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Results for “Pathologic response”

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At least 397 records · Page 22Linked to original sources

PubMed2006

Association of activated transcription factor nuclear factor kappab with chemoradiation resistance and poor outcome in esophageal carcinoma.

PURPOSE: The lack of effective treatment for localized esosphageal cancer leads to poor patient outcome. Nuclear factor kappaB (NF-kappaB), a transcriptional factor, is constitutively activated or treatment induced in esophageal cancer and may influence treatment outcomes. PATIENTS AND METHODS: Pre- and post-treatment cancer specimens from patients enrolled onto a clinical trial were studied for the expression of activated NF-kappaB protein and it was correlated with histologic features, pathologic response, metastatic potential, overall survival (OS), and disease-free survival (DFS). RESULTS: Forty-three patients undergoing the same therapy on a protocol were studied. Twenty-one (72%) of 29 patients achieving less than complete pathologic response (pathCR) had NF-kappaB positive cancer, but only one (7%) of 14 patients achieving pathCR had NF-kappaB positive cancer (P = < .001). Activated NF-kappaB was significantly associated with aggressive pathologic features such as perineural, lymphatic, and/or vascular invasion (P = .0004). Eight (38%) of 21 NF-kappaB positive patients developed metastases compared to none of 22 NF-kappaB negative patients (P = .001). At a median follow-up of 23 months, 10 (48%) of 21 NF-kappaB positive patients had died compared to only one (5%) of 22 NF-kappaB negative patients (P = .0013). Observations were similar for DFS (P = .0006). In a multivariate model (using baseline stage, pathCR or less than pathCR, age, presence of metastatic lymph nodes in the surgical specimen, and NF-kappaB expression) NF-kappaB activation was the only independent predictor of DFS (P = .010) and OS (P = .015). CONCLUSION: Our data suggest that esophageal cancers with activated NF-kappaB have aggressive clinical biology and poor treatment outcome. Additional understanding of NF-kappaB regulated pathways may uncover potential therapeutic targets.

Adult↗

PubMed2004

Phase I trial of preoperative doxorubicin-based concurrent chemoradiation and surgical resection for localized extremity and body wall soft tissue sarcomas.

PURPOSE: The primary objective of this phase I trial was to define the maximum-tolerated dose of continuous-infusion doxorubicin administered with standard preoperative radiation for patients with localized, potentially resectable soft tissue sarcomas of the extremities or body wall. PATIENTS AND METHODS: Twenty-seven patients with radiographically resectable intermediate- or high-grade soft tissue sarcomas were treated. Preoperative external-beam radiation was administered in 25 2-Gy fractions (total dose, 50 Gy). Concurrent continuous-infusion doxorubicin was administered by an initial bolus (4 mg/m(2)) and subsequent 4-day continuous infusion (12.5, 15.0, 17.5, or 20.0 mg/m(2)/wk). Radiographic restaging was performed 4 to 7 weeks after chemoradiation, and patients with localized disease underwent surgical resection. RESULTS: Chemoradiation was completed as an outpatient procedure in 25 patients (93%). The maximum-tolerated dose of continuous-infusion doxorubicin combined with standard preoperative radiation was 17.5 mg/m(2)/wk; at this dose level, seven (30%) of 23 patients had grade 3 dermatologic toxicity. Macroscopically complete resection (R0 or R1) was performed in all 26 patients who underwent surgery. Among 22 patients who were treated with doxorubicin 17.5/mg/m(2)/wk with concurrent radiation and subsequent surgery, 11 patients (50%) had 90% or greater tumor necrosis, including two patients who had complete pathologic responses. CONCLUSION: Preoperative doxorubicin-based chemoradiation appears safe and feasible. The maximum-tolerated dose of continuous-infusion doxorubicin with standard preoperative radiation was 17.5 mg/m(2)/wk. Pathologic response rates with this regimen are encouraging.

Adolescent↗

PubMed1987

Chemotherapy as a substitute for surgery in the treatment advanced resectable head and neck cancer. A report from the Northern California Oncology Group.

This trial determines the feasibility for patients with resectable Stages III/IV head and neck cancer who achieved a complete response to induction chemotherapy of eliminating surgery from their treatment program. Thirty patients were treated with three cycles of cisplatin and 5-fluorouracil (5-FU), followed by reendoscopy and biopsy. Twelve patients achieved a complete pathologic response at the primary and received radiation (interstitial and/or external beam) only. The remainder underwent surgical resection and postoperative radiation. At 2 years, the relapse-free survival was 52%, and the survival was 53% for the entire group. For the 12 complete responders who had surgery eliminated, the relapse-free survival was 60%, and the survival was 70%. This pilot study suggests that for patients with resectable disease who achieve a complete pathologic response to induction chemotherapy at their primary, it is feasible to omit surgery and treat with primary radiation without compromise in survival. This approach warrants further study in a randomized trial.

Adult↗

PubMed2006

[Neoadjuvant radiochemotherapy and surgery of locally advanced cervical carcinoma: review of 22 patients treated at the Bordet Institute].

OBJECTIVES: Concomitant chemoradiation is the "new gold standard" for dealing with locally advanced cervical carcinoma, but what about surgery? We don't know yet to what extent surgery is necessary and how radical it must be when it is performed. In this study, we present the analysis of the results obtained in patients treated by concomitant chemoradiation followed by radical surgery. MATERIALS AND METHODS: Twenty-two patients, median age 49 years, with I(b) - III(a) cervical tumors were enrolled to be treated by concomitant chemoradiation followed by radical surgery. The chemoradiation protocol included external radiotherapy to the pelvis: 45 Gy; Cisplatin 40 mg/m(2) in continuous intravenous infusion once a week (5 weeks) followed by brachytherapy one week later. Surgery was performed 4 to 6 weeks later and consisted in radical hysterectomy with pelvic lymphadenectomy. RESULTS: 20/22 patients underwent surgery after chemoradiation because of a diagnosis of lung metastases in one and presence of a nonresectable metastasis for the other. A complete pathological response was demonstrated in 12/20 patients (60%), a microscopic residual tumor in 7 patients (35%), and residual disease <1cm in 1 patient (5%). CONCLUSION: This study showed a particularly high rate of pathologic responses (T(0)+T(mic): 95%) and of local control. We don't know yet if surgery is a real necessity or if it could be less extended after concomitant chemoradiation.

Adult↗

PubMed2002

[Tumor downstaging through preoperative chemoradiotherapy in locally advanced rectal cancer].

OBJECTIVE: To evaluate the impact of preoperative chemoradiotherapy on patients with locally advanced rectal cancer by clinical and pathological characteristics. METHODS: From July 1994 to May 1995, 36 patients with locally advanced rectal cancer were treated. Pathology: adenocarcinoma 27, mucinous adenocarcinoma 7 and ductal adenocarcinoma 6. The protocol was carried out in sequence of chemo-->radio-->surgery-->chemotherapy. The treatment began with preoperative chemotherapy with folinic acid 50 mg followed by 5-FU bolus of 300 mg/m2 given for two cycles on d1-5 and d22-26 before irradiation. Radiation therapy was delivered to a dose of 45 Gy, 1.8 Gy per fraction, 5 days a week. Surgery was done 4-6 weeks after this preoperative treatments. Another 2 to 4 cycles of chemotherapy were added 2 to 4 weeks after operation. Twenty-one patients were treated by Dixon's operation, 14 patients by Mile's operation and 1 by local tumorectomy through the rectum. Radical operation was performed in 29 patients and palliative resection was done in 7 patients. RESULTS: Grade III hematological toxicity was observed in only 2(5.6%) patients. No patient had grade III or IV acute toxicity in the gastrointestinal, skin or urological systems. All patients underwent surgery. The perioperative morbidity rate was 13.8% with no mortality or late toxicity. As a result of this preoperative management, the tumor was reduced by an average of 28.0%, with a complete pathological response in 4(11.1%) patients. In 28 CR + PR (77.8%) patients, a downstaging in 19(52.8%) patients was observed. Sixty percent of positive lymph nodes as assessed by transrectal ultrasonography before therapy became pathologically negative postoperatively, with the frequency of lymph node metastasis decreased by 46.0%(83.0% to 37.0%). CONCLUSION: Preoperative radiochemotherapy is proved as a safe method with a tolerable toxicity. Complete pathological response, shrinkage of the primary tumor and decrease in lymph node metastasis are observed after preoperative radiochemotherapeutic regimen. An overall benefit of downstaging the primary tumor and a greatly enhanced effect of surgery is enjoyed by the patients.

Adult↗

PubMed2004

Effects of sarcoptic mange and its control with oil of Cedrus deodara, Pongamia glabra, Jatropha curcas and benzyl benzoate, both with and without ascorbic acid on growing sheep: epidemiology; assessment of clinical, haematological, cell-mediated humoral immune responses and pathology.

The aim of this study was to evaluate the therapeutic efficacy of commonly used acaricidal drugs in India and also to assess the effect of ascorbic acid (AA) as adjunct therapy in 72 growing sheep with sarcoptic mange, aged 5-6 months and weighing 20.4-31.7 kg. Eight replicates of nine animals were formed based on sex, and day 0 body weight. Another set of 12 healthy sheep (5-6 months old) constituted the healthy control group. Drugs were applied locally on the affected parts daily and recovery changes in skin lesions were observed at the time of every application. L-Ascorbic acid was administered intramuscularly. Skin scrapings were collected daily from each group and examined for the presence of mites. Blood samples from each group were collected and analysed for total erythrocytes, leucocytes, haematocrit, haemoglobin and lymphocytes on 0, 14th and 28th day post-treatment (PT). Cell-mediated (CMI) and humoral immune (HI) responses were assessed on 0 and 28 days PT. Within groups treated with the drug alone, recovery in oil of Jatropha curcas group was faster and lesions were free from mites after the eighth application. For each drug, the recovery was faster with AA as an adjunct therapy when compared with the group treated with the drug alone. Within all groups, recovery in oil of J. curcas plus ascorbic acid (OJC-AA) group was fastest and the lesions were mite-free after three applications. The overall mean values were higher for all haematological parameters in OJC-AA group. Recovery with respect to suppressed CMI and HI responses during infection was also faster in this group. Gross and microscopic pathological studies revealed a marked adverse effect of infection on skin, kidney, spleen and liver. The OJC-AA group indicated faster recovery. It is concluded from this study that oil of J. curcas was found more efficacious in controlling sarcoptic mange in sheep and AA might be beneficial as adjunct in case of sarcoptic mange to get quick recovery with lesser applications of main therapy. However, the pharmacology of AA with reference to health of skin needs to be investigated.

Animals↗

PubMed1997

Cisplatin-, epirubicin- and paclitaxel-containing chemotherapy in uterine adenocarcinoma.

PURPOSE: To evaluate the toxic effects and antitumour activity of a multidrug regimen with cisplatin, epirubicin and paclitaxel (CEP) as initial therapy in patients with uterine adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients with histologically-confirmed diagnoses of locally advanced, recurrent or metastatic cervical or endometrial adenocarcinoma entered the study. Treatment consisted of epirubicin (E) given at 70 mg/m2 followed by paclitaxel (P) (175 mg/m2 over three hours) and cisplatin (C) (50 mg/m2), repeated every three weeks. Eligibility criteria also included age < or = 75 years, no previous chemotherapy, no previous radiotherapy to the tumour parameters, bidimensionally-measurable lesions, no previous or ongoing cardiac disease, and renal and liver function within normal limits. Complete blood cell counts were repeated weekly, and tumor response was assessed every three cycles. A maximum of eight courses was administered in responding patients. RESULTS: From January 1996 to January 1997, 30 patients with endometrial adenocarcinoma and 19 with cervical adenocarcinoma entered the study, for a total of 213 cycles of treatment. In patients with endometrial carcinoma the overall clinical and pathological response rates were 73% (95% CI, range 54%-88%) and 35% (95% CI, range 16%-57%) respectively; in patients with locally advanced cervical carcinoma the overall clinical and pathological response rates were 64% and 62%. WHO grade 3-4 neutropenia occurred in 61% of the patients, with one possible toxic death. Retreatment had to be delayed for at least one week because of persisting neutropenia in 34% of the patients. Mild peripheral neuropathy and stomatitis were observed in 46% and 23% of the patients. One patient presented acute congestive heart failure after the third cycle of treatment. CONCLUSION: The high antitumour activity and the good tolerability of CEP suggest that this regimen should be prospectively compared to standard combinations as initial treatment of advanced endometrial carcinoma.

Adenocarcinoma↗

PubMedDate not supplied

Epidoxorubicin versus no treatment as consolidation therapy in advanced ovarian cancer: results from a phase II study.

To compare the effect of epidoxorubicin given for 4 months versus no treatment in the survival of patients with advanced ovarian cancer and complete pathologic response after first-line surgery and chemotherapy with platinum-based schedules, we conducted a multicenter randomized clinical trial. Patients with histologic diagnosis of epithelial ovarian cancer FIGO stage III or IV at first diagnosis; complete pathologic response at second-look laparotomy/laparoscopy or complete clinic response; and those who have had first-line therapy including surgery and one regimen containing cisplatin or carboplatinum were eligible for the study and were randomly allocated to epidoxorubicin 120 mg/sqm or no treatment. A total of 64 women were allocated to epidoxorubicin and 74 to no treatment. There were 20 and 19 deaths, respectively, in the epidoxorubicin and no-treatment groups. The 3-year percent overall survival was 79.0% and 78.7%, respectively, in the no-treatment and epidoxorubicin groups (log-rank test, P= 0.93).

Adenocarcinoma↗

PubMed1995

Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states.

It has recently become accepted that the activated immune system communicates to brain via release of pro-inflammatory cytokines. This review examines the possibility that pro-inflammatory cytokines (interleukins and/or tumor necrosis factor) mediate a variety of commonly studied hyperalgesic states. We will first briefly review basic immune responses and inflammation. We will then develop the concept of illness responses and provide evidence for their existence and for the dramatic changes in neural functioning that they cause. Lastly, we will examine the potential roles that both pro-inflammatory cytokines and the neural circuits that they activate may play in the hyperalgesic states produced by irritants, inflammatory agents, and nerve damage. The possibility is raised that apparently diverse hyperalgesic states may converge in the central nervous system and activate similar or identical neural circuitry.

Animals↗

PubMed2004

Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction.

BACKGROUND: Patients with localized esophageal carcinoma often develop locoregional and distant disease recurrence. The current study investigated the outcome of a new chemotherapy combination as induction therapy before chemoradiotherapy. METHODS: Forty-three patients with resectable carcinoma of the esophagus or gastroesophageal junction were enrolled. Most of the tumors were endoscopic ultrasonography (EUS) (EUS)T3 (84%) and (EUS)N1 (63%). The patients received < or = 2 6-week cycles of CPT-11 and cisplatin followed by chemoradiotherapy (45 grays with 5-fluorouracil and paclitaxel). Five to six weeks after chemoradiotherapy, the patients underwent staging and surgery. The feasibility, curative resection rates, overall and disease-free survival rates, rate of significant pathologic response, and patterns of disease recurrence were assessed. RESULTS: Of the 43 patients, 39 (91%) underwent an R0 resection. Two patients (5%) died after surgery. A pathologic complete response (pathCR) was observed in 11 (28%) of the 39 patients (or 26% of the 43 patients). In addition, 16 patients (41% of 39 patients or 37% of 43 patients) had < 10% viable tumor in the surgical specimen (pathPR). A comparison of endoscopic ultrasonograpy T and N classifications with surgical T and N classifications demonstrated significant down-staging (P < 0.01). The median survival period of all 43 patients was 22.1 months. Patients who had achieved a pathCR or pathPR had a longer median survival (25.6 months) than those who achieved less than a pathPR (18.5 months; P = 0.52). None of the clinical parameters examined were found to correlate with survival or pathologic response. CONCLUSIONS: CPT-11-based induction chemotherapy resulted in substantial pathCR and pathPR rates, both of which lead to a favorable survival outcome. The three-step strategy needs to be developed further, with the investigation of targeted therapies with chemotherapy and radiotherapy.

Adenocarcinoma↗

PubMed1997

The expanding spectrum of Bartonella infections: II. Cat-scratch disease.

Recent advancements and developments in molecular biotechnology have allowed more precise reclassification of many microorganisms. With the use of these new taxonomy tools, several organisms previously thought to belong to other genera have been recently described as bartonellae. Of the 11 organisms now described as Bartonella spp., only four have been shown to be pathogenic for humans. Table 1 lists the four Bartonella human pathogens along with the their known epidemiology and the scope and range of disease associated with each. All are now considered to be bacteria and can be grown on blood-enriched agar although primary isolation in some may best be achieved in cell tissue culture. B. bacilliformis infection is limited to certain geographic regions in South America where the only human reservoir and the sandfly vector(s) that spreads the disease reside together. Specific antibiotic treatment is dramatically effective in treating the highly fatal, acute intraerythrocytic hemolytic form of the disease, but their effectiveness in treating the vascular proliferative forms (verruga peruana) or the chronic asymptomatic, bacteremic, carrier state of the disease has not been effective. This disease should remain confined to its present endemic geographic areas in South American unless asymptomatic bacteremic persons from these areas migrate to areas where sandflies and humans exist that are capable of establishing this infection in new endemic areas. B. quintana and B. henselae cause a wide range of clinical diseases in humans, the type and extent of which varies significantly with the immune status of the host. In immunocompetent hosts the pathologic response is granulomatous, suppurative, extracellular and intracellular, generally self-limited and usually unresponsive to antibiotic treatment, even to those drugs to which the organism is shown to be sensitive in vitro. In contrast, in immunocompromised hosts the pathologic response is vasculoproliferative, organisms may be seen intracellularly but they are often seen in abundance in extracellular clumps and infection is usually progressive and fatal unless treated. In these patients clinical response to treatment with drugs that are effective in vitro against these organisms has usually been dramatic. Of these agents those that penetrate cells and are found in high concentrations intracellularly, such as erythromycin, clarithromycin, azithromycin, rifampin, doxycycline and gentamicin, appear to be most effective. These agents not only appear to provide the most dramatic treatment response in patients with BA, BP and PRFB and other manifestations of B. henselae (and B. quintana as well) in immunocompromised persons, they appear to be the most promising agents for treatment of persons with both typical and atypical CSD. Further studies will be necessary to more clearly elucidated the mechanisms responsible for the diverse clinical presentations of infection with these organisms in human hosts relative to their immune status. In addition clarification of the epidemiology of B. elizabethae infections in humans may be helpful in understanding the nature of infection with Bartonella organisms.

Bartonella henselae↗

PubMed1997

Docetaxel as neoadjuvant chemotherapy in patients with stage III breast cancer.

Optimal management of locally advanced breast cancer (stage III) generally includes a combination of primary chemotherapy followed by surgery (if feasible), and local radiotherapy and adjuvant chemotherapy with or without hormonal therapy. An ongoing phase II study is being performed to evaluate the use of 4 cycles of 100 mg/m2 of docetaxel (Taxotere) administered as a 1-hour intravenous infusion once every 3 weeks followed by surgery, 4 cycles of standard-dose doxorubicin/cyclophosphamide (Cytoxan, Neosar) chemotherapy, and radiation, with and without tamoxifen (Nolvadex) in patients with locally advanced breast cancer. Preliminary results from 33 patients included in this phase II study are reported here. A partial response was achieved in 22 patients (67%), with 6 patients (18%) experiencing a complete response with this regimen. One patient with a complete response was confirmed to have a complete pathologic response at the time of surgery. Febrile neutropenia was noted in 8 patients (24%) and in 8 of the 120 treatment cycles (7%) administered. Future trials aimed at increasing the number of pathologic complete responses in patients with stage III breast cancer may require the use of docetaxel in combination with other active agents or the use of dose-dense scheduling schemes.

Adult↗

PubMed1990

The value of MR imaging in monitoring the effect of chemotherapy on bone sarcomas.

We studied the value of MR imaging in monitoring the response of Ewing sarcoma and osteosarcoma to chemotherapy. Relative signal-intensity changes on MR images in the course of chemotherapy were compared with changes in tumor volume and histopathologic findings. MR scans (T1- and T2-weighted spin-echo images) were obtained in 20 patients with bone sarcoma. The first MR scan was obtained before the administration of chemotherapy in all patients. The follow-up scan was obtained in the course of treatment, before surgery. Tumor-volume and signal-intensity measurements of the intra- and extraosseous components of the tumor were analyzed. In 17 patients, histopathologic findings of the resected tumor were available for comparison with the MR images. In 12 of 17 patients there was complete agreement between changes in tumor volume, changes in the signal intensity of the extraosseous tumor component on T2-weighted images, and histopathology. In another four cases, changes in signal intensity correlated either with histopathology or with changes in tumor volume. In one patient with a pathologic fracture, no such correlation existed. A significant correlation was found between changes in signal intensities and pathologic response (r = .57, p = .02), as well as between changes in tumor volume and pathologic response (r = .53, p = .03). No correlation could be found between changes in signal intensity of the intraosseous tumor component and changes in tumor volume or histopathology. We conclude that the signal intensity of the extraosseous component of bone sarcomas on T2-weighted MR images in addition to changes in tumor volume may be useful in evaluating response to chemotherapy.

Adolescent↗

PubMed2001

Pathogenic effects of D23N Iowa mutant amyloid beta -protein.

Cerebral amyloid beta-protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. In these conditions the CAA is characterized by the deposition of Abeta within the cerebral vessel wall and, in severe cases, hemorrhagic stroke. Several mutations have been identified within the Abeta region of the Abeta protein precursor (AbetaPP) gene that appear to enhance the severity of CAA. We recently described a new mutation within the Abeta region (D23N) of AbetaPP that is associated with severe CAA in an Iowa kindred (Grabowski, T. J., Cho, H. S., Vonsattel, J. P. G., Rebeck, G. W., and Greenberg, S. M. (2001) Ann. Neurol. 49, 697-705). In the present study, we investigated the effect of this new D23N mutation on the processing of AbetaPP and the pathogenic properties of Abeta. Neither the D23N Iowa mutation nor the E22Q Dutch mutation affected the amyloidogenic processing of AbetaPP expressed in H4 cells. The A21G Flemish mutation, in contrast, resulted in a 2.3-fold increase in secreted Abeta peptide. We also tested synthetic wild-type and mutant Abeta40 peptides for fibrillogenesis and toxicity toward cultured human cerebrovascular smooth muscle (HCSM) cells. The E22Q Dutch, D23N Iowa, and E22Q,D23N Dutch/Iowa double mutant Abeta40 peptides rapidly assembled in solution to form fibrils, whereas wild-type and A21G Flemish Abeta40 peptides exhibited little fibril formation. Similarly, the E22Q Dutch and D23N Iowa Abeta40 peptides were found to induce robust pathologic responses in cultured HCSM cells, including elevated levels of cell-associated AbetaPP, proteolytic breakdown of smooth muscle cell alpha-actin, and cell death. Double mutant E22Q,D23N Dutch/Iowa Abeta40 was more potent than either single mutant form of Abeta in causing pathologic responses in HCSM cells. These data suggest that the different CAA mutations in AbetaPP may exert their pathogenic effects through different mechanisms. Whereas the A21G Flemish mutation appears to enhance Abeta production, the E22Q Dutch and D23N Iowa mutations enhance fibrillogenesis and the pathogenicity of Abeta toward HCSM cells.

Amino Acid Sequence↗

PubMed2002

Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor.

Cerebral amyloid beta-protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. Several mutations have been identified within the Abeta region of the Abeta protein precursor (AbetaPP) gene that appear to enhance the severity of CAA. A new mutation has been identified within the Abeta region (D23N) of AbetaPP that is associated with severe CAA in an Iowa kindred. Recently, we showed that E22Q Dutch, D23N Iowa, and E22Q/D23N Dutch/Iowa double-mutant Abeta40 peptides rapidly assemble in solution to form fibrils compared to wild-type Abeta40. Similarly, the E22Q Dutch and D23N Iowa Abeta40 peptides were found to induce robust pathologic responses in cultured human cerebrovascular smooth muscle (HCSM) cells, including elevated levels of cell-associated AbetaPP, proteolytic breakdown of actin, and cell death. Double-mutant E22Q/D23N Dutch/Iowa Abeta40 was more potent than either single-mutant form of Abeta in causing pathologic responses in HCSM cells. These in vitro data suggested that the E22Q Dutch and D23N Iowa substitutions promote fibrillogenesis and the pathogenicity of Abeta towards HCSM cells. Moreover, the presence of both CAA substitutions in the same Abeta peptide further enhances the fibrillogenic and pathogenic properties of Abeta. We also have generated transgenic mouse models to examine the effects of single and double CAA mutations in AbetaPP in vivo. Preliminary analysis of transgenic mouse brains indicates that expression of double-mutant E22Q/D23N Dutch/Iowa AbetaPP leads to robust deposition of Abeta in a vascular-weighted manner.

Amino Acid Sequence↗

PubMed2006

Pretherapy nuclear factor-kappaB status, chemoradiation resistance, and metastatic progression in esophageal carcinoma.

BACKGROUND: Transcriptional factor nuclear factor-kappaB (NF-kappaB) seems to be associated with aggressive clinical biology (chemoradiation resistance and metastatic progression) of esophageal cancer. We hypothesized that activated NF-kappaB would define clinical biology irrespective of the type of chemotherapy or sequence administered. METHODS: Pretherapy and/or posttherapy cancer specimens were examined for activated NF-kappaB and correlated with pathologic response to chemoradiation, metastatic potential, overall survival, disease-free survival, and type of chemotherapy or sequence used. FINDINGS: Eighty patients undergoing chemotherapy and concurrent radiation were studied. Activated NF-kappaB prior to any therapy was associated with the lack of complete pathologic response (pathCR, P = 0.006). Forty-five (78%) of 58 patients achieving <pathCR had activated NF-kappaB in pretherapy and/or posttherapy cancer specimens versus 2 (9%) of 22 patients with pathCR (P = 0.001). Twenty-four (51%) of 47 patients with activated NF-kappaB in cancer developed metastases versus 7 (21%) of 22 patients with negative NF-kappaB in cancer (P = 0.01). At a median follow-up of 32 months, 25 (53%) of 47 patients with activated NF-kappaB cancer had died versus 3 (9%) of 33 patients with negative NF-kappaB cancer. NF-kappaB activation was the only independent predictor of disease-free survival (P = 0.01) and overall survival (P = 0.007) in a multivariate model. The class of chemotherapy or its sequence had no effect on NF-kappaB expression or patient outcome. CONCLUSIONS: Our data are the first to show that pretreatment-activated NF-kappaB significantly correlates with clinical biology of esophageal cancer, and most importantly, with pathCR. To therapeutically exploit NF-kappaB-regulated genes and their pathways, further research is warranted.

Adult↗

PubMed2006

Complementary use of local excision and transanal endoscopic microsurgery for rectal cancer after neoadjuvant chemoradiation.

BACKGROUND: Neoadjuvant therapies have significantly improved local control and survival of patients with rectal cancer. Nevertheless, although a complete pathologic response can be achieved in 30% of cases, a transabdominal surgical resection is always required. This study aimed, for the first time, to test in the literature the feasibility of local excision combined with transanal endoscopic microsurgery (TEM) as a surgical option for patients treated with neoadjuvant chemoradiation. METHODS: Between July 1997 and December 2002, 30 patients with rectal cancer affected by an extraperitoneal tumor entered a protocol consisting of neoadjuvant chemoradiation followed by surgery. The surgical treatment, consisting of open surgery, local excision, or TEM, was planned according to the patient's clinical response after chemoradiation and distance from the anal verge. RESULTS: A significant clinical downstaging was observed in eight patients. Five of these patients underwent TEM, and three had local excision. Consequently, open surgery was performed for 22 patients. Histology showed six cases of complete pathologic response: three in the open surgery group and three in the transanal excision group. After a mean follow-up period of 47 months, the disease-free survival rate was 77% in the open surgery group and 100% in TEM or local excision group. CONCLUSIONS: The findings suggest the complementary feasibility of TEM and local excision after neoadjuvant chemoradiation. However, randomized trials are needed to confirm the oncologic safety of this approach.

Aged↗

PubMed2004

Expression of endothelin-A-receptor predicts unfavourable response to neoadjuvant chemotherapy in locally advanced breast cancer.

Endothelin-1 (ET-1) and its receptors (ETAR and ETBR), referred to as the endothelin (ET) axis, are overexpressed in breast carcinomas and appear to influence tumour growth and progression. The objective of this study was to determine the effect of expression of the ET axis in breast carcinomas on response to cytotoxic chemotherapy. The study included 44 patients with locally advanced breast cancer participating in a prospective phase III study evaluating high-dose neoadjuvant chemotherapy of epirubicin and cyclophosphamide. Expression of ET-1, ETAR and ETBR was determined by semiquantitative immunohistochemical analysis of breast cancer tissue from prechemotherapy tru-cut biopsies. Immunohistochemical staining was positive for ET-1 in 61.5%, for ETAR in 35% and for ETBR in 35.9% of breast carcinomas. Pathological response to chemotherapy was significantly decreased in ETAR-positive patients (P=0.002). In total, 50% of ETAR-positive patients as compared to 7.7% of ETAR-negative patients attained pathologically 'no change'. Logistic regression confirmed ETAR as an independent predictive marker for pathological response (P=0.009). These data indicate that increased expression of ETAR in breast carcinomas is associated with resistance to chemotherapy. Determination of ETAR status may serve as a predictive marker for identifying patients less likely to be responsive to conventional chemotherapy.

Adult↗