. Intrathecal chemotherapy benefits a selected subset of patients. The challenge to the future is to delineate the molecular mechanisms underlying LM and to develop novel therapeutic or prophylactic modalities to combat LM.

Abstract: Sentinel lymph node (SLN) mapping has been widely applied in the staging of solid neoplasms including colon and rectal cancer Since the first reported feasibility study in 1997, there have been numerous publications validating SLN mapping as a highly accurate and powerful upstaging technique for colon and rectal cancer In addition to refining the technical aspects of this procedure, these studies have investigated the use of other tracers and operative techniques, while determining the indications, limitations, and pitfalls of SLN mapping in patients with colorectal cancers This chapter reviews the rationale for performing SLN mapping for the accurate staging of colon and rectal cancers, and provides a brief review of the historical background of the development of the procedure Landmark publications, which have contributed to the current status of the technique, are discussed We will focus on the technical details of the procedure, and on the pathological evaluation of the specimen and the SLNs The various tracers and techniques of SLN mapping in colon and rectal cancer will be discussed We have performed SLN mapping in more than 240 consecutive patients over the past 7 years The success rates for identifying at least one SLN for colon and rectal cancer were 100% and 906%, respectively The accuracy rates were 958% and 100%, respectively In terms of upstaging, 323% of colon cancer patients with nodal metastases and 167% of rectal patients with nodal metastases were upstaged by the detection of micrometastases found in the SLNs only Finally, we will also discuss the current role as well as the future research directions for SLN mapping in colon and rectal cancer

Abstract: There is now clear evidence that the prevalence of co-morbidity among older cancer patients is high and that older patients (with comorbidity) are often treated less aggressively, which seems to have a negative influence on survival However, would outcomes really improve if more patients were treated, according to the guidelines that were developed on the basis of results in groups of younger patients without co-morbidity? Would more complications occur in older patients with co-morbidity? If that is the case, is it possible to develop special treatment regimens for older cancer patients with co-morbidity and adapt the guidelines? It remains relevant to study the influence of age and co-morbidity on toxicity from treatment, quality of life and prognosis in unselected groups of patients

Abstract: Leptomeningeal dissemination of primary CNS tumors varies widely by histologic subtype. In certain tumors including medulloblastoma, ependymoma, germ cell tumors, and primary CNS lymphoma, seeding of the cerebrospinal fluid space is a critical factor in determining stage, prognosis and appropriate therapy. Other tumor types, such as glioma, may have radiographic evidence of leptomeningeal metastases without clear impact on prognosis or therapy.

Abstract: The NTRK1 gene encodes the high affinity receptor for Nerve Growth Factor, and its action regulates neural development and differentiation. Deregulation of NTRK1 activity is associated with several human disorders. Loss of function mutations cause the genetic disease Congenital Insensitivity to Pain with Anhidrosis (CIPA). Constitutive activation of NTRK1 has been detected in several tumor types. An autocrine loop involving NTRK1 and NGF is responsible for tumor progression in prostate carcinoma and in breast cancer. Somatic rearrangements of NTRK1, producing chimeric oncogenes with constitutive tyrosine kinase activity, have been detected in a consistent fraction of papillary thyroid tumors. The topic of this review is the thyroid TRK oncogenes; the modalities of activation, the mechanism of action, and the contribution of activating sequences will be discussed.

Abstract: The sentinel node (SN) concept was clearly outlined by Virchow in the mid-nineteenth century, and Braithwaite used the term “glands sentinel” in 1923. However, it was not until Morton, Cochran et al. published their landmark report in 1992 that the clinical relevance of the SN was fully appreciated. Since then, the validity of the concept has been confirmed in studies undertaken at a number of centers worldwide. It has become clear that SN status accurately reflects the status of the entire regional node field, not only in patients with melanoma but also in those with breast cancer and a wide range of other primary malignancies. New insights into lymphatic anatomy have been gained by preoperative lymphoscintigraphy, and the original blue dye mapping technique for SN identification has been supplemented by intraoperative use of a hand-held gamma probe to identify radioactivity in colloid particles injected at the primary tumor site. It has become clear that all three methods are required to achieve optimal accuracy of SN identification.

Abstract: To date, selective sentinel lymphadenectomy (SSL) should be considered a standard approach for staging patients with primary invasive melanoma greater than or equal to 1 mm. It is imperative that the multidisciplinary team master the techniques of preoperative lymphoscintigraphy, intraoperative lymphatic mapping, and postoperative pathologic evaluation of the sentinel lymph nodes (SLNs). An SLN is defined as a blue, “hot” and any subsequent lymph node greater than 10% of the ex vivo count of the hottest lymph node. Any enlarged or indurated lymph node in the nodal basin should be excised. Frozen sections are not recommended. For extremity melanoma, delayed SSL may be performed. Preoperative lymphoscintigraphy for extremity melanoma may be done the night before so that the surgery can be scheduled as the first case of the following day. Every surgeon who uses blue dye should be aware of the potential adverse reaction to isosulfan blue and treatment for such a potential fatal reaction. A complete lymph node dissection is done if the SLN is found to be positive. Elective lymph node dissection (ELND) should not be done if an SSL can be performed as a staging procedure. SSL has further been applied to stage the nodal basin for Merkel cell carcinoma and high-risk squamous cell carcinoma. It is important for investigators involved with the SSL to follow the clinical outcome of these patients, so that the role of SSL can be further defined.

Abstract: Nucleic acid immunization has garnered much attention as a promising approach for cancer therapeutic development. This innovative vaccine strategy uses non live, non replicating, non spreading DNA formulations which utilize the host’s cellular machinery for expression of proteins (antigens). Such novel delivered and expressed antigens become recognized by the host immune response and induce specific T and B cell responses against the gene encoded proteins. The foundational basis for DNA vaccines originated from the observation that delivery of gene sequences in vivo could lead to their expression [reviewed in (1)]. In the 1950s and 1960s experiments aimed at understanding the fundamental nature of the basis for cancer delivered as either nucleic acid or proteins to animals and followed tumor development. Tumor development segregated with nucleic acids and tumor bearing animals could seroconvert to tumor antigens, establishing the ability of nucleic acid transfer to drive protein expression and activate the immune response. In the 1980s the understanding that the immune response was a nemesis for gene therapy antigen delivery started to impact vector studies. Wolff et al. reported that activity of reporter genes could be detected for up to two months without a delivery system (2). Many investigators were focusing on if such proteins implemented for such gene therapy experiments could be employed to express antigens to stimulate the immune system. A study

Abstract: Over the last decade, several lines of evidence have been accumulated that support the existence of fPTC susceptibility genes. Preliminary clinical characteristics of fPTC have been identified, and linkage studies have identified the chromosomal locations of putative fPTC susceptibility genes. A logical clinical approach to fPTC is emerging.

Abstract: Treatment of leptomeningeal metastases is multifaceted and includes symptomatic therapy, intrathecal and systemic chemotherapy, and radiotherapy. As the majority of patients have widespread incurable systemic tumor, treatment is predominantly palliative; however, some patients with leukemia, lymphoma or breast cancer may have prolonged remissions and the possibility of cure.

Abstract: The review allows the following conclusions: 1. Some form of geriatric assessment appear beneficial for older cancer patients; this assessment may allow to estimate life-expectancy and tolerance of treatment, to reveal reversible conditions that may influence the treatment, and to provide a common language to classify older individuals in clinical practice and clinical trials. The geriatric assessment is also the background of any decision analysis related to the study and the management of older patients, capable to accommodate new insights in the biology of cancer and aging and to address problems related to the management of specific diseases. 2. Some age related changes may affect the pharmacology of antineoplastic agents in the majority of older individuals and justify some general guidelines for the administration of chemotherapy that include: Adjustment of the doses of the first chemotherapy to the glomerular filtration rate in individuals aged 65 and older. If no toxicity is observed, the following doses should be increased to prevent under-treatment Prophylactic use of filgrastim or pegfilgrastim in patients aged 65 and older receiving chemotherapy of moderate dose intensity, comparable to CHOP Maintenance of the hemoglobin of patients receiving chemotherapy at 12 gm/dl or higher Aggressive management of mucositis with timely fluid resuscitation Prevention of mucositis by substituting capecitabine for intravenous fluorinated pyrimidine

Abstract: The incidence of cancer increases with age in humans and in laboratory animals alike, but patterns of age-related distribution of tumors is different for different tissues and different tumors. Aging may increase or decrease the susceptibility of individual tissues to early carcinogens and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer by two mechanisms: tissue accumulation of cells in late stages of carcinogenesis and alterations in internal homeostasis, in particular, alterations in immune and endocrine system. Increased susceptibility to the effect of late-stage carcinogens is found both in aged animals and elderly humans, as predicted by the multistage model of carcinogenesis. Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include DAF-2 and InR and their homologues in mammals, and inactivation of the corresponding genes followed by the increase in life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effects of caloric restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway mimetic effects of life span extending mutations or calorie restriction could be a perspective direction in regulation of longevity. Some old and new observations suggest that antidiabetic biguanides could be promising candidates for both the life span extension and the prevention of cancer.

Abstract: Improvements in our understanding of tumor immunology have facilitated significant progress in the development of cancer vaccines. Early clinical trials have generated evidence for the safety of tumor vaccines, and have provided a suggestion of clinically significant bioactivity. They have also highlighted the challenges of cancer vaccine development. These include developing strategies for overcoming immune tolerance, and approaches for identifying the most active tumor rejection antigens for cancer vaccine formulation. Furthermore, these early studies highlight the importance of identifying important pharmacodynamic interactions between standard cancer treatment modalities and tumor vaccines. Surgical debulking is one approach for minimizing the impact of tumor burden, and patients with minimal residual disease are likely to be the most ideal candidates for vaccine therapy. The impact of chemotherapy on vaccine activity is a developing area of clinical research, with regard to both its positive and negative impact on the development of antigenspecific immunity. The impact of ionizing radiation on the immune response to cancer vaccines is an underdeveloped area that also warrants further investigation.

Abstract: Therapeutic cancer vaccines have characteristics that require a new paradigm for phase I and phase II clinical development. Effective development plans may take advantage of some of the following observations: Dose ranging safety trials are not appropriate for many cancer vaccines. Dose ranging trials to establish an optimal biologic dose are often not practical. We have presented an efficient design of Korn et al. (4) to identify an immunogenic dose. Vaccine efficacy can be efficiently evaluated with tumor response as endpoint utilizing a two stage design with only 9 patients in the first stage. If no partial or complete responses are observed in the initial 9 patients, accrual to the trial is terminated. Optimization of vaccine delivery by comparing results of single arm phase II studies using immunological response as endpoint is problematic because of assay variation and potential non-comparability of patients in different studies. Randomized screening studies can be used to efficiently optimize vaccine immunogenicity. Efficiency in use of patients depends on having assay variation and inter-patient variability small relative to the difference in immunogenicity to be detected. Phase II studies using time to progression as endpoint are most interpretable if they employ randomized designs with a no-vaccine control group. Such designs may use an inflated type 1 error rate, and need not be prohibitively large if patients with rapidly progressive disease are studied. Interim monitoring plans may effectively limit the size of the trials by terminating accrual early when results are not consistent with the targeted improvement.

Abstract: Replicative senescence appears to be a form of protection against cancer, but the means by which it may have this action are not yet clear. More research is needed to understand the fate of cells with short telomeres in tissues during aging, to understand the effects on neoplasia of telomere shortening in tissues in vivo, to understand whether telomere shortening results in the accumulation of senescent cells in tissues, and, if so, what effects this may have on tissue function.