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Martin W. Brechbiel - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of cell killing response from low linear energy transfer let radiation originating from 177lu radioimmunotherapy targeting disseminated intraPeritoneal tumor xenografts
International Journal of Molecular Sciences, 2016Co-Authors: Kwon Joong Yong, Diane E. Milenic, Kwamena E. Baidoo, Martin W. BrechbielAbstract:Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive Peritoneal Disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraPeritoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraPeritoneal Disease.
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Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel
PloS one, 2014Co-Authors: Kwon Joong Yong, Diane E. Milenic, Kwamena E. Baidoo, Martin W. BrechbielAbstract:To better understand the molecular basis of the enhanced cell killing effected by the combined modality of paclitaxel and ²¹²Pb-trastuzumab (Pac/²¹²Pb-trastuzumab), gene expression in LS-174T i.p. xenografts was investigated 24 h after treatment. Employing a real time quantitative PCR array (qRT-PCR array), 84 DNA damage response genes were quantified. Differentially expressed genes following therapy with Pac/²¹²Pb-trastuzumab included those involved in apoptosis (BRCA1, CIDEA, GADD45α, GADD45γ, GML, IP6K3, PCBP4, PPP1R15A, RAD21, and p73), cell cycle (BRCA1, CHK1, CHK2, GADD45α, GML, GTSE1, NBN, PCBP4, PPP1R15A, RAD9A, and SESN1), and damaged DNA repair (ATRX, BTG2, EXO1, FEN1, IGHMBP2, OGG1, MSH2, MUTYH, NBN, PRKDC, RAD21, and p73). This report demonstrates that the increased stressful growth arrest conditions induced by the Pac/²¹²Pb-trastuzumab treatment suppresses cell proliferation through the regulation of genes which are involved in apoptosis and damaged DNA repair including single and double strand DNA breaks. Furthermore, the study demonstrates that ²¹²Pb-trastuzumab potentiation of cell killing efficacy results from the perturbation of genes related to the mitotic spindle checkpoint and BASC (BRCA1-associated genome surveillance complex), suggesting cross-talk between DNA damage repair and the spindle damage response.
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pre clinical assessment of 177lu labeled trastuzumab targeting her2 for treatment and management of cancer patients with disseminated intraPeritoneal Disease
Pharmaceuticals, 2011Co-Authors: Geoffrey L Ray, Kwamena E. Baidoo, Martin W. Brechbiel, Paul S Albert, Lanea M M Keller, Diane E. MilenicAbstract:Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of (177)Lu was investigated. The combination of a 6.7 d half-life, lower energy β(-)-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make (177)Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-zparticle radiation. Radiolabeling trastuzumab-CHX-A"-DTPA with (177)Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraPeritoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of (177)Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered (177)Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with (177)Lu has potential for treatment of disseminated, HER2 positive, Peritoneal Disease.
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multimodality therapy potentiation of high linear energy transfer radiation with paclitaxel for the treatment of disseminated Peritoneal Disease
Clinical Cancer Research, 2008Co-Authors: Diane E. Milenic, Kwamena E. Baidoo, Kayhan Garmestani, Erik D Brady, Paul S Albert, Karen J Wong, Joseph Flynn, Martin W. BrechbielAbstract:Purpose: Studies herein explore paclitaxel enhancement of the therapeutic efficacy of α-particle-targeted radiation therapy. Experimental Design: Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 μg paclitaxel at 24 h before, concurrently, or 24 h after [ 213 Bi] or [ 212 Pb]trastuzumab. Results: Paclitaxel (300 or 600 μg) followed 24 h later with [ 213 Bi]trastuzumab (500 μCi) provided no therapeutic enhancement. Paclitaxel (300 μg) administered concurrently with [ 213 Bi]trastuzumab or [ 213 Bi]HuIgG resulted in median survival of 93 and 37 days, respectively; no difference was observed with 600 μg paclitaxel. Mice receiving just [ 213 Bi]trastuzumab or [ 213 Bi]HuIgG or left untreated had a median survival of 31, 21, and 15 days, respectively, 23 days for just either paclitaxel dose alone. Paclitaxel (300 or 600 μg) given 24 h after [ 213 Bi]trastuzumab increased median survival to 100 and 135 days, respectively. The greatest improvement in median survival (198 days) was obtained with two weekly doses of paclitaxel (600 μg) followed by [ 213 Bi]trastuzumab. Studies were also conducted investigating paclitaxel administered 24 h before, concurrently, or 24 h after [ 212 Pb]trastuzumab (10 μCi). The 300 μg paclitaxel 24 h before radioimmunotherapy (RIT) failed to provide benefit, whereas 600 μg extended the median survival from 44 to 171 days. Conclusions: These results suggest that regimens combining chemotherapeutics and high linear energy transfer (LET) RIT may have tremendous potential in the management and treatment of cancer patients. Dose dependency and administration order appear to be critical factors requiring careful investigation.
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potentiation of high let radiation by gemcitabine targeting her2 with trastuzumab to treat disseminated Peritoneal Disease
Clinical Cancer Research, 2007Co-Authors: Diane E. Milenic, Kayhan Garmestani, Erik D Brady, Paul S Albert, Joseph Flynn, Alia Abdulla, Martin W. BrechbielAbstract:Purpose: Recent studies from this laboratory with 212Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated Peritoneal Disease using 212Pb as an in vivo generator of 212Bi. The objective of the studies presented here was improvement of the efficacy of α-particle radioimmunotherapy using a chemotherapeutic agent. Experimental Design: In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by 212Pb radioimmunotherapy. Results: In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 μCi 212Pb-trastuzumab. Improvement in median survival was observed at 5 μCi 212Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 μCi versus 16 days for untreated mice ( P < 0.001). Multiple doses of gemcitabine combined with a single 212Pb radioimmunotherapy (10 μCi) administration was then evaluated. Mice received three doses of gemcitabine: one before 212Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy ( P < 0.001), specifically attributable to 212Pb-trastuzumab ( P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 μCi 212Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 μCi 212Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days ( P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before 212Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before 212Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because 212Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine). Conclusions: Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.
Diane E. Milenic - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of cell killing response from low linear energy transfer let radiation originating from 177lu radioimmunotherapy targeting disseminated intraPeritoneal tumor xenografts
International Journal of Molecular Sciences, 2016Co-Authors: Kwon Joong Yong, Diane E. Milenic, Kwamena E. Baidoo, Martin W. BrechbielAbstract:Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive Peritoneal Disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraPeritoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraPeritoneal Disease.
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Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel
PloS one, 2014Co-Authors: Kwon Joong Yong, Diane E. Milenic, Kwamena E. Baidoo, Martin W. BrechbielAbstract:To better understand the molecular basis of the enhanced cell killing effected by the combined modality of paclitaxel and ²¹²Pb-trastuzumab (Pac/²¹²Pb-trastuzumab), gene expression in LS-174T i.p. xenografts was investigated 24 h after treatment. Employing a real time quantitative PCR array (qRT-PCR array), 84 DNA damage response genes were quantified. Differentially expressed genes following therapy with Pac/²¹²Pb-trastuzumab included those involved in apoptosis (BRCA1, CIDEA, GADD45α, GADD45γ, GML, IP6K3, PCBP4, PPP1R15A, RAD21, and p73), cell cycle (BRCA1, CHK1, CHK2, GADD45α, GML, GTSE1, NBN, PCBP4, PPP1R15A, RAD9A, and SESN1), and damaged DNA repair (ATRX, BTG2, EXO1, FEN1, IGHMBP2, OGG1, MSH2, MUTYH, NBN, PRKDC, RAD21, and p73). This report demonstrates that the increased stressful growth arrest conditions induced by the Pac/²¹²Pb-trastuzumab treatment suppresses cell proliferation through the regulation of genes which are involved in apoptosis and damaged DNA repair including single and double strand DNA breaks. Furthermore, the study demonstrates that ²¹²Pb-trastuzumab potentiation of cell killing efficacy results from the perturbation of genes related to the mitotic spindle checkpoint and BASC (BRCA1-associated genome surveillance complex), suggesting cross-talk between DNA damage repair and the spindle damage response.
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pre clinical assessment of 177lu labeled trastuzumab targeting her2 for treatment and management of cancer patients with disseminated intraPeritoneal Disease
Pharmaceuticals, 2011Co-Authors: Geoffrey L Ray, Kwamena E. Baidoo, Martin W. Brechbiel, Paul S Albert, Lanea M M Keller, Diane E. MilenicAbstract:Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of (177)Lu was investigated. The combination of a 6.7 d half-life, lower energy β(-)-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make (177)Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-zparticle radiation. Radiolabeling trastuzumab-CHX-A"-DTPA with (177)Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraPeritoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of (177)Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered (177)Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with (177)Lu has potential for treatment of disseminated, HER2 positive, Peritoneal Disease.
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multimodality therapy potentiation of high linear energy transfer radiation with paclitaxel for the treatment of disseminated Peritoneal Disease
Clinical Cancer Research, 2008Co-Authors: Diane E. Milenic, Kwamena E. Baidoo, Kayhan Garmestani, Erik D Brady, Paul S Albert, Karen J Wong, Joseph Flynn, Martin W. BrechbielAbstract:Purpose: Studies herein explore paclitaxel enhancement of the therapeutic efficacy of α-particle-targeted radiation therapy. Experimental Design: Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 μg paclitaxel at 24 h before, concurrently, or 24 h after [ 213 Bi] or [ 212 Pb]trastuzumab. Results: Paclitaxel (300 or 600 μg) followed 24 h later with [ 213 Bi]trastuzumab (500 μCi) provided no therapeutic enhancement. Paclitaxel (300 μg) administered concurrently with [ 213 Bi]trastuzumab or [ 213 Bi]HuIgG resulted in median survival of 93 and 37 days, respectively; no difference was observed with 600 μg paclitaxel. Mice receiving just [ 213 Bi]trastuzumab or [ 213 Bi]HuIgG or left untreated had a median survival of 31, 21, and 15 days, respectively, 23 days for just either paclitaxel dose alone. Paclitaxel (300 or 600 μg) given 24 h after [ 213 Bi]trastuzumab increased median survival to 100 and 135 days, respectively. The greatest improvement in median survival (198 days) was obtained with two weekly doses of paclitaxel (600 μg) followed by [ 213 Bi]trastuzumab. Studies were also conducted investigating paclitaxel administered 24 h before, concurrently, or 24 h after [ 212 Pb]trastuzumab (10 μCi). The 300 μg paclitaxel 24 h before radioimmunotherapy (RIT) failed to provide benefit, whereas 600 μg extended the median survival from 44 to 171 days. Conclusions: These results suggest that regimens combining chemotherapeutics and high linear energy transfer (LET) RIT may have tremendous potential in the management and treatment of cancer patients. Dose dependency and administration order appear to be critical factors requiring careful investigation.
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potentiation of high let radiation by gemcitabine targeting her2 with trastuzumab to treat disseminated Peritoneal Disease
Clinical Cancer Research, 2007Co-Authors: Diane E. Milenic, Kayhan Garmestani, Erik D Brady, Paul S Albert, Joseph Flynn, Alia Abdulla, Martin W. BrechbielAbstract:Purpose: Recent studies from this laboratory with 212Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated Peritoneal Disease using 212Pb as an in vivo generator of 212Bi. The objective of the studies presented here was improvement of the efficacy of α-particle radioimmunotherapy using a chemotherapeutic agent. Experimental Design: In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by 212Pb radioimmunotherapy. Results: In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 μCi 212Pb-trastuzumab. Improvement in median survival was observed at 5 μCi 212Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 μCi versus 16 days for untreated mice ( P < 0.001). Multiple doses of gemcitabine combined with a single 212Pb radioimmunotherapy (10 μCi) administration was then evaluated. Mice received three doses of gemcitabine: one before 212Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy ( P < 0.001), specifically attributable to 212Pb-trastuzumab ( P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 μCi 212Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 μCi 212Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days ( P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before 212Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before 212Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because 212Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine). Conclusions: Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.
Rhonda K Yantiss - One of the best experts on this subject based on the ideXlab platform.
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the frontiers of appendiceal controversies mucinous neoplasms and pseudomyxoma peritonei
The American Journal of Surgical Pathology, 2021Co-Authors: Erika Hissong, Rhonda K YantissAbstract:Appendiceal mucinous neoplasms show a range of morphologic features and biological risk. At one end of the spectrum, high-grade adenocarcinomas are cytologically malignant with infiltrative invasion, lymph node metastases, and behavior similar to that of extra-appendiceal mucinous adenocarcinomas. At the other end, mucinous neoplasms confined to the mucosa are uniformly benign. Some cases lying between these extremes have potential risk to metastasize within the abdomen despite a lack of malignant histologic features. They show "diverticulum-like," pushing invasion of mostly low-grade epithelium through the appendix with, or without, concomitant organizing intra-abdominal mucin. The latter condition, widely termed "pseudomyxoma peritonei," tends to pursue a relentless course punctuated by multiple recurrences despite cytoreductive therapy, culminating in death for many patients. The combination of bland histologic features and protracted behavior of Peritoneal Disease has led some authors to question whether these metastatic tumors even represent malignancies. The World Health Organization and its cadre of experts widely promote usage of "low-grade appendiceal mucinous neoplasm" as an umbrella term to encompass benign and malignant conditions, as well as those that have uncertain biological potential. Although this practice greatly simplifies tumor classification, it causes confusion and consternation among pathologists, clinical colleagues, and patients. It also increases the likelihood that at least some patients will undergo unnecessary surveillance for, and treatment of, benign neoplasms and non-neoplastic conditions. The purpose of this review is to critically evaluate the relevant literature and discuss a practical approach to classifying appendiceal mucinous neoplasms that more closely approximates their biological risk.
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mucinous neoplasms of the appendix and peritoneum
Archives of Pathology & Laboratory Medicine, 2011Co-Authors: Nicole C Panarelli, Rhonda K YantissAbstract:Context.—Appendiceal mucinous neoplasms are considered enigmatic tumors of unpredictable biologic potential. Their importance lies in their potential to spread to the peritoneum and viscera in the form of gelatinous mucin deposits. Extra-appendiceal spread of these tumors is the most common etiology of pseudomyxoma peritonei, which is a descriptive term encompassing a number of neoplastic and nonneoplastic Peritoneal disorders. Many studies aimed at evaluating the biologic importance of appendiceal mucinous neoplasms and pseudomyxoma peritonei have employed inconsistent histologic criteria for their diagnosis and descriptive terminology for their classification. As a result, appendiceal mucinous neoplasms and associated Peritoneal Disease represents one of the most confusing and controversial areas in gastrointestinal pathology. Objectives.—To summarize the literature regarding the biologic potential of appendiceal mucinous neoplasms and pseudomyxoma peritonei and to discuss the similarities and differenc...
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prognostic significance of localized extra appendiceal mucin deposition in appendiceal mucinous neoplasms
The American Journal of Surgical Pathology, 2009Co-Authors: Rhonda K Yantiss, Jinru Shia, David S Klimstra, Hejin P Hahn, Robert D Odze, Joseph MisdrajiAbstract:Appendiceal mucinous neoplasms confined to the mucosa are benign, whereas those with disseminated Peritoneal mucin deposits often follow an indolent, but malignant, course. Not infrequently, appendiceal mucinous neoplasms are associated with localized periappendiceal mucin deposits, but lack diffuse Peritoneal involvement. Mucin deposits in these cases may be acellular or contain neoplastic epithelium (cellular mucin). Although some investigators consider both acellular and cellular periappendiceal mucin to pose no, or minimal, risk for recurrent Disease, the biologic importance of localized extra-appendiceal mucin has never been evaluated. We identified 65 patients with appendiceal mucinous neoplasms, all of whom had localized periappendiceal mucin deposits without diffuse Peritoneal involvement, and assessed them for the presence of extra-appendiceal epithelium and clinical outcome. Forty-nine (75%) appendices were submitted in total for histologic evaluation. Most (77%) cases showed acellular periappendiceal mucin, but 15 (23%) had scant extra-appendiceal epithelium (range: 1 to 12 cell clusters). Upon follow-up (mean: 48 mo), 2 (4%) patients with acellular periappendiceal mucin developed diffuse Peritoneal Disease, but neither of these appendices was submitted in total for histologic evaluation. In contrast, 5 of 15 (33%) patients with cellular periappendiceal mucin developed mucinous ascites, including 1 who eventually died of Disease (P=0.03). Thus, patients with appendiceal mucinous neoplasms and acellular periappendiceal mucin are unlikely to develop recurrent Disease. However, microscopic examination of the entire appendix is necessary, as lesions with extra-appendiceal tumor cells are more likely to progress to disseminated Disease and result in death of the patient, even if the mucin is paucicellular and confined to the periappendiceal region.
Alla Turlakow - One of the best experts on this subject based on the ideXlab platform.
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Peritoneal Carcinomatosis: Role of 18F-FDG PET
2015Co-Authors: Alla Turlakow, Steven M LarsonAbstract:Peritoneal carcinomatosis can be difficult to diagnose, as CT is insensitive, with Peritoneal biopsy and lavage often subject to problems of sampling error. The aim of our study was to eval-uate the role of 18F-FDG PET in detecting Peritoneal carcinoma-tosis in patients with stomach, ovarian, and adrenal cancer and mesothelioma and to compare the results with CT scans in the same patient group. Our secondary aim was to identify charac-teristic patterns of abdominal 18F-FDG uptake in biopsy-proven Peritoneal Disease and to correlate these patterns with available histologic and anatomic findings after surgery and structural imaging. Methods: The medical records of 88 patients with stomach (n 48), ovarian (n 13), and adrenal cancer (n 6) and mesothelioma (n 21) were reviewed for the presence of Peritoneal tumor on 18F-FDG PET and CT scans. The results were correlated with either contemporaneous Peritoneal biopsy or ascitic aspirate or with radiographic or clinical follow-up if histology was negative or unavailable. Of 24 patients with sus-pected Peritoneal tumor, 17 had biopsy-proven findings of peri-toneal Disease. Results: Of the 24 patients with suspected Peritoneal tumor, 18F-FDG PET was positive in 14 patients, with 1 of these scans being false-positive, CT was positive in 10 patients, and either PET or CT was positive in 18 patients. This yielded sensitivities of 57 % (13/23), 42 % (10/23), and 78 % (18/23), with uniformly high positive predictive values of 93 % (13/14), 100 % (10/10), and 95 % (18/19), respectively. We identified 2 distinctly abnormal scintigraphic patterns of focal and uniform 18F-FDG uptake corresponding to nodular and diffuse Peritoneal Disease on pathologic examination. Conclusion: 18F-FDG PET adds to conventional imaging in the staging of Peritoneal car-cinomatosis. It is also a useful diagnostic tool when Peritoneal biopsy is either unavailable or inappropriate. We have identified 2 distinct scintigraphic patterns that appear to predict the pres-ence of either nodular or diffuse Peritoneal pathology. Key Words: Peritoneal carcinomatosis; 18F-FDG PET; scinti-graphic pattern
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Peritoneal carcinomatosis role of 18f fdg pet
The Journal of Nuclear Medicine, 2003Co-Authors: Alla Turlakow, Henry W Yeung, Aida Sanchez Salmon, Homer A Macapinlac, Steven M LarsonAbstract:UNLABELLED: Peritoneal carcinomatosis can be difficult to diagnose, as CT is insensitive, with Peritoneal biopsy and lavage often subject to problems of sampling error. The aim of our study was to evaluate the role of (18)F-FDG PET in detecting Peritoneal carcinomatosis in patients with stomach, ovarian, and adrenal cancer and mesothelioma and to compare the results with CT scans in the same patient group. Our secondary aim was to identify characteristic patterns of abdominal (18)F-FDG uptake in biopsy-proven Peritoneal Disease and to correlate these patterns with available histologic and anatomic findings after surgery and structural imaging. METHODS: The medical records of 88 patients with stomach (n = 48), ovarian (n = 13), and adrenal cancer (n = 6) and mesothelioma (n = 21) were reviewed for the presence of Peritoneal tumor on (18)F-FDG PET and CT scans. The results were correlated with either contemporaneous Peritoneal biopsy or ascitic aspirate or with radiographic or clinical follow-up if histology was negative or unavailable. Of 24 patients with suspected Peritoneal tumor, 17 had biopsy-proven findings of Peritoneal Disease. RESULTS: Of the 24 patients with suspected Peritoneal tumor, (18)F-FDG PET was positive in 14 patients, with 1 of these scans being false-positive, CT was positive in 10 patients, and either PET or CT was positive in 18 patients. This yielded sensitivities of 57% (13/23), 42% (10/23), and 78% (18/23), with uniformly high positive predictive values of 93% (13/14), 100% (10/10), and 95% (18/19), respectively. We identified 2 distinctly abnormal scintigraphic patterns of focal and uniform (18)F-FDG uptake corresponding to nodular and diffuse Peritoneal Disease on pathologic examination. CONCLUSION: (18)F-FDG PET adds to conventional imaging in the staging of Peritoneal carcinomatosis. It is also a useful diagnostic tool when Peritoneal biopsy is either unavailable or inappropriate. We have identified 2 distinct scintigraphic patterns that appear to predict the presence of either nodular or diffuse Peritoneal pathology.
David L Morris - One of the best experts on this subject based on the ideXlab platform.
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evaluation of best supportive care and systemic chemotherapy as treatment stratified according to the retrospective Peritoneal surface Disease severity score psdss for Peritoneal carcinomatosis of colorectal origin
BMC Cancer, 2010Co-Authors: Joerg O W Pelz, Terence C Chua, Jesus Esquivel, Alexander Stojadinovic, Joerg Doerfer, David L Morris, Uwe Maeder, Christophthomas Germer, Alexander G KerscherAbstract:Background We evaluate the long-term survival of patients with Peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective Peritoneal Disease severity score (PSDSS) on outcomes.
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evaluation of best supportive care and systemic chemotherapy as treatment stratified according to the retrospective Peritoneal surface Disease severity score psdss for Peritoneal carcinomatosis of colorectal origin
BMC Cancer, 2010Co-Authors: Joerg O W Pelz, Terence C Chua, Jesus Esquivel, Alexander Stojadinovic, Joerg Doerfer, David L Morris, Uwe Maeder, Christophthomas Germer, Alexander KerscherAbstract:We evaluate the long-term survival of patients with Peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective Peritoneal Disease severity score (PSDSS) on outcomes. One hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987-2006 were identified from a prospective institutional database. These patients either received no chemotherapy, 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy. Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinically relevant factors. Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test. Median survival was 5 months (95% CI, 3-7 months) for patients who had no chemotherapy, 11 months (95% CI, 6-9 months) for patients treated with 5 FU/LV, and 12 months (95% CI, 4-20 months) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy. Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy (p = 0.026). PSDSS staging was identified as an independent predictor for survival on multivariate analysis [RR 2.8 (95%CI 1.5-5.4); p < 0.001]. A trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy. The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin.
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evaluation of preoperative computed tomography in estimating Peritoneal cancer index in colorectal Peritoneal carcinomatosis
Annals of Surgical Oncology, 2009Co-Authors: Derek Glenn, David L MorrisAbstract:Peritoneal Cancer Index (PCI) has been recognized as an independent prognostic indicator for long-term outcomes. It also influences the likelihood of complete cytoreduction, another principal determinant of long-term survival. The objective of this study was to evaluate the utility of preoperative CT in estimating PCI during the patient selection process. The efficacy of CT in demonstrating Peritoneal Disease was evaluated by comparing the radiological and intraoperative lesion size and PCI scores using the Wilcoxon signed-rank test. Tumor distribution was assessed in each abdominopelvic region as tumor present versus absent. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated in each abdominopelvic region. Overall, where CT identifies the presence of Disease, it portrayed lesion size accurately in 60%, underestimated in 33%, and overestimated in 7% of cases. Analysis of individual abdominopelvic regions demonstrated a statistically significant difference between radiologically and intraoperatively visualized lesion sizes (P < 0.05) except in the epigastrium, left upper, and left flank regions. The sensitivity of CT in detecting Peritoneal implants was influenced by lesion size. Small nodules (<0.5 cm) were visualized on CT with only a sensitivity of 11%, which is in contrast to 94% with nodules exceeding 5 cm. Radiological PCI scores significantly underestimated intraoperative PCI (P < 0.001). This study demonstrated that the sensitivity of CT in detecting Peritoneal implants was influenced by lesion size and CT PCI significantly underestimated clinical PCI. The role of CT in refining patient selection and improving prognosis remains to be closely evaluated.