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ABSTRACT: Complete surgical cytoreduction of peritoneal implants and immediate intraperitoneal (lP) chemotherapy offers the greatest survival in selected patients with peritoneal carcinomatosis. This study was undertaken to describe the metabolism and pharmacokinetics of normothermic intraperitoneal CPT-11, free and glucuronized SN-38, in a pig model. Thirteen pigs were used for experimentation. Animals were grouped for IV and IP CPT-1 1 administration. Eleven pigs underwent laparotomy through a midline incision and instillation of 100, 200, and 400mg IP CPT-11. Systemic venous blood, portal blood and peritoneal fluid samples were taken at 5, 10, 20, 30, and 45 min, then every hour up to 8 hr for the 100 mg. For the three groups, peritoneal CPT-11 exposition was on average 4.9 times greater in the peritoneum than in the systemic venous or portal circulations and the systemic CPT-11 fraction absorbed from the peritoneum linearly increased with time. Free SN-38 was measurable in the earliest peritoneal samples taken. The initial instillation dose of CPT-11 did not impact on the SN-38 converted fraction, which remained stable at approximately 0.04% during the first 4 hour. Mean peritoneal SN-38: CPT-11 AUC ratio was 0.043. OPT-11 peritoneal conversion into SN-38 appeared slightly Inferior to the systemic conversion ratio. This norrnothermic IP OPT-11 pharmacokinetic study performed in a pig model confirms the possibility to achieve at least a 30 times higher peritoneal than systemic exposure. Peritoneal exposure to active SN-38 begins at the moment of CPT-11 peritoneal instillation. A fixed and small traction of less than 0.1% of CPT-11 is converted into SN-38, underlying the importance of a sufficient initial IP dose of CPT-11.
Journal of Surgical Oncology 06/2010; 101(7):637-42. · 2.10 Impact Factor
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ABSTRACT: Complete surgical cytoreduction of peritoneal implants and immediate intraperitoneal (lP) chemotherapy offers the greatest survival in selected patients with peritoneal carcinomatosis. This study was undertaken to describe the metabolism and pharmacokinetics of normothermic intraperitoneal CPT-11, free and glucuronized SN-38, in a pig model. Thirteen pigs were used for experimentation. Animals were grouped for IV and IP CPT-1 1 administration. Eleven pigs underwent laparotomy through a midline incision and instillation of 100, 200, and 400mg IP CPT-11. Systemic venous blood, portal blood and peritoneal fluid samples were taken at 5, 10, 20, 30, and 45 min, then every hour up to 8 hr for the 100 mg. For the three groups, peritoneal CPT-11 exposition was on average 4.9 times greater in the peritoneum than in the systemic venous or portal circulations and the systemic CPT-11 fraction absorbed from the peritoneum linearly increased with time. Free SN-38 was measurable in the earliest peritoneal samples taken. The initial instillation dose of CPT-11 did not impact on the SN-38 converted fraction, which remained stable at approximately 0.04% during the first 4 hour. Mean peritoneal SN-38: CPT-11 AUC ratio was 0.043. OPT-11 peritoneal conversion into SN-38 appeared slightly Inferior to the systemic conversion ratio. This norrnothermic IP OPT-11 pharmacokinetic study performed in a pig model confirms the possibility to achieve at least a 30 times higher peritoneal than systemic exposure. Peritoneal exposure to active SN-38 begins at the moment of CPT-11 peritoneal instillation. A fixed and small traction of less than 0.1% of CPT-11 is converted into SN-38, underlying the importance of a sufficient initial IP dose of CPT-11. J. Surg. Oncol. 2010; 101:637–642. © 2010 Wiley-Liss, Inc.
Journal of Surgical Oncology 05/2010; 101(7):637 - 642. · 2.10 Impact Factor
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Rami Younan,
A Bougrine,
K Watters,
A Mahboubi,
M Bouchereau-Eyegue,
A Loutfi,
F Tremblay,
D Bouffard,
A Belisle,
G Leblanc,
E Nassif,
G Martin,
E Patocskai,
M Alenezi,
S Meterissian
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ABSTRACT: Standard of care is to perform a complete lymph node dissection (CLND) in melanoma patients with positive sentinel lymph nodes (SLNs). However, less than 20% will have metastases in non-SLNs. The S classification was described to predict the non-SLN status, hoping to identify a subset of patients who can be spared the CLND. We tried to validate the feasibility and usefulness of this classification.
We performed a retrospective chart review. All melanoma cases between 1996 and 2006 were included, and 359 patients with SLN biopsies were identified. All pathology slides were reviewed with an emphasis on the S classification.
There were 365 SLN biopsies performed. A total of 82 patients (22.8%) had positive SLNs, while 277 patients (77.2%) had negative SLNs. There were 22 patients classified as SI, 18 as SII, 37 as SIII, and 5 were unclassified. On CLND, only 10 patients (12.2%) had positive non-SLNs. None of these were classified as SI while 2 patients (11%) were classified as SII and 8 (22%) as SIII. The S category was found to be a predictor of non-SLN status, and this reached statistical significance (P = 0.044). On univariate analysis, only an increasing Breslow depth and ulceration were predictive of a non-SI status.
Our results suggest that the S classification is easily feasible and predicts the status of non-SLNs. No patient with SI status was found to have additional non-SLN positive nodes. A larger-scale, prospective trial should be done to confirm these results and possibly spare patients the morbidity of CLND with a positive SLN.
Annals of Surgical Oncology 05/2010; 17(5):1414-21. · 4.17 Impact Factor
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Canadian journal of surgery. Journal canadien de chirurgie 10/2009; 52(5):E197-8. · 1.05 Impact Factor
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ABSTRACT: At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on technical aspects of cytoreductive surgery (CRS) for peritoneal surface malignancy was obtained through the Delphi process. Five conflicting points were discussed: radicality of the peritonectomy procedure, cytoreduction of neoplastic nodules <2.5 mm, the timing of bowel anastomoses in relation to hyperthermic intraperitoneal chemotherapy (HIPEC) and indications of protective ostomies. According to the panel of experts a partial parietal peritonectomy restricted to the macroscopically involved regions could be indicated in all listed clinical conditions with the exception of peritoneal mesothelioma. No expert was of the opinion that a radical parietal peritonectomy is advisable irrespective of the disease being treated. All the experts agreed that electrovaporization of small (<2.5 mm) non-infiltrating metastatic nodules in the mesentery would be appropriate, even if theoretically the HIPEC affords microscopic cytoreduction. The panel also agreed that in the closed technique for HIPEC administration the intestinal anastomoses should be fashioned after completion of the perfusion. Finally when considering the place for protective ostomies the experts voted for a flexible approach allowing the surgeon to exercise discretion for individual patients.
Journal of Surgical Oncology 10/2008; 98(4):232-6. · 2.10 Impact Factor
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ABSTRACT: At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on technical aspects of cytoreductive surgery (CRS) for peritoneal surface malignancy was obtained through the Delphi process. Conflicting points concerning drugs, carrier solution and optimal temperature for hyperthermic intraperitoneal chemotherapy (HIPEC) were discussed.
Journal of Surgical Oncology 10/2008; 98(4):247-52. · 2.10 Impact Factor
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ABSTRACT: To reach a consensus for reporting complications related to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Reporting the adverse events related to CRS + HIPEC is not standardized yet. Post-operative complications can be divided in two categories: the effects of surgical manipulation per se and the toxic effects of the heated intraoperative chemotherapy. Additive and/or synergistic effects also exist. Different centers have published their experience with regard to the complications associated with the procedure. Various classification systems have been used which makes a temptative comparison of the different techniques and results almost impossible. An effort was made here to review the existing major classification systems: The Bozzetti classification, the Clavien classification (and two proposed modifications from Feldman et al. and Elias et al.) and the Common terminology criteria for adverse events (CTCAE) version 3.0 of the National Institute of Health (NIH) criteria. A related document was sent to an international panel of experts. The CTCAE was adopted by the panel of experts as the unique classification system to be used for reporting complications related to CRS + HIPEC.
Journal of Surgical Oncology 10/2008; 98(4):253-7. · 2.10 Impact Factor
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ABSTRACT: At the Fifth International Workshop on Peritoneal Surface Malignancy (PSM), held in Milan, December 2006, the consensus on technical aspects of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was obtained through the Delphi process. The following topics were discussed: pre-operative workup; eligibility to CRS + HIPEC; intra-operative staging system; technical aspects of surgery; residual disease classification systems; HIPEC: nomenclature and modalities; drugs, carrier solution and optimal temperature; morbidity grading systems. Conflicting points regarding above-mentioned topics were elaborated and voted in two rounds by a panel of international experts in local-regional therapy. The purpose of this manuscript is to describe the organization and the methodology of the consensus statements and to interpret and discuss the implications of the most striking results.
Journal of Surgical Oncology 10/2008; 98(4):217-9. · 2.10 Impact Factor
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ABSTRACT: The purpose of this study was to analyze the postoperative pancreatic morbidity of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal surface malignancies (PSM).
Two hundred and sixty five patients (87M/178F) with PSM underwent 270 consecutive procedures. The mean age was 52 years (range: 22-79 years). CRS was performed using peritonectomy procedures. HIPEC through the closed abdomen technique was conducted using cisplatin (CDDP 25 mg/m2/L of perfusate)+mitomycin C (MMC 3.3 mg/m2/L of perfusate) or CDDP (43 mg/L of perfusate)+doxorubicin (Dx 15.25 mg/L of perfusate), at 42.5 degrees C. Diagnosis and classification of postoperative pancreatic fistula (POPF) were performed according to the international study group on pancreatic fistula criteria. Serum amylase alterations were graded according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) v3.
POPF was observed in 13 (4.8%) cases. Three cases were classified as major (grade C). Two cases presented postoperative pancreatitis. G3-4 alteration of amylase was observed in 12.3% of the cases. Performing splenectomy and CDDP dosage for HIPEC >240 mg were proven to be independent risk factors for both G3-4 hyperamylasemia and POPF.
CRS+HIPEC presented an acceptable rate of pancreatic morbidity which did not contribute to the mortality related to the procedure. Most of the POPF were mild and/or easily controlled by conservative measures. Although not specific a normal amylasemia could be a useful marker of pancreatic integrity after CRS+HIPEC.
Annals of Surgical Oncology 01/2008; 14(12):3443-52. · 4.17 Impact Factor
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ABSTRACT: The purpose of this study was to analyze the postoperative systemic toxicity and procedure-related mortality (PRM) of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal surface malignancies (PSMs).
A total of 242 (84 males/158 females) patients with PSM underwent 247 consecutive procedures. The mean age was 52 years (range 22-79). CRS was performed using peritonectomy procedures. The HIPEC technique through the closed abdomen was conducted with cisplatin (CDDP 25 mg/m(2)/l of perfusate)+mitomycin C (MMC 3.3 mg/m(2)/l perfusate) or CDDP (43 mg/l perfusate)+doxorubicin (Dx 15.25 mg/l perfusate) at 42.5 degrees C. These dosages were reduced by 30% when the patient had received systemic chemotherapy before the CRS+HIPEC. Systemic toxicities were graded according to the NCI CTCAE v3 criteria.
G3-5 systemic toxicity rate was 11.7 % and adverse events were bone marrow suppression, 13; nephrotoxicity, 14; neutropenic infection, 2 and pulmonary toxicity, 1. Independent risk factors for G3-5 systemic toxicity after multivariate analysis were a dose of CDDP for HIPEC of 240 mg or more (OR 2.78, CI 95% 1.20-6.45) and CDDP+Dx schedule for HIPEC (OR 2.36, CI 95% 1.02-5.45). PRM was 1.2%.
CRS+HIPEC presented acceptable systemic toxicity and PRM rates. Independent risk factors for systemic toxicity were the CDDP+Dx schedule and CDDP dose for HIPEC.
Annals of Surgical Oncology 10/2007; 14(9):2550-8. · 4.17 Impact Factor
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ABSTRACT: A relatively high frequency of germ-line genomic rearrangements in MLH1 and MSH2 has been reported among Lynch Syndrome (HNPCC) patients from different ethnic populations. To investigate the underlying molecular mechanisms, we characterized the DNA breakpoints of 11 germ-line deletions, six for MLH1 and five for MSH2. Distinct deletion patterns were found for the two genes. The five cases of MSH2 deletions result exclusively from intragenic unequal recombination mediated by repetitive Alu sequences. In contrast, five out of the six MLH1 deletions are due to recombinations involving sequences of no significant homology (P=0.015). A detailed analysis of the DNA breakpoints in the two genes, previously characterized by other groups, validated the observation that Alu-mediated unequal recombination is the main type of deletion in MSH2 (n=34), but not in MLH1 (n=21) (P<0.0001). Plotting the distribution of known DNA breakpoints among the introns of the two genes showed that, the highest breakpoint density is co-localized with the highest Alu density. Our study suggests that Alu is a promoting factor for the genomic recombinations in both MLH1 and MSH2, and the local Alu density may be involved in shaping the deletion pattern.
Human Mutation 04/2006; 27(4):388. · 5.69 Impact Factor
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ABSTRACT: The purpose of this prospective Phase II study was to analyze morbidity and mortality of cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP) in the treatment of peritoneal surface malignancies.
A total of 205 patients (50 with peritoneal mesothelioma, 49 with pseudomyxoma peritonei, 41 with ovarian cancer, 32 with abdominal sarcomatosis, 13 with colon cancer, 12 with gastric cancer, and 8 with carcinomatosis from other origins) underwent 209 consecutive procedures. Four patients underwent the intervention twice because of disease relapse. There were 70 men and 135 women. Mean age was 52 years (range, 22-76 yrs). CRS was performed by using peritonectomy procedures. IPHP through the closed abdomen technique was conducted with a preheated (42.5 degrees C) perfusate containing cisplatin + mitomycin C or cisplatin + doxorubicin.
Major morbidity rate was 12%. The most significant complications were 23 anastomotic leaks or bowel perforations, 4 abdominal bleeds, and 4 sepses. Operative mortality rate was 0.9%. On logistic regression model multivariate analysis, extent of cytoreduction (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.29-6.40) and dose of cisplatin for IPHP > or = 240 mg (OR, 3.13; 95% CI, 1.24-7.90) were independent risk factors for major morbidity. Ten patients presented with Grade 3 to 4 toxicity.
CRS + IPHP presented acceptable morbidity, toxicity, and mortality rates, all of which support prospective Phase III clinical trials.
Cancer 03/2006; 106(5):1144-53. · 4.77 Impact Factor
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ABSTRACT: Diffuse malignant peritoneal mesothelioma (DMPM) is a subset of peritoneal mesothelioma with a poor clinical outcome. We performed a prognostic analysis in a cohort of DMPM patients treated homogeneously by cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP).
Forty-nine DMPM patients who underwent 52 consecutive procedures were enrolled onto the study. Cytoreductive surgery was performed according to the peritonectomy technique, and the IPHP was performed with cisplatin plus doxorubicin or cisplatin plus mitomycin C. We assessed the correlation of the clinicopathologic variables (previous surgical score, age, sex, performance status, previous systemic chemotherapy, carcinomatosis extension, completeness of cytoreduction, IPHP drug schedule, mitotic count [MC], nuclear grade, and biological markers [epidermal growth factor receptor, p16, matrix metalloproteinase 2 and matrix metalloproteinase 9]) with overall and progression-free survival.
The mean age was 52 years (range, 22-74 years). The mean follow-up was 20.3 months (range, 1-89 months). Regarding the biological markers, the rates of immunoreactivity of epidermal growth factor receptor, p16, matrix metalloproteinase 2, and matrix metalloproteinase 9 were 94%, 60%, 100%, and 85%, respectively. The strongest factors influencing overall survival were completeness of cytoreduction and MC, whereas those for progression-free survival were performance status and MC. No biological markers were shown to be of prognostic value.
Completeness of cytoreduction, performance status, and MC seem to be the best determinants of outcome. These data warrant confirmation by a further prospective formal trial. No biological markers presented a significant correlation with the outcome. The overexpression of epidermal growth factor receptor, matrix metalloproteinase 2, and matrix metalloproteinase 9 and absent or reduced expression of p16 might be related to the underlining tumor kinetics of DMPM and warrant further investigation with other methods.
Annals of Surgical Oncology 03/2006; 13(2):229-37. · 4.17 Impact Factor
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ABSTRACT: In the current study, the authors report the clinicopathologic features of patients with peritoneal diffuse malignant mesothelioma (DMM) who were treated in a uniform fashion at a single institution to assess prognostic factors.
Thirty-five patients were treated with cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The tumors were classified into epithelial, sarcomatoid, and biphasic types. Immunohistochemistry stains were performed for calretinin, WT-1, pCEA, Ber-EP4, epidermal growth factor receptor (EGFR), p16, matrix metalloprotease-2 (MMP-2), and MMP-9. Statistical correlation was evaluated for age, gender, completeness of cytoreduction (CC), tumor histotype, mitotic count (MC), necrosis, nuclear grade (NG), and biologic markers with regard to overall survival (OS) and progression-free survival (PFS).
The patient group was comprised of 15 men and 20 women with a median age of 52 years (range, 24-73 yrs). Twenty-five patients underwent optimal cytoreduction. There were 32 epithelial tumors and 3 biphasic tumors, and 3 patients had an NG of 1, 19 had an NG of 2, and 13 had an NG of 3. The mean MC was 14.1 (range, 0-160 per 50 high-power fields). Necrosis was present in 11 cases. All the tumors were found to be positive for calretinin and WT-1 and were negative for pCEA and Ber-EP4. The NG and MC were found to be significantly associated with OS (P = 0.02 and P = 0.01, respectively) whereas CC was found to be associated with both OS (P = 0.05) and PFS (P = 0.03). No biologic markers were found to be of prognostic significance.
The results of the current study indicate that NG, MC, and CC may be useful prognostic factors in patients treated with CRS and IPHP. The expression of EGFR, MMP-2, and MMP-9 and absent and/or reduced expression of p16 in DMMs confirms the results of previous studies suggesting their role in tumor pathogenesis and kinetics.
Cancer 12/2005; 104(10):2181-8. · 4.77 Impact Factor
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Daisuke Nonaka M.D,
Shigeki Kusamura M.D,
Dario Baratti M.D,
Paolo Casali M.D,
Antonello Domenico Cabras M.D,
Rami Younan M.D,
Juan Rosai M.D,
Marcello Deraco M.D,
Daisuke Nonaka,
Shigeki Kusamura,
Dario Baratti,
Paolo Casali,
Antonello Domenico Cabras, Rami Younan,
Juan Rosai,
Marcello Deraco
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ABSTRACT: BACKGROUND
In the current study, the authors report the clinicopathologic features of patients with peritoneal diffuse malignant mesothelioma (DMM) who were treated in a uniform fashion at a single institution to assess prognostic factors.METHODS
Thirty-five patients were treated with cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The tumors were classified into epithelial, sarcomatoid, and biphasic types. Immunohistochemistry stains were performed for calretinin, WT-1, pCEA, Ber-EP4, epidermal growth factor receptor (EGFR), p16, matrix metalloprotease-2 (MMP-2), and MMP-9. Statistical correlation was evaluated for age, gender, completeness of cytoreduction (CC), tumor histotype, mitotic count (MC), necrosis, nuclear grade (NG), and biologic markers with regard to overall survival (OS) and progression-free survival (PFS).RESULTSThe patient group was comprised of 15 men and 20 women with a median age of 52 years (range, 24–73 yrs). Twenty-five patients underwent optimal cytoreduction. There were 32 epithelial tumors and 3 biphasic tumors, and 3 patients had an NG of 1, 19 had an NG of 2, and 13 had an NG of 3. The mean MC was 14.1 (range, 0–160 per 50 high-power fields). Necrosis was present in 11 cases. All the tumors were found to be positive for calretinin and WT-1 and were negative for pCEA and Ber-EP4. The NG and MC were found to be significantly associated with OS (P = 0.02 and P = 0.01, respectively) whereas CC was found to be associated with both OS (P = 0.05) and PFS (P = 0.03). No biologic markers were found to be of prognostic significance.CONCLUSIONS
The results of the current study indicate that NG, MC, and CC may be useful prognostic factors in patients treated with CRS and IPHP. The expression of EGFR, MMP-2, and MMP-9 and absent and/or reduced expression of p16 in DMMs confirms the results of previous studies suggesting their role in tumor pathogenesis and kinetics. Cancer 2005. © 2005 American Cancer Society.
Cancer 11/2005; 104(10):2181 - 2188. · 4.77 Impact Factor
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ABSTRACT: Peritonectomy and intraperitoneal hyperthermic perfusion (IPHP) are increasingly used in the management of carcinomatosis of various sites of origin. We analyzed the risk factors for bowel complications with primary anastomoses and the closed technique for IPHP.
From 1995 to 2004, 203 consecutive procedures were performed at the National Cancer Institute of Milan. We retrospectively analyzed this series of patients. Treated pathologies included peritoneal mesothelioma; pseudomyxoma peritonei; colorectal, ovarian, or gastric carcinomatosis; and abdominal sarcomatosis. All digestive anastomoses were performed before the IPHP. Only one defunctioning stoma was used.
We found a bowel complication rate of 10.8%. The bowel complications:anastomoses ratio was 11.3%. On univariate analysis we found a statistically significant association between bowel complications and the following variables: sex, previous systemic chemotherapy status, number of anastomoses ( fewer than two vs. two or more), duration of the procedure (<8.7 vs. >or=8.7 hours), and extent of cytoreduction. After multivariate analysis, male sex (odds ratio [OR], 4.2), no previous systemic chemotherapy (OR, 3.5), and duration of the procedure >or=8.7 hours (OR, 6.3) were considered independent risk factors for bowel complications.
Bowel complications are not increased when primary unprotected anastomoses are performed during peritonectomy and IPHP when the closed technique is used. Male sex, duration of the procedure, and no previous systemic chemotherapy are independent unfavorable risk factors.
Annals of Surgical Oncology 11/2005; 12(11):910-8. · 4.17 Impact Factor
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ABSTRACT: An alternative to completion thyroidectomy for well-differentiated thyroid carcinoma is to ablate the remnant lobe with 131 I. The purpose of this study is to review our own experience with large remnant ablation.
A retrospective review of 169 patients with well-differentiated thyroid cancer treated at one institution over a 14-year period was undertaken. Seventy-one patients who underwent partial thyroidectomy (PT) followed by 131 I ablation were identified. This group was compared to 98 patients treated with total thyroidectomy (TT).
Mean follow-up was 6.2 years for the 71 PT + 131 I versus 4.7 years for the 98 TT patients (P = .184). Recurrence occurred in 4 of 71 PT + I 131 patients (5.6%) versus 9 of 98 TT patients (9.2%) (P = .393). Other than a tendency for the size of the primary to be slightly larger and for the histology to be follicular carcinoma in the PT + 131 I patients, the 2 groups were nearly identical in age, gender, and other prognostic factors such as capsular invasion and metastases.
Large-dose ablation with 131 I is a viable alternative to completion thyroidectomy. Recurrence rates over an average 6-year period are similar to TT. Long-term monitoring of these cohorts is required.
Surgery 01/2005; 136(6):1275-80. · 3.10 Impact Factor
