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1.  A positive-margin resection model recreates the postsurgical tumor microenvironment and is a reliable model for adjuvant therapy evaluation 
Cancer Biology & Therapy  2012;13(9):745-755.
Up to 30% of cancer patients undergoing curative surgery develop local recurrences due to positive margins. Patients typically receive adjuvant chemotherapy, immunotherapy and/or radiation to prevent such relapses. Interestingly, evidence supporting these therapies is traditionally derived in animal models of primary tumors, thus failing to consider surgically induced tumor microenvironment changes that may influence adjuvant therapy efficacy. To address this consideration, we characterized a murine model of local cancer recurrence. This model was reproducible and generated a postoperative inflammatory tumor microenvironment that resembles those observed following human cancer surgery. To further validate this model, antagonists of two pro-inflammatory mediators, TGFβ and COX-2, were tested and found to be effective in decreasing the growth of recurrent tumors. We appreciated that preoperative TGFβ inhibition led to wound dehiscence, while postoperative initiation of COX-2 inhibition resulted in a loss of efficacy. In summary, although not an exact replica of all human cancer surgeries, our proposed local recurrence approach provides a biologically relevant and reliable model useful for preclinical evaluation of novel adjuvant therapies. The use of this model yields results that may be overlooked using traditional preclinical cancer models that fail to incorporate a surgical component.
doi:10.4161/cbt.20557
PMCID: PMC3606205  PMID: 22617772
Surgical model; adjuvant therapy; cancer recurrence; immunotherapy; oncology; tumor microenvironment
2.  Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control following surgical or radiation therapy of cancer in mice 
Tumor recurrence from residual local or micro-metastatic disease remains a problem in cancer therapy. In patients with soft-tissue sarcoma and patients with inoperable non-small cell lung cancer, local recurrence is common and significant mortality is caused by the subsequent emergence of metastatic disease. Thus, while the aim of the primary therapy is curative, the outcome may be improved by additional targeting of residual microscopic disease. We demonstrate in a murine model that surgical removal of a large primary sarcoma results in local recurrence in approximately 50% of animals. Depletion of CD8 T cells results in local recurrence in 100% of animals, indicating that these cells are involved in control of residual disease. We further demonstrate that systemic adjuvant administration of αOX40 at surgery eliminates local recurrences. In this model, αOX40 acts to directly enhance tumor antigen-specific CD8 T cell proliferation in the lymph node draining the surgical site, and results in increased tumor antigen-specific cytotoxicity in vivo. These results are also corroborated in a murine model of hypofractionated radiation therapy of lung cancer. Administration of αOX40 in combination with radiation significantly extended survival compared to either agent alone, and resulted in a significant proportion of long-term tumor free survivors. We conclude that αOX40 increases tumor antigen-specific CD8 T cell cytotoxic activity resulting in improved endogenous immune control of residual microscopic disease, and we propose that adjuvant αOX40 administration may be a valuable addition to surgical and radiation therapy for cancer.
doi:10.1097/CJI.0b013e3181ee7095
PMCID: PMC3563298  PMID: 20842057
CD134; Costimulation; Surgery; Radiation; CD8
3.  Optimizing Surgical and Imatinib Therapy for the Treatment of Gastrointestinal Stromal Tumors 
Introduction
The discovery of activating KIT and PDGFRα mutations in gastrointestinal stromal tumors (GISTs) represented a milestone as it allowed clinicians to use tyrosine kinase inhibitors, like imatinib, to treat this sarcoma. Although surgery remains the only potentially curative treatment, patients who undergo complete resection may still experience local recurrence or distant metastases. Therapeutic strategies that combine surgical resection and adjuvant imatinib may represent the best treatment to maximize patient outcomes. In addition to the use of imatinib in the adjuvant and metastatic settings, neoadjuvant imatinib, employed as a cytoreductive therapy, can decrease tumor volume, increase the probability of complete resection, and may reduce surgery-related morbidities. Thus, selected patients with metastatic disease may be treated with a combination of preoperative imatinib and metastasectomy. However, it is critical that patients with GIST be evaluated by a multidisciplinary team to coordinate surgery and targeted therapy in order to maximize clinical outcomes.
Discussion
Following a systematic literature review, we describe the presentation, diagnosis, and treatment of GIST, with a discussion of the risk assessment for imatinib therapy. The application of surgical options, combined with adjuvant/neoadjuvant or perioperative imatinib, and their potential impact on survival for patients with primary, recurrent, or metastatic GIST are discussed.
doi:10.1007/s11605-013-2243-0
PMCID: PMC3824223  PMID: 23775094
Gastrointestinal stromal tumor; GIST; Imatinib; Tyrosine kinase inhibitor; Outcomes
4.  Emerging drug discovery approaches for selective targeting of “precursor” metastatic breast cancer cells: highlights and perspectives 
Breast cancer is a prevalent disease and a major cause of morbidity and cancer-related deaths among women worldwide. A significant number of patients at the time of primary diagnosis present metastatic disease, at least to locoregional lymph nodes, which results in somewhat unpredictable prognosis that often prompts adjuvant systemic therapies of various kinds. The time course of distant recurrence is also unpredictable with some patients sustaining a recurrence within months after diagnosis, even during adjuvant treatments, while others can experience recurrence years or decades after initial diagnosis. To date, clinically approved therapeutics yielded marginal benefits for patients with systemic metastatic breast disease, since despite high clinical responses to various therapies, the patients virtually always become resistant and tumor relapses. Molecular profiling studies established that breast cancer is highly heterogeneous and encompasses diverse histological and molecular subtypes with distinct biological and clinical implications in particular in relation to the incidence of progression to metastasis. The latter has been recognized to result from late genetic events during the multistep progression proposed by the dominant theory of carcinogenesis. However, there is evidence that the dissemination of primary cancer can also be initiated at a very early stage of cancer development, originating from rare cell variants, possibly cancer stem-like cells (CSC), with invasive potential. These precursor metastatic cancer cells with stem-like properties are defined by their ability to self-renew and to regenerate cell variants, which have high plasticity and intrinsic invasive properties required for dissemination and tropism toward specific organs. Equally relevant to the CSC hypothesis for metastasis formation is the epithelial-mesenchymal transition (EMT) process, which is critical for the acquisition of cancer cell invasive behavior and for selection/gain of CSC properties. These exciting concepts have led to the formulation of various approaches for targeting precursor metastatic cells, and these have taken on greater priority in therapeutic drug discovery research by both academia and pharmaceuticals. In this review, we focus on current efforts in medicinal chemistry to develop small molecules able to target precursor metastatic cells via interference with the CSC/EMT differentiation program, self-renewal, and survival. It is not meant to be comprehensive and the reader is referred to selected reviews that provide coverage of related basic aspects. Rather, emphasis is given to promising molecules with CSC/EMT signaling at the preclinical stage and in clinical trials that are paving the way to new generations of anti-metastasis drugs.
PMCID: PMC3204890  PMID: 22046485
Breast cancer; metastasis; cancer stem cells; EMT; experimental therapy
5.  Malignant Salivary Gland Tumors: Role of Radiation Therapy 
Malignant salivary gland tumors are rare. They represent less than one percent of all head and neck tumors. Approximately three fourths of all salivary gland tumors occur in the major salivary glands.
Traditionally, the treatment of choice for these tumors is surgery. The majority of these tumors reoccur after curative surgical procedures. Local recurrence rate following surgery varies with the histology, grade, and extent of the disease.
In spite of high local recurrence rate following curative surgical treatment of these tumors, radiotherapy has seldom been used as an adjuvant to surgery. The value of elective postoperative radiation therapy for subclinical microscopic disease was not recognized. Review of the literature supports the improved local control rate with the use of immediate postoperative radiotherapy. Radiation therapy proved to be effective as an adjuvant to surgery. A local control rate of better than 40 percent can be achieved by radiation therapy as a sole modality in inoperable and locally advanced cases. Radiation therapy provides an excellent palliation for locally advanced tumors or symptomatic metastases.
PMCID: PMC2537511  PMID: 537118
6.  Combination therapy in high-risk stage II or stage III colon cancer: current practice and future prospects 
Colon cancer represents the second leading cause of cancer-related deaths. For patients who have undergone curative surgery, adjuvant therapy can reduce the risk of recurrence and death from relapsed or metastatic disease. Postoperative chemotherapy with a 5-fluorouracil-based regimen combined with oxaliplatin is the current standard of care for stage III patients. However, there is still controversy in stage II disease about the real impact of adjuvant monotherapy or combined therapy on survival. Better identification of a subgroup of patients with a higher risk of recurrence can select patients who might benefit from adjuvant therapy. For the elderly population, there is a well-established role for postoperative therapy, although the most appropriate regimen remains to be defined. Targeted agents for combined adjuvant therapy in stage II and III colon cancer is a promising area, but to date, there is no evidence supporting its use in this setting. Results from large prospective trials with targeted therapy have been disappointing and new drugs and strategies are needed to define the role of these types of agents in the adjuvant scenario of colon cancer.
doi:10.1177/1758834010367905
PMCID: PMC3126021  PMID: 21789139
adjuvant chemotherapy; colon cancer; combined therapy; high-risk stage II; stage III
7.  Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer 
Nature medicine  2010;16(2):214-218.
Post-surgery adjuvant chemotherapy for breast cancer has effectively reduced metastatic recurrence rates1. However, a significant proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes critical for tumor response to specific chemotherapy drugs is a challenge, but necessary to improve outcomes2. Using integrated genomics, we identified a small number of over-expressed and amplified genes from chromosome 8q22 significantly associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. The association was confirmed in an analysis of multiple independent cohorts. Two of these genes, the anti-apoptotic gene YWHAZ, and LAPTM4B, a novel lysosomal gene, sensitized tumor cells to anthracyclines when either was depleted by siRNA knockdown and induced drug resistance when either was over-expressed. Over-expression of LAPTM4B resulted in sequestration of drug, delaying its appearance in the nucleus. Over-expression of these two genes was associated with poor tumor response to anthracycline treatment in a neo-adjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and over-expression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines, and are permissive for metastatic recurrence. These two genes may predict anthracycline resistance and influence selection of chemotherapy.
doi:10.1038/nm.2090
PMCID: PMC2826790  PMID: 20098429
8.  Merkel cell carcinoma adjuvant therapy: Current data support radiation but not chemotherapy 
Merkel cell carcinoma is a skin cancer with 30% mortality and an incidence that has tripled in the past 15 years. There is agreement that surgical excision with negative margins is an appropriate therapeutic first step and that sentinel lymph node biopsy is a powerful prognostic indicator. Following excision of detectable cancer, optimal adjuvant therapy is not well established. A role for adjuvant radiotherapy is increasingly supported by retrospective data suggesting a nearly four-fold decrease in local recurrences if radiation is added to surgery. In contrast, a role for adjuvant chemotherapy is not well supported. The rationale for chemotherapy in this disease is based on small-cell lung cancer, a more common neuroendocrine tumor for which chemotherapy is the primary treatment modality. Several issues call into question the routine use of adjuvant chemotherapy in Merkel cell carcinoma: lack of evidence for improved survival; the associated morbidity and mortality; important differences between small-cell lung cancer and Merkel cell carcinoma; and rapid development of resistance to chemotherapy. Importantly, chemotherapy suppresses immune function that plays an unusually large role in defending the host from the development and progression of Merkel cell carcinoma. Taken together, these arguments suggest that adjuvant chemotherapy for Merkel cell carcinoma patients should largely be restricted to clinical trials.
Merkel cell carcinoma is a neuroendocrine cancer that typically presents as a rapidly growing non-specific nodule on sun exposed skin in people over 65 years of age. The recent increase in incidence to over 1000 cases a year in the United States has led Merkel cell carcinoma to become the second most common cause of non-melanoma skin cancer death.1,2 Optimal management for Merkel cell carcinoma beyond surgical excision is not agreed on, and no randomized trials have been carried out. Sentinel lymph node biopsy has been shown to be powerful in predicting subsequent recurrences as well as in determining if further nodal treatment is indicated.3,4
doi:10.1016/j.jaad.2007.03.011
PMCID: PMC1950220  PMID: 17482714
9.  Prognosis After Ipsilateral Breast Tumor Recurrence and Locoregional Recurrences in Patients Treated by Breast-Conserving Therapy in Five National Surgical Adjuvant Breast and Bowel Project Protocols of Node-Negative Breast Cancer 
Journal of Clinical Oncology  2009;27(15):2466-2473.
Purpose
Locoregional failure (LRF) after breast-conserving therapy (BCT) is associated with increased risk of distant disease and death. The magnitude of this risk has not been adequately characterized in patients with lymph node-negative disease.
Patients and Methods
Our study population included 3,799 women randomly assigned to five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative disease (ie, B-13, B-14, B-19, B-20, and B-23) who underwent lumpectomy and whole breast irradiation with or without adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated, along with distant-disease–free interval (DDFI) and overall survival (OS) after these events. Cox models were employed to model mortality by using clinical and pathologic factors jointly with these events.
Results
Four hundred nineteen patients (11.0%) experienced LRF: 342 (9.0%) experienced IBTR, and 77 (2.0%) experienced oLRR. The 12-year cumulative incidences of IBTR and oLRR in patients treated with adjuvant systemic therapy were 6.6% and 1.8%, respectively. Overall, 37.1% of IBTRs and 72.7% of oLRRs occurred within 5 years of diagnosis. Older age, black race, higher body mass index (BMI), larger tumors, and occurrence of IBTR or oLRR were significantly associated with increased mortality. The 5-year OS after IBTR and oLRR were 76.6% and 34.9%, respectively. Adjusted hazard ratios for mortality associated with IBTR and oLRR were significantly higher in estrogen receptor (ER)–negative patients than in ER-positive patients (P = .002 and P < .0001, respectively). Patients with early LRF had worse OS and DDFI than those with later-occurring LRF.
Conclusion
Although LRF is uncommon in patients with node-negative breast cancer who are treated with lumpectomy, radiation, and adjuvant systemic therapy, those who do develop LRF have substantially worse OS and DDFI.
doi:10.1200/JCO.2008.19.8424
PMCID: PMC2684852  PMID: 19349544
10.  The Risk Factors Influencing between the Early and Late Recurrence in Systemic Recurrent Breast Cancer 
Journal of Breast Cancer  2012;15(2):218-223.
Purpose
Patients with recurrent breast cancer usually die of their disease, even after radical surgery and adjuvant therapies which could reduce the odds of dying. Many studies analyzed and compared patients who died of recurrent disease with those that died without recurrent disease. However, less attention has been paid to evaluating factors associated with the timing of recurrence. Thus, the objective of this study is to investigate the correlation between various factors and the timing of recurrence.
Methods
We retrospectively reviewed the data of 95 recurrent breast cancer patients who underwent curative surgery to determine the prognostic factors such as menopausal status, operation method, stage, nodal status, histologic grade, nuclear grade, extensive intraductal carcinoma component, hormone receptor, p53, c-erbB-2, Ki-67, and molecular subtype. We had attempted to compare the recurrent patients within 2 years after operation and adjuvant chemotherapies as the early recurrence with those over 2 years as the late recurrence.
Results
Histologic grade (p=0.005), nuclear grade (p<0.001), p53 (p=0.022), and Ki-67 (p<0.001) were significant different factors that influenced the systemic recurrence between early recurrence and late recurrence. In stage I/II, histologic grade (p=0.001), nuclear grade (p<0.001), and Ki-67 (p=0.005) were significant factors that influenced the systemic early recurrence. In stage III, nuclear grade (p=0.024), and Ki-67 (p=0.001) were significant factors that influenced the systemic early recurrence. But subtypes (p=0.189, p=0.132, p=0.593, p=0.083) are not associated with the timing of recur rence.
Conclusion
In systemic recurrent breast cancer patients, the risk factors such as histologic grade, nuclear grade, p53 and Ki-67 are also associated with the timing of recurrence. We sug gest that these patients should be proper treated and be closely followed up.
doi:10.4048/jbc.2012.15.2.218
PMCID: PMC3395746  PMID: 22807940
Breast neoplasms; Recurrence; Risk factors
11.  Management of stage II/III rectal cancer 
Pelvic and distant recurrences in rectal cancer can be associated with substantial morbidity, and patients with stage II and III disease are at increased risk for both local and distant failure when compared to patients with earlier stage disease. Refinement of surgical techniques have helped to reduce the risk of recurrence, and adjuvant therapies such as radiation to the tumor and regional lymph nodes and 5-fluorouracil-based systemic therapies have helped to further provide local control and may have an impact on overall survival. Numerous studies have been completed internationally in an effort to determine the optimal treatment regimen for this patient population. The importance of pre-therapy staging is of key importance as sequencing of therapy appears to significantly impact outcome. In the United States, patients with stage II/III rectal cancer are recommended to undergo preoperative concurrent pelvic radiation and chemotherapy followed by surgery several weeks later in order to maximize treatment response, which is then followed by approximately 4 months of adjuvant 5-fluorouracil-based systemic therapy. In Europe, there is substantial evidence supporting the use of neoadjuvant radiation therapy, however the role of concurrent chemotherapy remains a question of debate. Regardless of definitive management strategy, close follow-up in the post-treatment setting is important for early tumor detection and for managing treatment-related side-effects.
doi:10.3978/j.issn.2078-6891.2010.002
PMCID: PMC3397578  PMID: 22811815
SStage II/III rectal cancer; Combined modality therapy; neoadjuvant therapy; Radiation Therapy; 5-Fluorouracil
12.  Genomic “Dark Matter” in Prostate Cancer: Exploring the Clinical Utility of ncRNA as Biomarkers 
Prostate cancer is the most diagnosed cancer among men in the United States. While the majority of patients who undergo surgery (prostatectomy) will essentially be cured, about 30–40% men remain at risk for disease progression and recurrence. Currently, patients are deemed at risk by evaluation of clinical factors, but these do not resolve whether adjuvant therapy will significantly attenuate or delay disease progression for a patient at risk. Numerous efforts using mRNA-based biomarkers have been described for this purpose, but none have successfully reached widespread clinical practice in helping to make an adjuvant therapy decision. Here, we assess the utility of non-coding RNAs as biomarkers for prostate cancer recurrence based on high-resolution oligonucleotide microarray analysis of surgical tissue specimens from normal adjacent prostate, primary tumors, and metastases. We identify differentially expressed non-coding RNAs that distinguish between the different prostate tissue types and show that these non-coding RNAs can predict clinical outcomes in primary tumors. Together, these results suggest that non-coding RNAs are emerging from the “dark matter” of the genome as a new source of biomarkers for characterizing disease recurrence and progression. While this study shows that non-coding RNA biomarkers can be highly informative, future studies will be needed to further characterize the specific roles of these non-coding RNA biomarkers in the development of aggressive disease.
doi:10.3389/fgene.2012.00023
PMCID: PMC3284255  PMID: 22371711
prostate cancer; prognosis; microarrays; clinical progression; non-coding RNA
13.  The Effect of Oncotype DX Recurrence Score on Treatment Recommendations for Patients with Estrogen Receptor–Positive Early Stage Breast Cancer and Correlation with Estimation of Recurrence Risk by Breast Cancer Specialists 
The Oncologist  2011;16(11):1520-1526.
The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor–positive early stage breast cancer. Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with recurrence scores. Recurrence scores provide useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.
Purpose.
The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor–positive (ER-positive) early stage breast cancer. This study has two primary endpoints: to evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations and to compare the estimated recurrence risk predicted by breast oncology specialists to RS.
Methods.
One hundred fifty-four patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested.
Results.
Ninety-five (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively. RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations. There was no significant difference in recommendations between groups of participants.
Conclusions.
Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.
doi:10.1634/theoncologist.2011-0045
PMCID: PMC3233285  PMID: 22016474
Breast cancer; Risk assessment; Adjuvant chemotherapy; Gene expression profiling
14.  Treatment of cutaneous melanoma: current approaches and future prospects 
Melanoma is the most aggressive and deadly type of skin cancer. Surgical resection with or without lymph node sampling is the standard of care for primary cutaneous melanoma. Adjuvant therapy decisions may be informed by careful consideration of prognostic factors. High-dose adjuvant interferon alpha-2b increases disease-free survival and may modestly improve overall survival. Less toxic alternatives for adjuvant therapy are currently under study. External beam radiation therapy is an option for nodal beds where the risk of local recurrence is very high. In-transit melanoma metastases may be treated locally with surgery, immunotherapy, radiation, or heated limb perfusion. For metastatic melanoma, the options include chemotherapy or immunotherapy; targeted anti-BRAF and anti-KIT therapy is under active investigation. Standard chemotherapy yields objective tumor responses in approximately 10%–20% of patients, and sustained remissions are uncommon. Immunotherapy with high-dose interleukin-2 yields objective tumor responses in a minority of patients; however, some of these responses may be durable. Identification of activating mutations of BRAF, NRAS, c-KIT, and GNAQ in distinct clinical subtypes of melanoma suggest that these are molecularly distinct. Emerging data from clinical trials suggest that substantial improvements in the standard of care for melanoma may be possible.
doi:10.2147/CMR.S6073
PMCID: PMC3004577  PMID: 21188111
melanoma; resection; immune modulation; small molecule kinase inhibitors; chemotherapy; clinical trials
15.  Preoperative transarterial Embolisation in bone tumors 
World Journal of Radiology  2012;4(5):186-192.
Bone tumors include a variety of lesions, both primary and metastatic. The treatment modalities for bone tumors vary with the individual lesion, but in general surgical excision is the treatment of choice with other adjunctive therapies. However, surgery for many bone tumors is complex due to several factors including tumor bulk, vascularity, vicinity to vital structures and potentially inaccessible location of the lesion. Transarterial Embolisation (TAE) is one of the important adjuvant treatment modalities and in some cases it may be the primary and curative treatment. Preoperative TAE has proved to be effective in both primary and metastatic bone tumors. It reduces tumor vascularity and intraoperative blood loss, the need for blood transfusion and associated complications, allows better definition of tissue planes at surgery affording more complete excision, and hence reduced recurrence. Preoperative chemoEmbolisation has also been shown to increase the sensitivity of some tumors to subsequent chemotherapy and radiotherapy. There are several techniques and embolic agents available for this purpose, but the ultimate aim is to achieve tumor devascularization. In this review, we discuss the techniques including the choice of embolic agent, application to individual lesions and potential complications.
doi:10.4329/wjr.v4.i5.186
PMCID: PMC3386530  PMID: 22761978
Blood loss; Surgical; Bone tumors; Embolisation; Radiology; Interventional
16.  Systemic therapy strategies for head-neck carcinomas: Current status 
Head and neck cancers, most of which are squamous cell tumours, have an unsatisfactory prognosis despite intensive local treatment. This can be attributed, among other factors, to tumour recurrences inside or outside the treated area, and metastases at more distal locations. These tumours therefore require not only the standard surgical and radiation treatments, but also effective systemic modalities. The main option here is antineoplastic chemotherapy, which is firmly established in the palliative treatment of recurrent or metastatic stages of disease, and is used with curative intent in the form of combined simultaneous or adjuvant chemoradiotherapy in patients with inoperable or advanced tumour stages. Neoadjuvant treatment strategies for tumour reduction before surgery have yet to gain acceptance. Induction chemotherapy protocols before radiotherapy have to date been used in patients at high risk of distant metastases or as an aid for decision-making (“chemoselection”) in those with extensive laryngeal cancers, prior to definitive chemoradiotherapy or laryngectomy. Triple-combination induction therapy (taxanes, cisplatin, 5-fluorouracil) shows high remission rates with significant toxicity and, in combination with (chemo-)radiotherapy, is currently being compared with simultaneous chemoradiotherapy; the current gold standard with regards to efficacy and long-term toxicity.
A further systemic treatment strategy, called “targeted therapy”, has been developed to help increase specificity and reduce toxicity. An example of targeted therapy, EGFR-specific antibodies, can be used in palliative settings and, in combination with radiotherapy, to treat advanced head and neck cancers. A series of other novel biologicals such as signal cascade inhibitors, genetic agents, or immunotherapies, are currently being evaluated in large-scale clinical studies, and could prove useful in patients with advanced, recurring or metastatic head and neck cancers. When developing a lasting, individualised systemic tumour therapy, the critical evaluation criteria are not only efficacy and acute toxicity but also (long-term) quality-of-life and the identification of dedicated predictive biomarkers.
doi:10.3205/cto000085
PMCID: PMC3544206  PMID: 23320055
head-neck carcinoma; squamous-cell carcinoma of the head and neck; medical therapy; chemotherapy; antibody; targeted therapy; biological
17.  MicroRNAs as a potential prognostic factor in gastric cancer 
AIM: To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer.
METHODS: The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available. Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples, preserving the small RNA fraction. Initial profiling using miR microarrays was performed to identify potential biomarkers of recurrence after resection. The expression of the differential miRs was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 mo of surgery (bad-prognosis group, n = 14, 31%) and those who did not (good-prognosis group, n = 31, 69%).
RESULTS: Three miRs, miR-451, miR-199a-3p and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs patients with bad prognosis (P < 0.0002, 0.0027 and 0.0046 respectively). High expression of each miR was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of the differential miRs was verified by qRT-PCR, showing high correlation to the microarray data and similar separation into prognosis groups.
CONCLUSION: This study identified three miRs, miR-451, miR-199a-3p and miR-195 to be predictive of recurrence of gastric cancer. Of these, miR-451 had the strongest prognostic impact.
doi:10.3748/wjg.v17.i35.3976
PMCID: PMC3199555  PMID: 22046085
MicroRNA; Prognosis; Recurrence; Gastric cancer
18.  Survival in Metastatic Recurrent Breast Cancer after Adjuvant Chemotherapy: Little Evidence for Improvement Over the Past Three Decades 
Cancer  2012;119(6):1140-1148.
Purpose
Population-based studies have shown improved survival for patients diagnosed with metastatic breast cancer (MBC) over time, presumably due to the availability of new and more effective therapies. The objective of this analysis was to determine if survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.
Methods
Adjuvant chemotherapy trials coordinated by the Eastern Cooperative Oncology Group (ECOG) that accrued patients between 1978–2002 were reviewed. Survival following distant recurrence was estimated for progressive time periods, and adjusted for baseline covariates in a Cox proportional hazards model.
Results
Of the 13,785 patients who received adjuvant chemotherapy in 11 trials, 3447 (24.4%) developed distant recurrence; median survival following recurrence was 20 months (95% confidence intervals: 19, 21). Factors associated with inferior survival included shorter distant recurrence free interval (DRFI), ER- and PR-negative disease number of positive axillary nodes at diagnosis and black race (p<0.0001 for all). When time-period of recurrence was added to the model, it was not significantly associated with survival for the general population with recurrence. Survival improved over time only in hormone-receptor negative patients with a DRFI ≤ 3 years, both among the 5 recent and entire trial datasets (p=0.01 and p=0.05 respectively).
Conclusions
In contrast to reports from population-based studies, we did not observe general improvement in survival over the last three decades for patients who developed distant recurrence after adjuvant chemotherapy after adjusting for DRFI. Improved survival for hormone-receptor negative patients with a short DRFI suggests benefit from trastuzumab.
doi:10.1002/cncr.27819
PMCID: PMC3593800  PMID: 23065954
breast cancer; distant recurrence; survival; distant recurrence free interval; metastatic disease
19.  Mucinous Adenocarcinomas with Intra-Abdominal Dissemination: A Review of Current Therapy 
The Oncologist  2010;15(8):836-844.
An update of the most recent data on the current therapy for pseudomyxoma peritonei and mucinous colorectal adenocarcinoma with metastatic disease confined to the peritoneum is provided.
Peritoneal carcinomatosis has been considered a terminal disease with a median survival time of 5.2–12.6 months. Systemic chemotherapy and cytoreductive surgery (CRS) have long been used to treat macroscopic disease, with limited success. However, a comprehensive treatment approach involving cytroreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) has evolved into a novel approach for peritoneal carcinomatosis. Surgery removes the primary cancer and any dissemination within the peritoneal cavity and adjuvant HIPEC eradicates macroscopic or microscopic tumor residue, thus reducing the risk for recurrence. This approach offers a new potential treatment option for patients with metastatic disease confined to the peritoneum. The present review provides an update of the most recent data on the current therapy for pseudomyxoma peritonei (PMP) and mucinous colorectal adenocarcinoma (MCA) with metastatic disease confined to the peritoneum.
doi:10.1634/theoncologist.2010-0052
PMCID: PMC3228029  PMID: 20656916
Pseudomyxoma peritonei; Mucinous colorectal cancer; Treatment; Peritoneal carcinomatosis
20.  Magnetic Resonance Imaging of Rectal Cancer 
ABSTRACT
Magnetic resonance imaging (MRI)is a useful modality for the evaluation of rectal cancer, providing superior anatomic/pathologic visualization when compared with endorectal ultrasound (EUS) and computed tomography (CT). Preoperative MRI is useful for tissue characterization and tumor staging, which determines the surgical approach and need for neoadjuvant/adjuvant therapy. Important prognostic factors include the circumferential resection margin (CRM), T and N stages, and extent of local invasion. Postoperative MRI to assess the extent of tumor recurrence enables early resection, which can greatly prolong survival. MRI criteria for local recurrence include T2 hyperintensity, early dynamic rim enhancement, and nodular morphology. Future research in MRI of rectal cancer is geared toward developing optimal imaging techniques including high-resolution MRI, whole-body scans, and parallel imaging; imaging of lymph nodes by MR lymphography; and response to therapy using diffusion/perfusion-weighted MR and functional imaging.
doi:10.1055/s-2008-1080997
PMCID: PMC2780213  PMID: 20011416
Magnetic resonance; rectal cancer; preoperative; postoperative; recurrence
21.  Progranulin as a Prognostic Biomarker for Breast Cancer Recurrence in Patients Who Had Hormone Receptor-Positive Tumors: A Cohort Study 
PLoS ONE  2012;7(6):e39880.
Background
Progranulin (PGRN) is considered to play an important role in breast cancer tumorigenesis and in inhibiting tamoxifen-induced apoptosis. We aimed to determine whether PGRN levels are associated with breast cancer recurrence after curative surgery.
Methodology/Principal Findings
We evaluated the associations between preoperative serum PGRN levels and breast cancer recurrence in a cohort of 697 newly diagnosed breast cancer patients who underwent curative surgery between April 2001 and December 2004. The mean age ± standard deviation (SD) was 46±9.8 years, and all patients with hormone receptor (HR)-positive tumors received adjuvant tamoxifen therapy. At a median follow-up of 62.2 months (range, 2.9–98.2), 89 patients (12.8%) had experienced a recurrence and 51 patients (7.3%) had died. In the HR-positive group, serum PGRN levels were associated with recurrence according to the log-rank test for trend (p for trend  = 0.049). There was no association between PGRN levels and recurrence in the HR-negative group (p for trend  = 0.658). Adjusted hazard ratios, including possible confounders, revealed a linear relationship between serum PGRN levels and recurrence in the HR-positive group (p for trend  = 0.049), and this association was further strengthened after excluding patients who had no lymph node metastasis (p for trend  = 0.038).
Conclusions/Significance
Serum PGRN levels were clinically significant for predicting recurrence in patients with HR-positive breast cancer during adjuvant tamoxifen therapy.
doi:10.1371/journal.pone.0039880
PMCID: PMC3382586  PMID: 22761921
22.  Gene Expression Signatures That Predict Outcome of Tamoxifen-Treated Estrogen Receptor-Positive, High-Risk, Primary Breast Cancer Patients: A DBCG Study 
PLoS ONE  2013;8(1):e54078.
Background
Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy.
Methodology/Principal Findings
Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric bootstrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (n = 623). Three gene signatures were identified, the strongest being a 2-gene combination of BCL2-CDKN1A, exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (n = 503) confirmed the potential of BCL2-CDKN1A. The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25).
Conclusions/Significance
A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.
doi:10.1371/journal.pone.0054078
PMCID: PMC3546921  PMID: 23342080
23.  Development and Validation of a Prognostic Nomogram for Recurrence-Free Survival after Complete Surgical Resection of Localized, Primary Gastrointestinal Stromal Tumor (GIST): A Retrospective Analysis 
The lancet oncology  2009;10(11):1045-1052.
Background
An optimal staging system to estimate the risk of recurrence following the complete resection of localized, primary gastrointestinal stromal tumor (GIST) has not been established. Recently, it has been shown that adjuvant imatinib mesylate prolongs recurrence-free survival (RFS) following the resection of localized, primary GIST. We sought to develop a nomogram to predict RFS after surgery in the absence of adjuvant therapy to help guide patient selection for adjuvant imatinib therapy.
Methods
A nomogram to predict RFS based on tumor size (in cm), location (stomach, small intestine, colon/rectum, or other), and mitotic index (<5 or ≥5 mitoses per 50 high power fields) was developed from 127 patients treated at Memorial Sloan-Kettering Cancer Center. The nomogram was tested in cohorts of patients from the Spanish national registry (GEIS; n=212) and the Mayo Clinic (Mayo; n=148). The nomogram was evaluated by calculating concordance probabilities as well as testing calibration of predicted RFS with observed RFS. Concordance probabilities were also compared with those of 3 commonly employed staging systems.
Findings
The nomogram had a concordance probability of 0.78 (±0.02) in the MSKCC dataset and 0.76 (±0.03) and 0.80 (±0.02) in the validation cohorts. The nomogram predictions were well calibrated. Remodeling the nomogram to include tyrosine kinase mutation status did not improve its discriminatory ability. Concordance probabilities of the nomogram were superior to those of the 2 NIH staging systems (0.76 (±0.03) versus 0.70 (±0.04) (p=0.04) and 0.66 (±0.04) (p=0.01) in the GEIS validation cohort; 0.80 (±0.02) versus 0.74 (±0.02) (p=0.04) and 0.78 (±0.02) (p=0.05) in the Mayo cohort) and equivalent to the AFIP-Miettinen staging system (0.76 (±0.03) versus 0.73 (±0.004) (p=0.28) in the GEIS cohort; 0.80 (±0.02) versus 0.76 (±0.003) (p=0.09) in the Mayo cohort). Nomogram predictions of RFS appeared better calibrated than predictions made using the AFIP-Miettinen system.
Interpretation
The nomogram accurately predicts RFS following the resection of localized, primary GIST and may be useful to select patients for adjuvant imatinib therapy.
doi:10.1016/S1470-2045(09)70242-6
PMCID: PMC3175638  PMID: 19793678
gastrointestinal stromal tumor; GIST; nomogram; recurrence; prognosis; survival; imatinib mesylate; staging; surgery
24.  Multidisciplinary management of gastric and gastroesophageal cancers 
Carcinomas of the stomach and gastroesophageal junction are among the five top leading cancer types worldwide. In spite of radical surgical R0 resections being the basis of cure of gastric cancer, surgery alone provides long-term survival in only 30% of patients with advanced International Union Against Cancer (UICC) stages in Western countries because of the high risk of recurrence and metachronous metastases. However, recent large phase-III studies improved the diagnostic and therapeutic options in gastric cancers, indicating a more multidisciplinary management of the disease. Multimodal strategies combining different neoadjuvant and/or adjuvant protocols have clearly improved the gastric cancer prognosis when combined with surgery with curative intention. In particular, the perioperative (neoadjuvant, adjuvant) chemotherapy is now a well-established new standard of care for advanced tumors. Adjuvant therapy alone should be carefully discussed after surgical resection, mainly in individual patients with large lymph node positive tumors when neoadjuvant therapy could not be done. The palliative treatment options have also been remarkably improved with new chemotherapeutic agents and will further be enhanced with targeted therapies such as different monoclonal antibodies. This article reviews the most relevant literature on the multidisciplinary management of gastric and gastroesophageal cancer, and discusses future strategies to improve locoregional failures.
doi:10.3748/wjg.14.3773
PMCID: PMC2721432  PMID: 18609699
Gastric cancer; Chemotherapy; Chemoradiation; Adjuvant; Neoadjuvant
25.  Adjuvant Radio-chemotherapy for extrahepatic biliary tract cancers 
BMC Cancer  2011;11:267.
Background
Extrahepatic biliary duct cancers (EBDC) are uncommon malignancies characterized by a poor prognosis with high rate of loco-regional recurrence. The purpose of the present study is to assess the feasibility and the potential impact of adjuvant radiotherapy (RT) in a series of patients treated in one institution.
Methods
Twenty three patients with non-metastatic bile duct cancer treated surgically with curative intent (4 gallbladder, 7 ampullary and 12 cholangiocarcinoma) received 3D conformal external beam RT to a median total dose of 50.4Gy. Concurrent chemotherapy based on 5-FU was delivered to 21 patients (91%). Surgical margins were negative in 11 patients (48%), narrow in 2 (9%), and microscopically involved in 8 (35%). Eleven patients (55%) had metastatic nodal involvement. The average follow-up time for all patients was 30 months (ranging from 3-98).
Results
Acute gastrointestinal grade 2 toxicity (RTOG scale) was recorded in 2 patients (9%). Nausea or vomiting grade 1 and 2 was observed in 8 (35%) and 2 patients (9%) respectively. Only one patient developed a major late radiation-induced toxicity. The main pattern of recurrence was both loco-regional and distant (liver, peritoneum and/or lung). No difference was observed in loco-regional control according to the tumor location. The 5-year actuarial loco-regional control rate was 48.3% (67% and 30% for patients operated on with negative and positive/narrow/unknown margins respectively, p = 0.04). The 5-year actuarial overall survival was of 35.9% for the entire group (61.4% in case of negative margins and 16.7% in case of positive/narrow/unknown margins, p = 0.07).
Conclusions
Postoperative RT with 50-60 Gy is feasible with acceptable acute and late toxicities. The potential benefit observed in our series may support the use of adjuvant RT in patients with locally advanced disease. Prospective randomized trials are warranted to confirm definitively the role of RT in this tumor location.
doi:10.1186/1471-2407-11-267
PMCID: PMC3141778  PMID: 21702920

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