Complete Response to Neoadjuvant Chemoradiation for Rectal Cancer Does Not Influence Survival

Background: Up to 30% of patients with locally advanced rectal cancer have a complete clinical or pathologic response to neoadjuvant chemoradiation. This study analyzes complete clinical and pathologic responders among a large group of rectal cancer patients treated with neoadjuvant chemoradiation.Methods: From 1987 to 2000, 141 consecutive patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative 5-fluorouracil-based chemotherapy and radiation. Clinical restaging after treatment consisted of proctoscopic examination and often computed tomography scan. One hundred forty patients then underwent operative resection, with results tracked in a database. Standard statistical methods were used to examine the outcomes of those patients with complete clinical or pathologic responses.Results: No demographic differences were detected between either clinical complete and clinical partial responders or pathologic complete and pathologic partial responders. The positive predictive value of clinical restaging was 60%, and accuracy was 82%. By use of the Kaplan-Meier life table analysis, clinical complete responders had no advantage in local recurrence, disease-free survival, or overall survival rates when compared with clinical partial responders. Pathologic complete responders also had no recurrence or survival advantage when compared with pathologic partial responders. Of the 34 pathologic T0 tumors, 4 (13%) had lymph node metastases.Conclusions: Clinical assessment of complete response to neoadjuvant chemoradiation is unreliable. Micrometastatic disease persists in a proportion of patients despite pathologic complete response. Observation or local excision for patients thought to be complete responders should be undertaken with caution.Presented in part at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.     

Selection of local therapy after neoadjuvant chemotherapy in patients with stage IIIA,B breast cancer

Background: Stage IIIA,B breast cancer is commonly treated with neoadjuvant chemotherapy because of high objective response rates and improved operability. Criteria for subsequent selection of local therapy—mastectomy, radiotherapy, or both—are not well defined. We adopted a policy of selective local therapy based on rebiopsy of the breast and clinical axillary lymph node status at the time of best response to chemotherapy. Methods: Between 1980 and 1993, 126 patients with stage IIIA,B breast cancer were treated with neoadjuvant chemotherapy and definitive local therapy. The long-term incidence of locoregional failure (in-breast, chest wall, axilla, supraclavicular, neck), relapse-free survival, and overall survival was determined. Results: The overall clinical objective response rate to chemotherapy was 95.2%. Eighty-three patients underwent mastectomy, with negative margins achieved in 91.6%. Forty-two patients had breast preservation; the overall in-breast recurrence rate was 19.0% (8 of 42 patients). The overall locoregional recurrence rate by site was: chest wall—8.7% (11 of 126 patients), axilla—8.7% (11 of 126 patients), supraclavicular—5.6% (7 of 126 patients), and neck—4.0% (5 of 126 patients). The axillary recurrence rate was 6.6% (5 of 76 patients) for clinically negative axilla treated with radiotherapy only, and 12.0% (6 of 50 patients) for clinically positive axilla treated with surgery only. The overall long-term survival probabilities (6 years) according to stage were: stage IIIA—58.0%, stage IIIB_noninflam—58.0%, stage IIIB_inflam—36.0%. Conclusions: These findings support a selective approach to local therapy in patients with stage IIIA,B breast cancer. This approach provides local control in most patients, and allows for breast preservation and elimination of axillary dissection in selected patients. Presented at the 49th Annual Cancer Symposium of the Society of Surgical Oncology, Atlanta, Georgia, March 21–24, 1996.     

Durability of giant hiatus hernia repair in 455 patients over 20 years

Introduction

The surgical management of symptomatic giant hiatus hernia (GHH) aims to improve quality of life (QoL) and reduce the risk of life threatening complications. Previous reports are predominantly those with small sample sizes and short follow-up periods. The present study sought to assess a large cohort of patients for recurrence and QoL over a longer time period.

Methods

This was a follow-up study of a prospectively collected database of 455 consecutive patients. Primary repair of GHH was evaluated by endoscopy/barium meal for recurrence and a standardised symptom questionnaire for QoL. Recurrence was assessed for size, elapsed time, oesophagitis and symptoms.

Results

Objective and subjective review was achieved in 91.9% and 68.6% of patients. The median age was 69 years (range: 15–93 years) and 64% were female. Laparoscopic repair was completed in 95% (mesh in 6% and Collis gastroplasty in 7%). The 30-day mortality rate was 0.9%. The proportion of patients alive at five and ten years were 90% and 75% respectively. Postoperative QoL scores improved from a mean of 95 to 111 (p<0.01) and were stable over time (112 at 10 years).The overall recurrence rate was 35.6% (149/418) at 42 months; this was 11.5% (48/418) for hernias >2cm and 24.2% (101/418) for <2cm. The rate of new recurrence at 0–1 years was 13.7% (>2cm = 3.4%, <2cm = 10.3%), at 1–5 years it was 30.8% (>2cm = 9.5%, <2cm = 21.3%), at 5–10 years it was 40.1% (>2cm = 13.8%, <2cm = 26.3%) and at over 10 years it was 50.0% (>2cm = 25.0%, <2cm = 25.0%). Recurrence was associated with oesophagitis but not decreased QoL. Revision surgery was required in 4.8% of cases (14.8% with recurrence). There were no interval major GHH complications.

Conclusions

Surgery has provided sustained QoL improvements irrespective of recurrence. Recurrence occurred progressively over ten years and may predispose to oesophagitis.     

腹腔镜食管裂孔疝修补术的初步探讨

目的探讨腹腔镜食管裂孔疝修补和胃底折叠术（Toupet手术）治疗食管裂孔疝的临床效果。方法 2009年1月～2010年5月,21例患者行腹腔镜食管裂孔疝（Ⅰ型9例,Ⅱ型4例,Ⅲ型6例,Ⅳ型2例）修补,采用单纯缝合膈肌脚,补片完全缝合,补片缝合加钉合等方法修补食管裂孔疝,并同期行部分胃底折叠术。结果本组患者手术均获成功,手术时间85～170min。无中转开腹及死亡病例。术后平均住院7d。术后随访1～16个月,20例临床症状完全消失,1例改善不明显,无明确复发病例。结论腹腔镜食管裂孔疝修补和胃底折叠术安全有效,应根据患者情况采用个体化的修补方式。     

Budd-Chiari syndrome: spectrum of appearances of acute, subacute, and chronic disease with magnetic resonance imaging

The purpose of this study was to describe our collective experience in the magnetic resonance (MR) investigation of patients with proven acute, subacute, and chronic Budd-Chiari syndrome and to demonstrate the spectrum of appearances on T1- and T2-weighted as well as dynamic post-gadolinium spoiled gradient-echo imaging. All patients with proven Budd-Chiari syndrome who underwent MR examinations between June, 1992 and October, 1998 were included in the study. Fourteen patients were included in the study: four with acute, three with subacute, three with chronic, and four with acute superimposed on either subacute (two) or chronic (two) Budd-Chiari syndrome. MR imaging features were retrospectively evaluated to determine: a) liver morphology, b) pattern of signal intensity (SI) on T1-weighted images, c) pattern of SI on T2 weighted images, d) dynamic enhancement characteristics, e) presence or absence of visible venous thrombosis, and f) presence or absence of venous macroscopic collaterals. The MR findings were correlated with surgical, histopathological, and laboratory data to determine imaging characteristics related to the chronicity of the disease process. Hepatic venous thrombosis or absence of hepatic venous flow was demonstrated in all patients in the study. In the four patients with acute Budd-Chiari syndrome, the liver periphery was moderately low signal on T1 and moderately high signal on T2-weighted images relative to the central liver; both early and late gadolinium-enhanced images revealed diminished peripheral enhancement. In the three patients with subacute Budd-Chiari syndrome, the liver periphery was moderately low signal on T1, and moderately high signal on T2-weighted images, while early and late gadolinium-enhanced images revealed heterogenously increased enhancement within the liver periphery. In the three patients with chronic Budd-Chiari syndrome, the SI differences between peripheral and central liver were minimal on T1- and T2-weighted images, and enhancement differences were also minimal. Extensive bridging intrahepatic and capsular venous collaterals were visualized in chronic cases. In the four patients with acute Budd-Chiari syndrome superimposed on more chronic disease, a combination of gadolinium enhancement patterns was observed on MR images. Enhancement patterns between central and peripheral liver were different for acute, subacute, and chronic Budd-Chiari syndromes, suggesting differentiation between these phases of the disease process. Application of this pattern approach permitted recognition of acute changes superimposed on more chronic disease.     

Megakaryocytopoiesis and granulopoiesis of W/Wv mice studied in long- term bone marrow cultures

Megakaryocytopoiesis and granulopoiesis of marrow cells from W/Wv mice were studied using a continuous liquid marrow culture system. Cells in the suspension phase were assayed weekly over a 16-week period for total nucleated cells, megakaryocytes, granulocytes, megakaryocytes and granulocyte-macrophage progenitor cells (CFU-Ms, CFU-GMs), and spleen colony-forming cells (CFU-Ss). Without hydrocortisone supplementation, proliferation of megakaryocytes, granulocytes, and their progenitor cells was significantly less in W/Wv cultures than in +/+ cultures. These cells became undetectable in both W/Wv and +/+ cultures at seven to 11 weeks in culture, after which only monocytes and macrophages proliferated in the cultures. Treatment of cultures with hydrocortisone improved megakaryocytopoiesis and granulopoiesis in both W/Wv and +/+ cultures. Following an initial lag phase of three to four weeks, proliferation of megakaryocytes, granulocytes, and their progenitor cells in W/Wv cultures equalled that observed in +/+ cultures and was sustained for 16 to 24 weeks. This improvement was associated with a sustained reduction in monocytes and macrophages. Despite improvements in megakaryocytopoiesis and granulopoiesis, production of macroscopic and microscopic spleen colonies by cells from W/Wv cultures remained severely reduced or absent. Studies of DNA synthesis rates of fresh marrow cells indicated that significantly fewer CFU-Ms and CFU-GMs were in cycle in W/Wv mice compared with +/+ mice. However, in hydrocortisone-treated W/Wv cultures, DNA synthesis rates of CFU-Ms and CFU-GMs increased markedly and equalled those observed for +/+ cultures. These results suggest that the improvements in megakaryocytopoiesis and granulopoiesis in hydrocortisone-treated liquid cultures is associated with a reduction in monocytes and macrophages and that progenitor cells of W/Wv mice have a proliferative defect that is correctable by hydrocortisone treatment in vitro.     

Molecular characterization of quinine/quinidine drug-dependent antibody platelet interaction using monoclonal antibodies

Two murine monoclonal antibodies, FMC 25 and AN 51, directed against distinct epitopes on the glycoprotein Ib complex, have been used to further define the mechanism of quinine/quinidine drug-dependent antibody interaction with platelets. FMC 25, directed against an epitope on glycoprotein IX, had no effect on platelet aggregation induced by collagen or adenosine diphosphate and little, if any, effect on ristocetin-induced platelet agglutination. FMC 25 and its (Fab)2 fragment, however, were potent inhibitors of drug-dependent antibody- induced platelet aggregation and blocked binding of drug-dependent antibody to platelets as assessed by indirect platelet immunofluorescence. In contrast, AN 51, directed against an epitope on the alpha-subunit of glycoprotein Ib, blocked ristocetin-induced, factor VIII/von Willebrand factor (FVIII/vWF)-dependent platelet agglutination but not drug-dependent antibody-induced platelet aggregation or binding of drug-dependent antibody to platelets. Selective proteolytic removal of the majority of the alpha-subunit of glycoprotein Ib (glycocalicin) from platelets by treatment with calcium- dependent protease did not affect binding of drug-dependent antibody. In addition, a quinidine-dependent antiplatelet antibody immunoprecipitated glycoprotein Ib complex from normal platelets and the membrane-associated proteolytic remnant of the glycoprotein Ib complex from calcium-dependent protease-treated platelets. Preincubation of drug-dependent antibody with purified glycoprotein Ib complex inhibited subsequent binding of antibody to platelets, but the separated components, glycoprotein Ib and glycoprotein IX, were both ineffective, suggesting that the normal interaction between glycoprotein Ib and glycoprotein IX in the intact complex was necessary for drug-dependent antibody recognition. The functional response of platelets to drug-dependent antibody was not mediated by way of platelet Fc receptor, since aggregation of washed platelets by acetone- aggregated IgG was not inhibited by FMC 25 (Fab)2. FVIII/vWF was not required for drug-dependent antibody-induced platelet aggregation. The combined evidence is consistent with quinine/quinidine-dependent antibody-platelet interaction occurring by way of a FVIII/vWF- independent, Fc receptor-independent mechanism that probably involves binding of antibody to glycoprotein IX or the beta-subunit of glycoprotein Ib or both.     

A phase I trial of carboxyamido-triazole and paclitaxel for relapsed solid tumors: potential efficacy of the combination and demonstration of pharmacokinetic interaction.

PURPOSE: Preclinical and clinical investigation of the combination of the antiangiogenesis/anti-invasion agent carboxyamido-triazole (CAI) administered with the cytotoxic agent paclitaxel (PAX). EXPERIMENTAL DESIGN: Colony-forming assays were used to test the activity of CAI plus PAX on A2780 human ovarian cancer. The sequence of CAI followed by PAX (CAI>Pax) was modeled in nude mice to test for potential additive toxicity. The Phase I clinical dose escalation schema tested p.o. administered CAI in PEG-400 (50-100 mg/m(2)) or micronized CAI (250 mg/m(2)) for 8 days followed by a 3-h infusion of PAX (110-250 mg/m(2)) every 21 days. Patients were assessed for toxicity, pharmacokinetics of CAI and PAX, and disease outcome. RESULTS: In preclinical studies, CAI>Pax was additive in A2780 human ovarian cancer cell lines when CAI (1 or 5 microM) preceded subtherapeutic doses of PAX. CAI did not reverse PAX resistance and collateral resistance to CAI was documented in PAX-resistant cells. CAI>PAX administration had no overt additive toxicity in nude mice. Thirty-nine patients were treated on a dose-escalation Phase I trial using daily oral CAI for 8 days followed by the PAX infusion. Pharmacokinetic analysis revealed that PAX caused an acute increase in circulating CAI concentrations in a dose-dependent fashion. No additive or cumulative toxicity was observed, and grade 3 nonhematological toxicity was rare. Three partial responses and two minor responses were observed. CONCLUSIONS: The sequential combination of CAI and PAX is well tolerated, and the activity observed suggests that further study of the combination is warranted.