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Results for “Pathologic response”

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PubMed2005

Pulmonary resection after high-dose and low-dose chest irradiation.

BACKGROUND: The purpose of this study is to assess the safety and efficacy of pulmonary resection after low and high dose neoadjuvant radiotherapy with concurrent chemotherapy. PATIENTS AND METHODS: A retrospective cohort study using an electronic prospective database from January 1998 to August 2004. All patients had N2, stage IIIa, nonsmall cell lung cancer, and received neoadjuvant carboplatinum-based chemotherapy with similar doses. In addition, some patients received high-dose chest radiation (HD) equal to or greater than 60 Gy and were compared with those who received low-dose radiation (LD) less than 60 Gy. All bronchial stumps were buttressed with an intercostal muscle. RESULTS: There were 104 patients, 50 in the LD group and 54 patients in the HD group. Median dose of radiation was 45 Gy (range 35-50.4) in the LD group and 60 Gy (range 60-66.7) in the HD group. Complete pathologic response rate was 10% compared to 28% favoring the HD group (p = 0.04). Median length of stay for both groups was 4 days and the ICU was avoided in 74%. Major morbidity and mortality rates were similar: 8% compared to 9% and 2% compared to 3.7% for the low and high dose groups, respectively. Pneumonectomy was a significant risk factor for morbidity (OR = 17.0). CONCLUSIONS: Pulmonary resection after preoperative chest radiation is safe even after 60 Gy or higher. Sixty or higher may afford an increase in complete pathologic response and it does not seem to increase morbidity or mortality. However, if pneumonectomy is known to be required we prefer to avoid neoadjuvant radiotherapy and use chemotherapy alone.

Adult↗

PubMed2003

Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer.

Simultaneous chemoradiation is used in unresectable pancreatic cancer for palliation. It is not known if the use of adjuvant surgery will benefit this group of patients. From November 1991 to September 1998, 47 patients with unresectable pancreatic cancer were treated with simultaneous preoperative radiation therapy (45 Gy) and chemotherapy. Chemotherapy followed three different protocols: cisplatin, 5-fluorouracil +/- paclitaxel; cisplatin, 5-fluorouracil (protracted infusion); and docetaxel and gemcitabine. Whipple pancreatoduodenectomy was performed 1 month after the end of radiation in patients selected for resection. Twenty-three unresectable tumors after preoperative treatment (47%) received an additional dose (10-12 Gy) of radiotherapy using intraoperative or external radiation therapy. Twelve patients (26%) were considered to have clinically resectable tumors after the preoperative treatment. Nine patients had surgery (19% of the total number of patients), and 2 of them had complete pathologic response. After chemoradiation, two patients died of pneumonia and gastrointestinal bleeding, respectively, and another two patients died in the postoperative period. Local recurrence was observed in 22% of the patients and 57% had distant metastases. Three-year survival rates for patients with unresectable and resectable tumors was 0% (median survival 10 months) and 48% (median survival 23 months), respectively (p = 0.0004). Preoperative treatment with chemotherapy and radiotherapy in patients with unresectable pancreatic cancer is feasible. In some patients, the tumor can be resected, and in addition some cases of complete pathologic response were found. Long-term survivors were observed in the group of resected tumors. More effective chemotherapy regimens are needed because the majority of the patients died of metastatic disease.

Adenocarcinoma↗

PubMed2003

Multimodality treatment for esophageal cancer: the role of surgery and neoadjuvant therapy.

Treatment of esophageal cancer has traditionally included surgery as the initial modality. Neoadjuvant chemoradiation therapy has been introduced with the goal of downstaging tumors before surgical resection; however, its role in esophageal cancer remains controversial. We report 116 patients who underwent esophagogastrectomy with reconstruction for carcinoma of the esophagus or esophagogastric junction over a 10-year period (January 1, 1990 to June 1, 2001). Forty patients underwent neoadjuvant radiation and chemotherapy followed by surgery. Hospital mortality in this group was 7.5 per cent, complete pathologic response (CPR) was 37.5 per cent, and overall 3- and 5-year survival rates were 47 and 38 per cent. Five-year survival in the 15 patients with CPR was 85 per cent. Five patients underwent neoadjuvant single-agent therapy (four chemotherapy and one radiation) followed by surgery, and none survived to 3 years. Seventy-one patients underwent surgery without neoadjuvant therapy. Hospital mortality in this group was 1.4 per cent, with 3- and 5-year survival of 21 and 17 per cent--a decreased long-term survival compared with the neoadjuvant therapy group despite the observation that patients who underwent neoadjuvant therapy had a larger tumor size on presentation (5.5 +/- 0.4 cm vs 3.8 +/- 0.2 cm; P = 0.002). Squamous cell carcinomas seemed to be more responsive to neoadjuvant radiation and chemotherapy followed by surgery than were adenocarcinomas, with a CPR of 44.4 versus 35.5 per cent; however, 5-year survival rates in these complete responders were not significantly different (100% and 78%, respectively; P = 0.97). We report that esophagogastrectomy in conjunction with neoadjuvant therapy results in increased survival compared with surgery without neoadjuvant therapy (P < 0.01), although there may be an increased perioperative mortality associated with neoadjuvant therapy. Further studies are needed to evaluate the role of preoperative chemoradiation and to better identify the pretreatment characteristics of patients with a complete pathological response.

Adenocarcinoma↗

PubMed2000

Charge alterations of E22 enhance the pathogenic properties of the amyloid beta-protein.

Cerebral amyloid angiopathy (CAA) due to amyloid beta-protein (Abeta) is a key pathological feature of patients with Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D). The CAA in these disorders is characterized by deposition of Abeta in the smooth muscle cells within the cerebral vessel wall. Recently, a new mutation in Abeta, E22K, was identified in several Italian families that, like HCHWA-D, is associated with CAA and hemorrhagic stroke. These two similar disorders, stemming from amino acid substitutions at position 22 of Abeta, implicate the importance of this site in the pathology of HCHWA. Previously we showed that HCHWA-D Abeta(1-40) containing the E22Q substitution induces robust pathologic responses in cultured human cerebrovascular smooth muscle cells (HCSM cells), including highly elevated levels of cell-associated Abeta precursor (AbetaPP) and cell death. In the present study, a series of E22 mutant Abeta(1-40) peptides were synthesized, and their pathogenic properties toward cultured HCSM cells were evaluated. Quantitative fluorescence analyses showed that mutant Abeta(1-40) peptides either containing a loss of charge (E22Q and E22A) or a change of charge (E22K) bind to the surface of HCSM cells and form amyloid fibrils. Similarly, this same group of E22 mutant Abeta(1-40) peptides caused enhanced pathologic responses in HCSM cells. In contrast, wild-type E22 or the charge-preserving E22D Abeta(1-40) peptides were devoid of any of these pathogenic properties. These data suggest that a change or loss of charge at position 22 of Abeta enhances the pathogenic effects of the peptide toward HCSM cells and may contribute to the pathogenesis of the phenotypically related HCHWA disorders.

Amino Acid Substitution↗

PubMedDate not supplied

Serial endoscopic ultrasound in the assessment of response to chemoradiotherapy for carcinoma of the esophagus.

The aim of the study was to assess whether endoscopic ultrasound (EUS) could accurately measure the locoregional response to chemoradiotherapy in patients with carcinoma of the esophagus. Seventeen patients with esophageal carcinoma underwent EUS examination before and on completion of chemoradiotherapy. The EUS findings were correlated with the results of histologic examination of the esophagectomy specimen. The accuracy of EUS in these patients was compared with the accuracy of EUS in a control group of 17 patients treated by surgery alone. In 16 of 17 patients EUS-determined tumor (T) stage was unchanged following treatment and in one patient there was T-stage progression. No patient demonstrated downstaging of the primary tumor according to classical EUS criteria. In 10 of 17 patients a reduction in maximum tumor depth of >/=2 mm was observed (range 2 to 18 mm). Histologic examination revealed that four patients with squamous cell carcinoma had experienced a complete pathologic response. These four patients had significantly lower posttreatment EUS tumor depths compared to patients without a complete response (5.0 vs. 9.0 mm; P <0.05). Based on the post-treatment EUS examination, the accuracy was 59% for T stage and 59&percnt for node (N) stage. The accuracy of EUS in patients treated by surgery alone was 94% for T stage and 94% for N stage, indicating a significant reduction in the accuracy of EUS in patients following chemoradiotherapy (P <0.05). The accuracy of EUS examination in patients with carcinoma of the esophagus treated by chemoradiotherapy was poor. EUS did not detect downstaging of the primary tumor, even in the presence of a complete pathologic response. EUS assessment of maximum tumor depth was a better measure of response to therapy.

Adenocarcinoma↗

PubMed2001

Neoadjuvant therapy for adenocarcinoma of the rectum: tumor response and acute toxicity.

PURPOSE: This study was designed to evaluate the down-staging effect and acute toxicity of preoperative radiation and chemoradiation for primary adenocarcinoma of the rectum. METHODS: The results of pretreatment staging with transrectal ultrasound and computed tomography were compared with final histologic stage in 260 consecutive patients who underwent neoadjuvant therapy and proctectomy for primary adenocarcinoma of the rectum. Patients underwent short-course radiation (2,000 cGy in five fractions), long-course radiation (4,500 cGy in 25 fractions), or chemoradiation (4,500 cGy in 25 fractions with concurrent chemotherapy). RESULTS: Down-staging of one or more T stages occurred in 116 of 260 (45 percent) patients overall (short-course radiation 34/82 (42 percent), long-course radiation 55/122 (45 percent), chemoradiation 27/56 (48 percent), P = not significant). Down-staging of one or more N stages occurred in 85 of 178 (48 percent) patients overall (short-course radiation 12/45 (27 percent), long-course radiation 49/86 (57 percent), chemoradiation 24/47 (51 percent), P = 0.003). Complete pathologic response was observed in 16 of 260 (6 percent) patients overall (short-course radiation 4/82 (5 percent), long-course radiation 5/122 (4 percent), chemoradiation 7/56 (13 percent), P = 0.08). Resection with negative margins (distal, proximal, and radial) was achieved in 211 of 227 patients (93 percent) in whom complete radial margin data were available. Permanent stomas were created in 35 percent of patients; temporary stomas were created in 15 percent. Thirty-three Grade 3 or 4 toxicities occurred in 22 of 260 (8 percent) patients overall during neoadjuvant therapy. Toxicity was more frequent in patients receiving chemoradiation (14/56; 25 percent) and long-course radiation (8/122; 7 percent) than in those receiving short-course radiation (0/82; 0 percent), P < 0.0001. Perioperative complications occurred in 93 patients overall (36 percent). The postoperative mortality rate was 0.4 percent (1/260). There was no significant difference in the complication rate between patients treated with short-course radiation (26/82; 32 percent), long-course radiation (46/122; 36 percent), and chemoradiation (21/56; 38 percent). CONCLUSION: Neoadjuvant therapy for adenocarcinoma of the rectum is well tolerated and can produce substantial down-staging and a high curative resection rate. Chemoradiation can achieve high complete pathologic response rates, although toxicity during neoadjuvant therapy is greater than for radiation alone. Short-course radiation can achieve down-staging of both T stage and N stage.

Adenocarcinoma↗

PubMed2004

Results of a planned interim toxicity analysis with trimodality therapy, including carboplatin AUC = 4, paclitaxel, 5-fluorouracil, amifostine, and radiation for locally advanced esophageal cancer: preliminary analyses and treatment recommendations from the North Central Cancer Treatment Group.

PURPOSE: An aggressive trimodality approach from the Minnie Pearl Cancer Research Network [carboplatin AUC = 6, days 1 and 22; 5-fluorouracil 225 mg/m2 continuous infusion, days 1-42, paclitaxel 200 mg/m2, days 1 and 22; 45 Gy] has resulted in remarkable pathologic response rates but notable toxicity. This trial was designed to mitigate this toxicity by starting with a lower carboplatin dose, AUC = 4, and by adding subcutaneous amifostine. METHODS: This phase II trial included patients with locally advanced, potentially resectable esophageal cancer. All were to receive the above regimen with modifications of carboplatin AUC = 4 and amifostine 500 mg subcutaneously before radiation. All were then to undergo an esophagectomy. A planned interim toxicity analysis after the first 10 patients was to determine whether the carboplatin dose should escalate to AUC = 6. RESULTS: Ten patients were enrolled, and all required dose reductions/omissions during neoadjuvant therapy. One patient died from paclitaxel anaphylaxis. Six patients manifested a complete pathologic response. CONCLUSION: With this regimen, carboplatin AUC = 4 for patients with locally advanced esophageal cancer is appropriate.

Journal Article↗

PubMed1997

[Survival in ovarian cancer treated in a gynecological department of a central hospital].

The characteristics of 73 patients with all stages of epithelial ovarian cancer were retrospectively analysed with emphasis on prognostic factors and survival. The patients underwent total hysterectomy, bilateral oophorectomy and infracolic omentectomy. Efforts were made to reduce the tumor burden as much as possible without endangering the general health status of the patient. Postoperative treatment was cisplatin 60 mg/m2 body surface and cyclophosphamide 50 mg/m2 every four weeks (CP). Patients with low general health status were offered either treosulphane 1 g daily for four weeks alternating with four weeks without treatment, or no treatment. Patients in FIGO stage IA and B generally received no postoperative chemotherapy treatment. Fifteen percent were in FIGO stage I, 7% in stage II, 5% in stage III and 23% in stage IV. Fifteen patients could be radically operated, however, only three patients who were in stage III. Fifty-four patients were treated with CP, 11 with treosulphane and eight patients did not receive postoperative treatment. In 28 patients second look laparotomy was performed. Only six patients had a complete pathological response, two of these in stage III. Stage and tumour grade could be identified as prognostic factors. Three-year survival was 70% in stage I, 67% in stage II, 28% in stage III and 0% in stage IV. Survival in 43 patients in stage III and IV was statistically compared to 265 patients from a prospective, randomized study by the Danish Ovarian Cancer Group (DACOVA), comparing cyclophosamide and cisplatin with and without doxorubicin. We found no statistical difference in survival between patients in our material and the DACOVA-material except in patients with low grade tumours whose survival in the CAP-arm of the DACOVA-study was superior. The rate of complete pathological response was significantly better in the DACOVA-study.

Adult↗

PubMed2000

Phase I-II trial of preoperative chemoradiation in locally advanced cervical carcinoma.

BACKGROUND: 5-Fluorouracil and cisplatin are characterized by in vitro synergism as well as radiosensitization. A phase I-II study was carried out on patients with invasive cervical carcinoma (FIGO IIB-IIIA) undergoing concomitant chemoradiation with 5-fluorouracil and cisplatin followed by radical surgery. METHODS: Twenty-six patients of 53 years median age, 24 with IIB tumor and 2 with IIIA tumor, all with squamous carcinoma, entered the study. The chemoradiation protocol included external radiotherapy to the pelvis: 39.6 Gy (180 cGy/daily); 5-fluorouracil: 1 g/m(2)/daily, in continuous intravenous infusion days 1-4 and 27-30; cisplatin: 20 mg/m(2)/daily days 1-4 and 27-30. Four weeks after the end of chemoradiotherapy, patients underwent restaging and then radical surgery with pelvic and lumboaortic lymphadenectomy. RESULTS: Twenty-six patients are evaluable for acute toxicity and 24 are evaluable for objective and pathologic response. Grade 3-4 thrombocytopenia or leukopenia was observed in 6 patients and grade 3 acute gastrointestinal toxicity in 3. After chemoradiation CR and PR were observed in 64 and 36% of cases, respectively (CR + PR = 100%). Two patients were excluded from surgery for other diseases. The remaining 24 patients were operated on; 23/24 patients showed negative section margins. The histology of the surgical specimen showed the absence of disease in 13 patients (54.2%), microscopic residual tumor in 4 patients (16.6%), residual disease </=1 cm in 5 patients, and residual disease >1 cm in 2 patients. Median follow up was 33 months. Two-year actuarial local control was 91.7%. CONCLUSIONS: This study showed a particularly high rate of pathologic responses (complete + Tmic: 70.8%) and local control (2 years = 91.7%) in patients with advanced cervical cancer undergoing moderate doses of radiotherapy with concomitant chemotherapy followed by radical surgery.

Adult↗

PubMed1992

Feeding studies in rats with mineral hydrocarbon food grade white oils.

This investigation compared the effects of feeding rats diets containing food grade white oil processed by either conventional oleum treatment or the more modern method of catalytic hydrogenation. In two separate experiments, male or female Fischer-344 rats were given free access for 90 days to diets containing 0, 10, 100, 500, 5,000, 10,000, or 20,000 ppm of either oleum-treated white oil (OTWO) or hydrotreated white oil (HTWO). There were no mortalities and no adverse clinical signs associated with feeding either white oil. Treatment-related effects evidenced by hematological, clinical chemical, and pathological changes were generally dose-related and more marked in female than in male rats, and the OTWO caused a greater pathological response than the HTWO. Tissue residues of saturated hydrocarbons were up to 5.2 times higher in female rats than in males. Rats fed 5,000 ppm or more of either white oil showed dose-related alterations in several hematological and clinical chemistry variates associated mainly with hepatic damage or functional alteration. At necropsy, mesenteric lymph nodes were enlarged, and increases in weight of liver, kidney, and spleen were significant. Microscopic changes were characterized by multifocal lipogranulomata in mesenteric lymph node and liver. No changes were observed in rats fed OTWO or HTWO for 90 days at dietary concentrations of 10 or 100 ppm, equivalent to a minimum intake of 0.65 and 6.4 mg/kg/day, respectively. Differences in degree of pathological response associated with each oil may have been due to their differences in specification rather than processing method.

Animals↗

PubMed2004

Can helminth antigens be exploited therapeutically to downregulate pathological Th1 responses?

In developing countries where helminth infections are highly prevalent, Th1 autoimmune diseases are almost never reported. A hypothesis suggesting that this may be due to effects of helminth infection on the immune system has been developed, and has inspired scientists to explore the possibility of using helminth antigens to treat autoimmune diseases. In animal models, helminth infection and helminth products have been successfully used to prevent different Th1-mediated autoimmune diseases. Results from initial studies were interpreted based upon the Th1/Th2 paradigm: A Th2-polarizing helminth infection correcting a Th1 autoimmune 'imbalance'. Intriguingly, however, allergies rarely develop in the host, despite the strong Th2 polarization induced by parasite antigens. Helminth infections act on the immune system of the host at many different levels. For this reason, identifying one or more products with therapeutic potential, from the 20,000 genes that a helminth can express, is a challenging task. In this review, we summarize the results achieved in animal models, and suggest possible approaches for the design of therapies appropriate for use in human Th1-mediated autoimmune pathologies.

Animals↗

PubMed1999

First-line high-dose sequential chemotherapy with rG-CSF and repeated blood stem cell transplantation in untreated inflammatory breast cancer: toxicity and response (PEGASE 02 trial).

Despite the generalization of induction chemotherapy and a better outcome for chemosensitive diseases, the prognosis of inflammatory breast cancer (IBC) is still poor. In this work, we evaluate response and toxicity of high-dose sequential chemotherapy with repeated blood stem cell (BSC) transplantation administered as initial treatment in 100 women with non-metastatic IBC. Ninety-five patients (five patients were evaluated as non-eligible) of median age 46 years (range 26-56) received four cycles of chemotherapy associating: cyclophosphamide (C) 6 g m(-2) - doxorubicin (D) 75 mg m(-2) cycle 1, C: 3 g m(-2) - D: 75 mg m(-2) cycle 2, C: 3 g m(-2) - D: 75 mg m(-2) - 5 FU 2500 mg m(-2) cycle 3 and 4. BSC were collected after cycle 1 or 2 and reinfused after cycle 3 and 4. rG-CSF was administered after the four cycles. Mastectomy and radiotherapy were planned after chemotherapy completion. Pathological response was considered as the first end point of this trial. A total of 366 cycles of chemotherapy were administered. Eighty-seven patients completed the four cycles and relative dose intensity was respectively 0.97 (range 0.4-1.04) and 0.96 (range 0.25-1.05) for C and D. Main toxicity was haematological with febrile neutropenia ranging from 26% to 51% of cycles; one death occurred during aplasia. Clinical response rate was 90% +/- 6%. Eighty-six patients underwent mastectomy in a median of 3.5 months (range 3-9) after the first cycle of chemotherapy; pathological complete response rate in breast was 32% +/- 10%. All patients were eligible to receive additional radiotherapy. High-dose chemotherapy with repeated BSC transplantation is feasible with acceptable toxicity in IBC. Pathological response rate is encouraging but has to be confirmed by final outcome.

Adenocarcinoma↗

PubMed1986

Neovascularization in urethane rat retinopathy demonstrated by thymidine labelling.

Rat urethane retinopathy produces sequential and progressive loss of the photoreceptor cells, proceeding from the posterior to the peripheral retina. The inner retina, the retinal pigment epithelium and the choriocapillaris are spared. After loss of the photoreceptor cells, a vasculopathy develops which includes progressive retinal capillary loss and formation of coil-like tufts of retinal vessels which are embedded in the retinal pigment epithelium. Some of the retinal vessels within the retinal pigment epithelium have changed their phenotype from continuous to fenestrated endothelial cells. To elucidate whether DNA synthesis was necessary for formation of the coil-like vessel tuft formation, an autoradiographic study was performed. At 12, 14, 16 and 20 weeks of age, times during which the vasculopathy is known to be forming, urethane and control rats were injected with 3 successive doses of methyl-3H-thymidine. Autoradiography of trypsin-digested retinal vessel preparations was compared with histological sections of the paired eye. The frequency of tritium labelled endothelial cells was much higher in the urethane rats than control animals, and were predominantly in the posterior pole, rather than the periphery. Labelled endothelial cells tended to be associated with, or near, the coil-like vessel tufts. Capillary dropout was observed in urethane, but not control animals. Frequently, adjacent endothelial cells were labelled, suggestive of mitosis. The occurrence of thymidine uptake and a change in phenotype of the endothelial cells leads us to suggest that new cell synthesis, or neovascularization, has occurred in these vessels. Since the retina is less than half the normal thickness and the choriocapillaris is intact, it appears unlikely that ischemia is responsible for inducing these pathological responses. We suggest that the retinal pigment epithelial cell is responsible for the increase in DNA synthesis and change in phenotype of the retinal endothelial cell.

Animals↗

PubMed1998

Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.

PURPOSE: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. RESULTS: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. CONCLUSION: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.

Adenocarcinoma↗

PubMed2002

Preoperative hyperfractionated radiotherapy for locally advanced rectal cancers: a phase I-II trial.

PURPOSE: To assess the toxicity, pathologic response rates, type of surgery, and oncologic results in a prospective Phase I-II trial using pure hyperfractionated radiotherapy (RT) preoperatively in locally advanced rectal cancer. METHODS AND MATERIALS: Between September 1997 and April 2000, 50 patients with T3-T4 or N1 rectal cancers were treated preoperatively with 50 Gy (45 Gy to the pelvis and a 5-Gy tumor boost) in 40 fractions of 1.25 Gy during 4 weeks. The pretreatment tumor stage as determined by CT and endorectal ultrasonography (80% of patients) included 1 Stage T2 (2%), 45 T3 (90%), and 4 T4 (8%). Nodal involvement (N1) was documented in 26 patients (52%). Surgery was performed at a median interval of 45 days (range 26-114 days) after RT completion. Seventeen patients who presented with pT4 or pN1 and/or pM1 received 5-fluorouracil-based chemotherapy postoperatively. RESULTS: All patients completed the RT schedule as planned. Severe acute toxicities included two Grade 3 skin reactions (4%) that did not require a break. The other acute toxicities were Grade 2 or less (skin, diarrhea, urinary, rectal tenesmus, and fatigue). A complete pathologic response was observed in 7 patients (14%), and microscopic residual cancer was found in 10 (20%). Of the 20 patients presenting with tumor located < or = 6 cm from the anal verge, sphincter-saving surgery was performed in 14 (70%). At 3 years, the actuarial locoregional control rate was 90.5%, and the disease-free survival rate was 74.6%. At a median follow-up of 32 months, 4 patients (8%) presented with severe late complications (Grade 3-4) that might have been RT related (one rectovaginal fistula, two chronic perineal fistulas, and one bilateral ureteral stenosis). CONCLUSION: In locally advanced rectal cancer, preoperative hyperfractionated RT to a total dose of 50 Gy is feasible, with acceptable acute and late toxicity and an objective downstaging effect. In view of these results, this schedule might be used as a basis for additional investigation regarding RT dose escalation or the addition of concomitant chemotherapy.

Adult↗

PubMed2000

Fibrillar amyloid beta-protein mediates the pathologic accumulation of its secreted precursor in human cerebrovascular smooth muscle cells.

Cerebrovascular deposition of the amyloid beta-protein (Abeta) is a key pathologic lesion seen in patients with Alzheimer's disease and certain related disorders, including hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). The deposition of Abeta has pronounced deleterious effects on smooth muscle cells within the cerebral vessel wall. We have previously shown that Abeta(1-40) possessing the E22Q HCHWA-D mutation extensively assembles into fibrils on the surface of cultured human cerebrovascular smooth muscle (HCSM) cells. This cell-surface Abeta fibril formation induces a series of pathologic responses in cultured HCSM cells, including a marked increase in the levels of cell-associated amyloid beta-protein precursor (AbetaPP) and cell death. In the present study, we investigated the relationship between HCSM cell-surface Abeta fibril formation and the striking increase in cell-associated AbetaPP. Time course studies showed that cell-surface HCHWA-D Abeta(1-40) fibril formation occurred rapidly, whereas both the increase in cell-associated AbetaPP and loss of cell viability were delayed responses. Domain analysis using site-specific antibodies indicated that the vast majority of the increase in cell-associated AbetaPP was secreted AbetaPP (sAbetaPP). Localization studies showed that the sAbetaPP was present on the HCSM cell surface. This result raised the possibility that sAbetaPP may bind back to HCSM cell-surface fibrils formed by HCHWA-D Abeta(1-40). Indeed, binding of biotinylated sAbetaPP to fibrillar HCHWA-D Abeta(1-40) was demonstrated by transmission electron microscopy. Furthermore, solid-phase binding assays showed that biotinylated sAbetaPP exhibited dose-dependent, saturable binding to fibrillar (but not soluble) HCHWA-D Abeta(1-40) with k(d) approximately 28 nM. Exon deletion experiments further defined a fragment of sAbetaPP (AbetaPP(18-119)), encoded by AbetaPP exons 2 and 3, to contain the fibrillar Abeta-binding domain. In addition, AbetaPP(18-119) effectively blocked the cell-surface accumulation of sAbetaPP and subsequent cell death in HCSM cells treated with pathogenic Abeta. Together, these findings could explain the accumulation of AbetaPP in cerebrovascular Abeta deposits observed both in vitro and in vivo and may contribute to the pathologic responses evoked by pathogenic forms of Abeta in HCSM cells.

Amino Acid Sequence↗

PubMed1994

Preoperative chemoradiation for adenocarcinoma of the pancreas and duodenum.

PURPOSE: This study was designed to evaluate the effects of preoperative chemoradiation on resectability, response, local control, and survival in patients with local or local-regional involvement from carcinoma of the pancreas or cancer of the duodenum and to assess the associated toxicity of such treatment. METHODS AND MATERIALS: This prospective pilot study of preoperative chemoradiation was initiated in 1986 for patients with clinical evidence of adenocarcinoma of the pancreas or duodenum without evidence of distant metastases. Radiation was given at 1.8 Gy per day to a total dose of 50.4 Gy. Two cycles of chemotherapy were given concurrent with radiation. On days 2-5 and 29-32, 5-fluorouracil (1 gm/m2/24 h x 4 days) was given, while mitomycin-C (10 mg/m2) was given on day 2 only. Surgical resection was 4-6 weeks following completion of chemoradiation. Thirty-one patients (17 male and 14 female) were entered on the protocol with a median potential follow-up of 4.5 years (range 6 months to 7.5 years). The median age was 64 years (range 32-73 years). Twenty-seven patients had pancreatic cancer (25 head, two body), while four patients had carcinoma arising from the duodenum. Twenty-one patients were initially judged to be unresectable and ten potentially resectable prior to chemoradiation. RESULTS: Twenty-nine of 31 patients completed the entire course of radiation and both cycles of chemotherapy. Acute toxicity from chemoradiation consisted of nausea, vomiting, diarrhea, stomatitis, or hematologic suppression which was moderate to severe (Grade 3 or 4) in seven patients (23%). One patient died of sepsis following the first week of therapy. Seventeen patients (55%) underwent curative resection with subtotal or total pancreatectomy or Whipple resection (four duodenum, 13 pancreas) and two (2/17) had pathologic nodal involvement, while (0/17) none had involved margins. A complete pathologic response was seen in all four (4/4) patients with duodenal cancer and in none (0/13) with pancreatic cancer who underwent resection. The median postoperative hospitalization stay was 22 days (range 4-144 days). Of 17 patients who underwent curative resection, there were two postoperative mortalities (12%). Late complications have included abscess, one; and nonmalignant ascites, five. Ten of the 31 patients are alive. For patients with pancreatic cancer the median survival is 9 months, while survival at 1 year and 3 years are 36% and 19% overall and 60% and 43% at 1 and 3 years for those undergoing resection. Six of the 27 patients (22%) with pancreatic cancer are alive without recurrence. All four patients with duodenal cancer are alive without recurrence (12 months, 23 months, 35 months, 90 months). CONCLUSION: Preoperative chemoradiation for cancer of the pancreas and duodenal region was relatively well-tolerated and enhanced resectability and downstaging of nodal metastases were suggested. The 3-year survival, particularly in patients who underwent resection, was high. For these reasons the applicability of this treatment regimen for pancreatic cancer is presently being studied in a group-wide multi-institutional Phase II trial. Chemoradiation for duodenal cancer has produced a complete pathologic response in all patients and survival has been excellent, suggesting efficacy of this regimen for duodenal cancer.

Adenocarcinoma↗

PubMed2004

Efficacy of intraperitoneal cisplatin as consolidation therapy in patients with pathologic complete remission following front-line therapy for epithelial ovarian cancer. Consolidative intraperitoneal cisplatin in ovarian cancer.

OBJECTIVE: The aim of this study is to evaluate the efficacy of intraperitoneal cisplatin as consolidation treatment in epithelian ovarian cancer patients with complete pathologic response following front-line platin-based chemotherapy. PATIENTS AND METHODS: Thirty patients who had no evidence of disease as assessed by second-look laparotomy following chemotherapy for stage III epithelial ovarian cancer were given three courses of intraperitoneal cisplatin (100 mg/m(2)) with three weekly intervals as consolidation therapy. RESULTS: Median age was 50 years. After a median follow-up period of 37 months, 16 patients are being followed with no evidence of disease. Eleven patients developed recurrent disease. Median disease-free survival was 50 months. Median overall survival is not reached. WHO grades 3-4 toxicity criteria were emesis in 19 patients (63.3%), abdominal pain in 5 (16.7%) and nephrotoxicity in 2 (6.7%) patients. Catheter-related complications were infection/peritonitis in one and catheter malfunction in one patient. There were no serious hematologic side effects that required transfusions or caused treatment delays. None of the patients developed serious neurologic toxicity. Treatment had to be stopped early in four patients who refused further treatment due to abdominal pain, nausea ::and vomiting. Dose reductions were required in five patients. CONCLUSION: Our results suggest that intraperitoneal cisplatin is a feasible regimen that may provide a favorable outcome in terms of progression-free survival in patients with a complete pathologic response following front-line treatment for ovarian cancer. Further randomized trials are required to evaluate the role of consolidation treatment in this setting.

Adult↗