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1.  Advanced stage micropapillary serous borderline ovarian tumor in a postmenopausal woman: a case report 
Serous borderline ovarian tumors (SBOT) generally occur in young women, present at early stages and are associated with an excellent prognosis. However, there are rare subtypes of SBOT which may exhibit a more aggressive course. In contrast with other types of SBOT, the micropapillary variant SBOT (SBOT-MP) tends to present at advanced stages. Herein, we present a rare case of a SBOT-MP that occurred in a 66-year-old woman, who had tumoral involvement on bilateral ovaries, sigmoid serosa and a positive peritoneal cytology. The currently recommended treatment options for these cases are also discussed.
doi:10.5152/jtgga.2012.30
PMCID: PMC3939243  PMID: 24592040
Borderline ovarian tumor; peritoneal implant; micropapillary; advanced stage; postmenopause
2.  Diagnosis, Treatment, and Follow-Up of Borderline Ovarian Tumors 
The Oncologist  2012;17(12):1515-1533.
Borderline ovarian tumors remain a controversial issue. This review informs readers about the recent data concerning this topic.
Learning Objectives
After completing this course, the reader will be able to: Compare the epidemiologic and reproductive risk factors in BOTs with those in ovarian cancers and describe the molecular background of development of BOTs.Use the pathological terminology with either original grouping of borderline category or new subclassification of BOTs and assess the major predictor of recurrence and survival.Determine an appropriate diagnostic algorithm for patients with symptoms suggesting malignant ovarian tumors that will identify borderline ovarian tumors when present.
This article is available for continuing medical education credit at CME.TheOncologist.com
Borderline ovarian tumors represent a heterogeneous group of noninvasive tumors of uncertain malignant potential with characteristic histology. They occur in younger women, are present at an early stage, and have a favorable prognosis, but symptomatic recurrence and death may be found as long as 20 years after therapy in some patients. The molecular changes in borderline ovarian tumors indicate linkage of this disease to type I ovarian tumors (low-grade ovarian carcinomas). The pathological stage of disease and subclassification of extraovarian disease into invasive and noninvasive implants, together with the presence of postoperative macroscopic residual disease, appear to be the major predictor of recurrence and survival. However, it should be emphasized that the most important negative prognostic factor for recurrence is just the use of conservative surgery, but without any impact on patient survival because most recurrent diseases are of the borderline type—easily curable and with an excellent prognosis. Borderline tumors are difficult masses to correctly preoperatively diagnose using imaging methods because their macroscopic features may overlap with invasive and benign ovarian tumors. Over the past several decades, surgical therapy has shifted from a radical approach to more conservative treatment; however, oncologic safety must always be balanced. Follow-up is essential using routine ultrasound imaging, with special attention paid to the remaining ovary in conservatively treated patients. Current literature on this topic leads to a number of controversies that will be discussed thoroughly in this article, with the aim to provide recommendations for the clinical management of these patients.
doi:10.1634/theoncologist.2012-0139
PMCID: PMC3528384  PMID: 23024155
Borderline ovarian tumor; Prognostic parameter; Ultrasound; Fertility; Conservative surgery; Recurrence
3.  Micropapillary Pattern in Newly Diagnosed Borderline Tumors of the Ovary: What's in a Name? 
The Oncologist  2011;16(2):133-135.
The study by Uzan and colleagues published in this issue of The Oncologist on the prognosis of patients with serous borderline tumors of the ovary with a micropapillary pattern is reviewed.
doi:10.1634/theoncologist.2010-0410
PMCID: PMC3228091  PMID: 21273513
4.  TGF-Beta Induces Serous Borderline Ovarian Tumor Cell Invasion by Activating EMT but Triggers Apoptosis in Low-Grade Serous Ovarian Carcinoma Cells 
PLoS ONE  2012;7(8):e42436.
Apoptosis in ovarian surface epithelial (OSE) cells is induced by transforming growth factor-beta (TGF-β). However, high-grade serous ovarian carcinomas (HGC) are refractory to the inhibitory functions of TGF-β; their invasiveness is up-regulated by TGF-β through epithelial-mesenchymal transition (EMT) activation. Serous borderline ovarian tumors (SBOT) have been recognized as distinct entities that give rise to invasive low-grade serous carcinomas (LGC), which have a relatively poor prognosis and are unrelated to HGC. While it is not fully understood how TGF-β plays disparate roles in OSE cells and its malignant derivative HGC, its role in SBOT and LGC remains unknown. Here we demonstrate the effects of TGF-β on cultured SBOT3.1 and LGC-derived MPSC1 cells, which express TGF-β type I and type II receptors. TGF-β treatment induced the invasiveness of SBOT3.1 cells but reduced the invasiveness of MPSC1 cells. The analysis of apoptosis, which was assessed by cleaved caspase-3 and trypan blue exclusion assay, revealed TGF-β-induced apoptosis in MPSC1, but not SBOT3.1 cells. The pro-apoptotic effect of TGF-β on LGC cells was confirmed in another immortalized LGC cell line ILGC. TGF-β treatment led to the activation of Smad3 but not Smad2. The specific TβRI inhibitor SB431542 and TβRI siRNA abolished the SBOT3.1 invasion induced by TGF-β, and it prevented TGF-β-induced apoptosis in MPSC1 cells. In SBOT3.1 cells, TGF-β down-regulated E-cadherin and concurrently up-regulated N-cadherin. TGF-β up-regulated the expression of the transcriptional repressors of E-cadherin, Snail, Slug, Twist and ZEB1. In contrast, co-treatment with SB431542 and TβRI depletion by siRNA abolished the effects of TGF-β on the relative cadherin expression levels and that of Snail, Slug, Twist and ZEB1 as well. This study demonstrates dual TGF-β functions: the induction of SBOT cell invasion by EMT activation and apoptosis promotion in LGC cells.
doi:10.1371/journal.pone.0042436
PMCID: PMC3419689  PMID: 22905131
5.  EGF-Induced EMT and Invasiveness in Serous Borderline Ovarian Tumor Cells: A Possible Step in the Transition to Low-Grade Serous Carcinoma Cells? 
PLoS ONE  2012;7(3):e34071.
In high-grade ovarian cancer cultures, it has been shown that epidermal growth factor (EGF) induces cell invasion by activating an epithelial-mesenchymal transition (EMT). However, the effect of EGF on serous borderline ovarian tumors (SBOT) and low-grade serous carcinomas (LGC) cell invasion remains unknown. Here, we show that EGF receptor (EGFR) was expressed, that EGF treatment increased cell migration and invasion in two cultured SBOT cell lines, SBOT3.1 and SV40 large T antigen-infected SBOT cells (SBOT4-LT), and in two cultured LGC cell lines, MPSC1 and SV40 LT/ST-immortalized LGC cells (ILGC). However, EGF induced down-regulation of E-cadherin and concurrent up-regulation of N-cadherin in SBOT cells but not in LGC cells. In SBOT cells, the expression of the transcriptional repressors of E-cadherin, Snail, Slug and ZEB1 were increased by EGF treatment. Treatment with EGF led to the activation of the downstream ERK1/2 and PI3K/Akt. The MEK1 inhibitor PD98059 diminished the EGF-induced cadherin switch and the up-regulation of Snail, Slug and ZEB1 and the EGF-mediated increase in SBOT cell migration and invasion. The PI3K inhibitor LY294002 had similar effects, but it could not block the EGF-induced up-regulation of N-cadherin and ZEB1. This study demonstrates that EGF induces SBOT cell migration and invasion by activating EMT, which involves the activation of the ERK1/2 and PI3K/Akt pathways and, subsequently, Snail, Slug and ZEB1 expression. Moreover, our results suggest that there are EMT-independent mechanisms that mediate the EGF-induced LGC cell migration and invasion.
doi:10.1371/journal.pone.0034071
PMCID: PMC3316602  PMID: 22479527
6.  Successful management of evisceration occurred after exploratory laparotomy for bilateral ovarian micropapillary serous borderline tumors 
Il Giornale di Chirurgia  2013;34(4):128-131.
Summary:
Micropapillary serous borderline tumor of the ovary is characterized by a more frequent association with extraovarian, especially invasive, implants. The aim of this study was to report the clinicopathological findings of a rare case of micropapillary serous borderline tumor of the ovary since there are less than 100 similar cases in the published literature. Additionally, the successful management of evisceration that complicated the postoperative stay of the patient is analyzed. The incidence of this severe complication is estimated between 0.29–2.3%. There are four main causes: suture tearing through the fascia, knot failure, suture failure, and extrusion of abdominal contents between sutures placed too far apart. At least 50% of the cases are due to technical error with a potentially lethal result.
PMCID: PMC3915579  PMID: 23660166
Ovarian borderline tumors; Micropapillary serous tumors; Ovarian cancer; Evisceration
7.  Age-Specific Administration of Chemotherapy and Long-Term Quality of Life in Stage II and III Colorectal Cancer Patients: A Population-Based Prospective Cohort 
The Oncologist  2011;16(12):1741-1751.
The age-specific pattern of administration of chemotherapy and its association with long-term survival and quality of life in stage II and III colorectal cancer patients were investigated. Chemotherapy was found to be associated with lower long-term quality of life, especially in younger survivors.
Learning Objectives
After completing this course, the reader will be able to: Critically appraise the current pattern of administration of chemotherapy in older patients with colorectal cancer.Describe the survival benefits associated with chemotherapy as well as its long-term effects on quality of life in stage II/III colorectal cancer patients.
This article is available for continuing medical education credit at CME.TheOncologist.com
Purpose.
To investigate the age-specific pattern of administration of chemotherapy and its association with long-term survival and quality of life (QoL) in stage II and III colorectal cancer patients.
Methods.
Chemotherapy allocation according to disease and patient characteristics was investigated in a population-based cohort of 562 stage II and III colorectal cancer patients. Five years after diagnosis, survival was determined and QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items and a tumor specific module. The association among chemotherapy, survival, and QoL was examined while controlling for potential confounders.
Results.
Chemotherapy was administered in 71% of patients aged <60 years and in only 20% of patients aged ≥80 years. A significant association between chemotherapy and longer survival time was found for stage III cancer only. Chemotherapy was associated with higher symptom levels for trouble with taste, anxiety, and hair loss. In age-specific analyses, younger survivors (<70 years at time of follow-up) with a history of chemotherapy reported significantly lower physical, role, and cognitive functioning and higher pain, appetite loss, hair loss, and trouble with taste symptom levels. In contrast, for older survivors (≥70 years), only two (hair loss and dry mouth) out of 38 QoL scores were significantly associated with chemotherapy.
Discussion.
Chemotherapy is associated with lower long-term QoL, especially in younger survivors. In cases of uncertain survival benefits of chemotherapy, consideration of its long-term effects on QoL should be incorporated into final decisions on treatment.
doi:10.1634/theoncologist.2011-0124
PMCID: PMC3248773  PMID: 22101506
Cancer survivors; Colorectal cancer; Chemotherapy; Long term; Quality of life; Survival
8.  The Prognostic Impact of Duration of Anemia During Chemotherapy in Advanced Epithelial Ovarian Cancer 
The Oncologist  2011;16(8):1154-1161.
A binary variable is introduced based on the duration of anemia, that is, a hemoglobin level <10 g/dL, during chemotherapy in advanced epithelial ovarian cancer patients for use as a potential prognostic factor for progression-free and overall survival.
Learning Objectives
After completing this course, the reader will be able to: Compare the prognostic factors for hemoglobin level in ovarian cancer patients.Explain the prognostic relationship between the duration of anemia during chemotherapy and survival in patients with advanced epithelial ovarian cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Objective.
To propose a measure of anemia to be used as a prognostic factor for progression-free survival and overall survival in advanced epithelial ovarian cancer patients.
Patients and Methods.
Seventy-six patients with International Federation of Gynecology and Obstetrics stage III and stage IV epithelial ovarian cancer who had received at least six courses of platinum- and taxane-based systemic chemotherapy and achieved clinical or pathologic complete response were included. A novel prognostic factor based on the duration of anemia was proposed and the impact of anemia on progression-free and overall survival times was analyzed by a log-rank test and a Cox proportional hazards model.
Results.
We introduce a binary variable, Hb1020, that takes a value of 1 if the duration of a hemoglobin (Hb) level <10 g/dL is ≥20% of the total duration of chemotherapy. We propose Hb1020 as a potential prognostic factor for epithelial ovarian cancer. The 5-year progression-free survival rates were 48.4% in the Hb1020 = 0 group (duration of Hb <10 g/dL <20% of total duration) and 17.7% in the Hb1020 = 1 group (p = .026). The 5-year overall survival rates were 64.6% and 45.0%, respectively (p = .015).
Conclusions.
Hb1020, based on the duration of anemia, is a potential prognostic factor for epithelial ovarian cancer. Using Hb1020, we will be able to administer highly optimized treatment for anemia to improve patient survival. Further independent studies are needed to confirm its prognostic role.
doi:10.1634/theoncologist.2010-0236
PMCID: PMC3228149  PMID: 21705663
Ovarian cancer; Anemia; Prognostic factor; Survival; Chemotherapy
9.  Prognostic Factors and Morbidities After Completion Surgery in Patients Undergoing Initial Chemoradiation Therapy for Locally Advanced Cervical Cancer 
The Oncologist  2010;15(4):405-415.
The study evaluates the prognostic factors and morbidities of patients undergoing completion surgery for locally advanced-stage cervical cancer after initial chemoradiation therapy.
Learning Objectives
After completing this course, the reader will be able to: Rate the prognostic factors for overall survival in patients undergoing completion surgery after initial chemoradiation therapy (CRT) for locally advanced cervical cancer.In cervical cancer patients undergoing completion surgery, consider using laparoscopy to decrease the morbidity of the surgery.In cervical cancer patients undergoing completion surgery, use PET-CT imaging to improve detection of para-aortic involvement.
This article is available for continuing medical education credit at CME.TheOncologist.com
Purpose.
The aim of this study was to evaluate the prognostic factors and morbidities of patients undergoing completion surgery for locally advanced-stage cervical cancer after initial chemoradiation therapy (CRT).
Patients and Methods.
Patients fulfilling the following inclusion criteria were studied: stage IB2–IVA cervical carcinoma, tumor initially confined to the pelvic cavity on conventional imaging, pelvic external radiation therapy with delivery of 45 Gy to the pelvic cavity and concomitant chemotherapy (cisplatin, 40 mg/m2 per week) followed by uterovaginal brachytherapy, and completion surgery after the end of radiation therapy including at least a hysterectomy.
Results.
One-hundred fifty patients treated in 1998–2007 fulfilled the inclusion criteria. Prognostic factors for overall survival in the multivariate analysis were the presence and level of nodal spread (positive pelvic nodes alone: hazard ratio [HR], 2.03; positive para-aortic nodes: HR, 5.46; p < .001) and the presence and size of residual disease (RD) in the cervix (p = .02). Thirty-seven (25%) patients had 55 postoperative complications. The risk for complications was higher with a radical hysterectomy (p = .04) and the presence of cervical RD (p = .01).
Conclusion.
In this series, the presence and size of RD and histologic nodal involvement were the strongest prognostic factors. Such results suggest that the survival of patients treated using CRT for locally advanced cervical cancer could potentially be enhanced by improving the rate of complete response in the irradiated area (cervix or pelvic nodes) and by initially detecting patients with para-aortic spread so that treatment could be adapted in such patients. The morbidity of completion surgery is high in this context.
doi:10.1634/theoncologist.2009-0295
PMCID: PMC3227965  PMID: 20332143
Chemoradiation therapy; Completion surgery; Locally advanced cervical cancer; Morbidities; Nodal involvement; Prognostic factors; Residual disease; Survival
10.  ZNF385B and VEGFA Are Strongly Differentially Expressed in Serous Ovarian Carcinomas and Correlate with Survival 
PLoS ONE  2012;7(9):e46317.
Background
The oncogenesis of ovarian cancer is poorly understood. The aim of this study was to identify mRNAs differentially expressed between moderately and poorly differentiated (MD/PD) serous ovarian carcinomas (SC), serous ovarian borderline tumours (SBOT) and superficial scrapings from normal ovaries (SNO), and to correlate these mRNAs with clinical parameters including survival.
Methods
Differences in mRNA expression between MD/PD SC, SBOT and SNO were analyzed by global gene expression profiling (n = 23), validated by RT-qPCR (n = 41) and correlated with clinical parameters.
Results
Thirty mRNAs differentially expressed between MD/PD SC, SBOT and SNO were selected from the global gene expression analyses, and 21 were verified (p<0.01) by RT-qPCR. Of these, 13 mRNAs were differentially expressed in MD/PD SC compared with SNO (p<0.01) and were correlated with clinical parameters. ZNF385B was downregulated (FC = −130.5, p = 1.2×10−7) and correlated with overall survival (p = 0.03). VEGFA was upregulated (FC = 6.1, p = 6.0×10−6) and correlated with progression-free survival (p = 0.037). Increased levels of TPX2 and FOXM1 mRNAs (FC = 28.5, p = 2.7×10−10 and FC = 46.2, p = 5.6×10−4, respectively) correlated with normalization of CA125 (p = 0.03 and p = 0.044, respectively). Furthermore, we present a molecular pathway for MD/PD SC, including VEGFA, FOXM1, TPX2, BIRC5 and TOP2A, all significantly upregulated and directly interacting with TP53.
Conclusions
We have identified 21 mRNAs differentially expressed (p<0.01) between MD/PD SC, SBOT and SNO. Thirteen were differentially expressed in MD/PD SC, including ZNF385B and VEGFA correlating with survival, and FOXM1 and TPX2 with normalization of CA125. We also present a molecular pathway for MD/PD SC.
doi:10.1371/journal.pone.0046317
PMCID: PMC3460818  PMID: 23029477
11.  Micropapillary bladder cancer: a review of Léon Bérard Cancer Center experience 
BMC Urology  2009;9:5.
Background
Micropapillary bladder cancer is a rare and aggressive variant of urothelial carcinoma. A retrospective review of our experience in management of patients with muscle-invasive or metastatic micropapillary bladder cancer was performed to better define the behavior of this disease.
Methods
We reviewed the records of the 11 patients with micropapillary bladder cancer who were evaluated and treated at Léon Bérard Cancer Center between 1994 and 2007, accounting for 1,2% of all urothelial tumors treated in this institution.
Results
Mean patients age was 60 years. The majority of patients (72%) were diagnosed after 2004. After a median follow-up of 31.7 months, median overall survival was 19 months. Two patients presented with stage II, one with stage III and eight with stage IV disease All 5 patients who had node positive metastases and treated with radical surgery and adjuvant chemotherapy relapsed and had a disease free survival of 9.6 months.
Conclusion
Micropapillary bladder cancer is probably an underreported variant of urothelial carcinoma associated with poor prognosis. Adjuvant chemotherapy might have a questionable efficacy and the optimal treatment strategy is yet to be defined.
doi:10.1186/1471-2490-9-5
PMCID: PMC2713271  PMID: 19534791
12.  The Anterior Gradient Homolog 3 (AGR3) Gene Is Associated with Differentiation and Survival in Ovarian Cancer 
Low-grade serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors, yet the progression from serous borderline tumors to low-grade serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the two groups. Expression profiles were generated from 6 human ovarian surface epithelia (HOSE), 8 serous borderline ovarian tumors (SBOT), 13 low-grade serous ovarian carcinomas (LG), and 24 high-grade serous ovarian carcinomas (HG). The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors; this finding was validated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P < 0.005) between SBOT, LG and HG tumors. Serous borderline ovarian tumors exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P = 0.013) and HG (P = 0.008) serous ovarian carcinoma groups. The progression of serous borderline ovarian tumors to low-grade serous ovarian carcinoma may involve the de-differentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with low-grade and high-grade serous ovarian carcinomas.
doi:10.1097/PAS.0b013e318212ae22
PMCID: PMC3095702  PMID: 21451362
AGR3; BCMP11; ovarian cancer; biomarker; cilia
13.  Early Detection and Treatment of Ovarian Cancer: Shifting from Early Stage to Minimal Volume of Disease Based on a New Model of Carcinogenesis 
The goal of ovarian cancer screening is to detect disease when confined to the ovary (stage I) and thereby prolong survival. We believe this is an elusive goal because most ovarian cancer, at its earliest recognizable stage, is probably not confined to the ovary. We propose a new model of ovarian carcinogenesis based on clinical, pathological, and molecular genetic studies that may enable more targeted screening and therapeutic intervention to be developed. The model divides ovarian cancer into two groups designated Type I and Type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis and develop from well established precursor lesions so-called “borderline” tumors. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing, highly aggressive neoplasms that lack well defined precursor lesions; most are advanced stage at, or soon after, their inception. These include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas. The Type II tumors are characterized by mutation of TP53 and a high level of genetic instability. Screening tests that focus on stage I disease may detect low-grade Type I neoplasms while missing the more aggressive Type II tumors which account for most ovarian cancers. A more rational approach to early detection of “ovarian cancer” should focus on low volume rather than low stage of disease.
doi:10.1016/j.ajog.2008.01.005
PMCID: PMC2532696  PMID: 18395030
14.  Current Status of Adjuvant Therapy for Pancreatic Cancer 
The Oncologist  2010;15(11):1205-1213.
The rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process are reviewed.
Learning Objectives
After completing this course, the reader will be able to: Explain the rationale for the use of adjuvant and neoadjuvant chemoradiation and/or chemotherapy in the treatment of patients with potentially resectable pancreatic cancer.Describe the limitations of prior prospective, randomized trials of adjuvant therapy strategies and the clinical implications of these limitations.Compare modern strategies for the multidisciplinary management of potentially resectable and borderline resectable pancreatic cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com.
In this article, we review the rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process. Localized pancreatic cancer is a systemic disease that requires nonoperative therapies to minimize the local and systemic recurrences that almost invariably occur in the absence of such therapy, even following complete surgical resection. A well-defined role exists for the systemic administration of gemcitabine or 5-fluorouracil in the postoperative setting. Although the survival benefit associated with adjuvant chemoradiation has not been as rigorously defined, its use is supported by extensive historic experience; chemoradiation should be considered particularly for patients at high risk for local recurrence. Delivery of chemotherapy and/or chemoradiation prior to surgery has multiple potential advantages, although the superiority of neoadjuvant therapy over standard postoperative therapy has yet to be demonstrated. Neoadjuvant therapy may be particularly beneficial among patients with borderline resectable cancers. Although the existing literature is confusing, and indeed controversial, available evidence suggests that systemic chemotherapy and/or chemoradiation should be offered to all patients with pancreatic cancer who undergo potentially curative resection. Well-designed prospective trials are needed to define the optimal adjuvant or neoadjuvant therapy strategy for these patients.
doi:10.1634/theoncologist.2010-0121
PMCID: PMC3227902  PMID: 21045189
Pancreatic cancer; Adjuvant therapy; Neoadjuvant therapy; Chemoradiation; Chemotherapy; Pancreaticoduodenectomy
15.  Micropapillary Pattern at the Invasive Front and Its Association with Unresectable Colorectal Carcinomas 
Disease markers  2013;35(5):451-455.
Unresectable colorectal carcinomas (CRCs) as considered incurable even if the primary tumors and the metastatic ones can undergo resection are correlated with poor prognosis. We evaluated the association between micropapillary pattern at the invasive front and unresectable CRCs. Thirty-four out of 264 (12.9%) CRC patients with stages III and IV were unresectable cases. The patients with unresectable CRCs had significantly worse survival than those with resectable CRCs (P < 0.001). Micropapillary pattern was evident in 12 (4.5%) out of 264 cases. This pattern was observed in 6 of 34 (17.6%) unresectable CRCs and in 6 of 230 (2.6%) resectable cases (P = 0.002). Unresectable CRCs revealed more frequently deeper invasion (odds ratio (OR), 1.175; 95% confidence interval (CI), 1.113–1.241), lymph node metastasis (OR, 2.356; 95% CI, 1.132–4.905), and presence of micropapillary pattern at the invasive front (OR, 8.000; 95% CI, 2.415–26.504) as compared to resectable cases. By multivariable logistic regression analysis, only micropapillary pattern was shown to be an independent predictor of unresectable CRCs (OR, 9.451; 95% CI, 2.468–36.196; P < 0.001). In conclusion, micropapillary pattern at the invasive front is associated with unresectable CRCs, and detection of it could help identify unresectable CRC cases.
doi:10.1155/2013/851623
PMCID: PMC3830847  PMID: 24288425
16.  Treatment for Advanced and Recurrent Endometrial Carcinoma: Combined Modalities 
The Oncologist  2010;15(8):852-861.
The treatment options available to treat recurrent and locally advanced endometrial cancer are reviewed.
Learning Objectives
After completing this course, the reader will be able to: Discuss the role of radiation therapy for advanced stage endometrial cancer in order to differentiate between patients who should receive only radiation therapy and patients requiring surgery and/or chemotherapy in addition to radiation.Evaluate the role of surgery for stage IV and recurrent endometrial cancer in order to select patients most likely to benefit from cytoreductive surgery.Evaluate the role of chemotherapy, particularly in conjunction with radiotherapy, in advanced stage endometrial carcinoma and select appropriate candidates for multimodality therapy.
This article is available for continuing medical education credit at CME.TheOncologist.com
Women with recurrent or advanced endometrial cancer constitute a heterogeneous group of patients. Depending on previous treatment, women with recurrent endometrial cancer may be appropriate candidates for surgery, radiation therapy, hormonal therapy, or chemotherapy. Women with advanced stage disease at presentation may also be appropriate candidates for systemic and local therapies. We review the treatment options available to treat recurrent and locally advanced endometrial cancer.
Treatment choice depends largely on the localization of disease, the patient’s performance status and previous treatment history, as well the tumor’s hormonal receptor status. Radiation therapy is appropriate for isolated vaginal recurrences in patients with no previous history of radiation therapy. Patients with recurrent low-grade tumors overexpressing estrogen and progesterone receptors may be treated with progestin therapy. Systemic therapy is appropriate for patients with disseminate recurrences or advanced stage disease at presentation, or for those with receptor-negative tumors. We review all these different treatment strategies available to patients with advanced or recurrent endometrial cancer.
doi:10.1634/theoncologist.2010-0091
PMCID: PMC3228028  PMID: 20660059
Endometrial cancer; Radiation; Chemotherapy; Hormonal therapy
17.  Neoplastic Meningitis from Solid Tumors: New Diagnostic and Therapeutic Approaches 
The Oncologist  2011;16(8):1175-1188.
The most recent and interesting developments on diagnostic and therapeutic approaches in the treatment of neoplastic meningitis from solid tumors are reviewed.
Learning Objectives
After completing this course, the reader will be able to: Compare the use of i.t. therapy and systemic therapies for patients with neoplastic meningitis.Describe new drugs showing promise for neoplastic meningitis.
This article is available for continuing medical education credit at CME.TheOncologist.com
Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%–15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography–computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity.
Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes.
In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches.
doi:10.1634/theoncologist.2011-0101
PMCID: PMC3228160  PMID: 21795431
Neoplastic meningitis; Leptomeningeal disease; Leptomeningeal carcinomatosis; Solid tumors; Targeted therapy; Brain tumors
18.  Assessment of the argyrophilic nucleolar organizer region area/nucleus ratio in ovarian serous epithelial adenomas, borderline tumors and cancers 
Introduction
There is a need to assess the value of the novel potentially useful biomarkers in ovarian tumors. The aim of study was to assess the value of sAgNOR analysis in ovarian serous epithelial tumors.
Material and methods
The analysis was performed in ovaries from 113 patients treated operatively due to serous ovarian tumors (30 adenomas, 14 borderline tumors and 69 cancers). After silver staining of paraffin specimens from surgery, sAgNOR in tumor cells was analyzed. Additionally, the value of the argyrophilic nucleolar organizer region area/nucleus ratio (sAgNOR) in the prediction of disease-free survival (DFS) and overall survival (OS) in 52 patients with serous ovarian cancer with complete follow-ups in November 2009 was evaluated. Age, grading, radicality of surgery and FIGO staging were analyzed as additional factors.
Results
sAgNOR in adenomas, borderline tumors and cancers was in the following ranges: (0.73 ±0.23) × 106, (0.81 ±0.18) × 106 and (0.96 ±0.33) × 106 [AgNOR/cm2] respectively. In cancers from G1 to G3 sAgNOR was (1.02 ±0.32) × 106 (G1), (0.98 ±0.37) × 106 (G2) and (0.82 ±0.24) × 106 (G3) [AgNOR/cm2] respectively. In univariate analysis, but not in multivariate analysis, staging negatively correlated with better DFS and OS. sAgNOR, age of patients, grading and radicality of surgery were not associated with DFS or OS in either univariate or multivariate analysis.
Conclusions
sAgNOR analysis is not sufficient to precisely characterize cellular kinetics in serous ovarian tumors, and the analysis of sAgNOR, mAgNOR and pAgNOR should be performed commonly. The prognostic significance of sAgNOR in patients with serous ovarian cancer was not proven.
doi:10.5114/aoms.2013.33066
PMCID: PMC3598139  PMID: 23515230
nucleolar organizer regions; argyrophilic; ovarian tumors; serous
19.  Update on Meningiomas 
The Oncologist  2011;16(11):1604-1613.
The epidemiology, risk factors, pathogenesis, prognostic factors, and treatment of patients with meningioma are examined.
Learning Objectives
After completing this course, the reader will be able to: Evaluate patients with grade II and III meningiomas for possible implementation of adjuvant radiation therapy.Describe options of systemic treatment of refractory meningiomas with hydroxyurea, somatostatin analogues, or CAV multi-agent chemotherapy.
This article is available for continuing medical education credit at CME.TheOncologist.com
Although meningiomas are the most common tumor in the central nervous system, their incidence, epidemiology, and clinical outcomes have historically been poorly defined. This has been attributed to their benign course, difficulty obtaining histologic diagnosis, and lack of uniform database registration. Their clinical behavior can range from a silent incidentaloma to a lethal tumor. Projections of an aging population should raise medical awareness of an expectant rise in the incidence of meningiomas. This disease increases with advancing age, has a female predilection, and exposure to ionizing radiation is associated with a higher risk for disease development. There have been minimal advances in treatment, except in radiation therapy. Although no U.S. Food and Drug Administration–approved systemic therapy exists, there are treatment options that include hydroxyurea and sandostatin. Currently, no molecularly targeted therapy has provided clinical benefit, although recurring molecular alterations are present and novel therapies are being investigated.
doi:10.1634/theoncologist.2011-0193
PMCID: PMC3233296  PMID: 22028341
Meningiomas; Brain tumor; Epidemiology; Tumor registry
20.  Selective Application of Routine Preoperative Axillary Ultrasonography Reduces Costs for Invasive Breast Cancers 
The Oncologist  2011;16(7):942-948.
Costs associated with the use of highly sensitive axillary ultrasonography in patients with stage ≥T2 invasive breast cancer are evaluated.
Learning Objectives
After completing this course, the reader will be able to: Identify patients likely to benefit from preoperative axillary ultrasound.Define the clinical implications of a preoperative axillary ultrasound and FNA in patient care.
This article is available for continuing medical education credit at CME.TheOncologist.com
Purpose.
Preoperative axillary sonography with fine needle aspiration (FNA) in patients with invasive breast cancer identifies patients with nodal metastasis who can be spared further surgery. Indiscriminate use of the diagnostic modality can increase costs and yield inaccurate results. We evaluate the costs associated with the use of highly sensitive axillary ultrasonography in patients with stage ≥T2 tumors.
Patients and Methods.
We constructed a decision analysis tree using TreeAge Pro 2009 software comparing direct hospital charges between patients with and without routine use of axillary ultrasound. Base case estimates were derived from our institutional data and compared with those derived from the literature. One- and two-way sensitivity analyses were performed to check the validity of our inferences.
Results.
We found that, for the base case estimate with 35% lymph node positivity in stage ≥T2 tumors and sensitivity of the axillary ultrasound set at 86% with a specificity of 40%, the strategy to perform preoperative axillary ultrasound yielded rollback costs of $15,215, compared with $15,940 for surgery plus sentinel lymph node biopsy (cost difference, $725 per patient favoring axillary ultrasound). On two-way sensitivity analysis, the cost benefit for axillary ultrasound was not seen in patients with a low risk for nodal metastasis.
Conclusion.
The adoption of routine preoperative axillary sonography with FNA is a lower-cost strategy than conventional strategies in patients with stage ≥T2 invasive breast cancer.
doi:10.1634/theoncologist.2010-0373
PMCID: PMC3228129  PMID: 21572122
Axillary ultrasound; Breast cancer; Cost analysis
21.  Fine needle aspiration cytology of a case of micropapillary variant of urothelial carcinoma of bladder 
Neoplastic urothelium has the capacity to demonstrate enormous plasticity. A variety of unusual morphological variants of urothelial carcinoma have been described. Micropapillary variant of urothelial carcinoma is a rare and recently described bladder tumor, associated with poor prognosis. We present the cytological features of micropapillary urothelial carcinoma in a 65-year-old man with bladder mass. The cytological features include tightly cohesive clusters of micropapillary component admixed with urothelial carcinoma. Histopathological sections showed small nests of tumor cells residing within the lacunae. Establishing a diagnosis of micropapillary urothelial carcinoma indicates a high-grade and high-stage tumor with poor outcome, requiring an aggressive therapy. It is thus important for the cytopathologist to recognise micropapillary variant of urothelial carcinoma, for early and better management of patients with bladder tumor.
doi:10.4103/0970-9371.83472
PMCID: PMC3159291  PMID: 21897549
Micropapillary; prognosis; urothelial carcinoma; variant
22.  CT appearance of primary peritoneal serous borderline tumour: a rare epithelial tumour of the peritoneum 
The British Journal of Radiology  2012;85(1009):e022-e025.
Primary peritoneal serous borderline tumour (PPSBT) is a rare epithelial neoplasm which is histologically identical to serous borderline tumour of the ovary. PPSBT is distinguishable from primary peritoneal serous carcinoma because the tumour cells do not invade the underlying tissue and affected patients have a good prognosis. We report the CT findings of surgically proven PPSBT in which multiple peritoneal cysts were seen. Although rare, PPSBT should be considered in the differential diagnosis of primary peritoneal tumours. Since the prognosis of the disease is good, conservation of the uterus and ovaries should be a consideration in young female patients during surgery.
doi:10.1259/bjr/26458228
PMCID: PMC3473926  PMID: 22190758
23.  "Surface epithelial changes" in uterine endometrioid carcinoma mimicking micropapillary serous borderline tumor of ovary: report of two cases and review of the literature 
Diagnostic Pathology  2011;6:13.
We encountered two cases of endometrioid carcinoma of uterus with extensive surface epithelial changes (SECs) mimicking serous borderline tumor (SBT) of the ovary. The first case was a well-differentiated endometrioid carcinoma arising in a background of complex atypical hyperplasia. The second case was moderately-differentiated endometrioid carcinoma with squamous and mucinous differentiation. The SECs comprised of thin microapapillae without hierarchal branching, lined by cuboidal cells with eosinophilic cytoplasm and mild to moderate nuclear atypia. These areas were reminiscent of SBTs of ovary, micropapillary type. This report expands the existing spectrum of SECs. Serous borderline tumor of ovary like surface epithelial changes could be misleading if present in an endometrial biopsy or curettings. Therefore, knowledge of this morphologic variation is important.
doi:10.1186/1746-1596-6-13
PMCID: PMC3038876  PMID: 21272308
24.  Micropapillary urothelial carcinoma: Cytologic features in a retrospective series of urine specimens 
CytoJournal  2013;10:4.
Background:
The micropapillary variant of urothelial carcinoma (uPC) is a rare variant of urothelial carcinoma that carries a poor prognosis. Definitive surgery may represent optimal management of low stage tumors. Urine cytology is indispensable in the screening and follow-up of urinary tract cancer. However, cytopathological criteria for diagnosis of uPC and its differentiation from conventional urothelial carcinoma (CUC) are not well-defined.
Materials and Methods:
Twenty-five cases of histologically confirmed micropapillary uPC from 21 patients were compared to 25 cases of histologically confirmed high-grade CUC.
Results:
In uPC cases, cell clusters were identified in 13 of 25 specimens from 10 patients. Six of the 13 specimens containing cell clusters corresponded to surgical pathology specimens in which micropapillary carcinoma accounted for at least 50% of total carcinoma. In contrast, only 1 of the 12 urine specimens devoid of cell clusters corresponded to surgical specimens in which micropapillary carcinoma accounted for at least 50% of total carcinoma. Cytomorphologic features of urinary specimens from patients with histologically confirmed micropapillary carcinoma were generally similar to those from patients with high-grade CUC, making it difficult to distinguish these entities in exfoliative urine specimens.
Conclusions and Summary:
Further investigation of the core cytopathological characteristics of uPC is warranted to refine its diagnostic criteria by exfoliative urine cytology.
doi:10.4103/1742-6413.107986
PMCID: PMC3623430  PMID: 23599723
Cytology; carcinoma; exfoliative; micropapillary; urothelial
25.  Is Renal Thrombotic Angiopathy an Emerging Problem in the Treatment of Ovarian Cancer Recurrences? 
The Oncologist  2012;17(12):1534-1540.
A retrospective review at two institutions was conducted to document the frequency and contributing factors to the emergence of chronic kidney disease among patients receiving long-term treatment for recurrent ovarian cancer.
Learning Objectives
After completing this course, the reader will be able to: Describe the need for additional vigilance regarding renal dysfunction when platinums, pegylated liposomal doxorubicin, bevacizumab, and gemcitabine are used for prolonged treatment of recurrent ovarian cancer in combination or sequentially following pre-existing renal damage.Describe and quantify the risk of chronic kidney disease in patients treated for ovarian cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background and Objective.
Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions.
Patients and Methods.
Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997–2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002–2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m2 for >3 months and were staged according to the National Kidney Foundation guidelines.
Results.
Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy.
Conclusions.
CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.
doi:10.1634/theoncologist.2011-0422
PMCID: PMC3528385  PMID: 22622146
Chronic kidney disease; Ovarian cancer; Pegylated liposomal doxorubicin; Renal thrombotic microangiopathy

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