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Older people with non small cell lung cancer in clinical stage IIIA and co-morbid conditions. Is curative irradiation feasible? Final results of a prospective study.

Radiotherapy (RT) is widely used in the management of lung cancer but age-oriented randomized trials are lacking in older-unfit patients. We started a prospective study to evaluate the toxicity and efficacy of definitive RT in very old-unfit patients with non-small cell lung cancer (NSCLC) in clinical stage IIIA, according to AJCC 1988. Forty patients, age > or = 75 years, Karnofsky Performance status (KPS) > or = 60, unfit to receive an aggressive combined treatment, were entered in the study. Each patient had one or more comorbidities, and the Charlson score was greater than two in 7/40. All patients were treated with radiation fields encompassing the primary tumor and grossly involved lymph nodes. A median radiation dose of 60 Gy/2 Gy day/5 days a week, was delivered. The 40 patients have been followed up, including those who died, for a potential median time of 4.6 years. As results, no treatment-related mortality, and clinically insignificant acute morbidity was recorded: in 28/40 cases a mild esophagitis occurred. Two patients showed a clinical radiation pneumonitis (RP). Late normal tissue damage was represented by lung fibrosis (40/40 patients). The treatment was efficacy since each patient obtained some clinical benefit from it. Median survival (MS) was 19 months (range 5-68); the 3 and 5-year actuarial survival was 18 and 12%, respectively. In conclusion, we think that older patients with concomitant illness can be submitted to curative 'involved field' irradiation and the results observed in this trial encourage to use curative RT in older subjects with local-regionally advanced NSCLC and co-morbid condition.

Aged↗

Supraglottic carcinoma: patterns of failure and salvage treatment after curatively intended radiotherapy in 410 consecutive patients.

PURPOSE: In a series of consecutive patients with squamous cell carcinoma of the supraglottic larynx, in which almost all were treated by primary radiotherapy, the study describes the path from diagnosis to cure or death, and evaluates the patterns of failure and the treatment of recurrences. METHODS AND MATERIALS: The analysis included 410 patients, 104 females and 306 males, treated between 1963 and 1991. Most patients were in Stage I (33%), and the remaining were in Stage II (18%), III (23%), and IV (26%). Primary intended curative treatment was delivered in 398 (radiotherapy, 394; surgery, 4) of 410 cases (98%). RESULTS: Initial radical treatment resulted in 173 cured patients and 225 patients with a recurrence. Curatively intended salvage could be applied in 158 patients: surgery in 154 patients (74 cured) and radiotherapy in 4 (none cured). Overall, 247 patients (60%) obtained tumor control, 179 (44%) without a laryngectomy. Sixty-three patients had a total laryngectomy, and five had a partial laryngectomy. The 5-year locoregional tumor control, disease-specific survival, and overall survival rates were 43%, 61%, and 47%, respectively. With a follow-up of 20 years posttreatment, 91 new primary malignant tumors were detected. CONCLUSIONS: Radiotherapy is effective in the treatment of supraglottic laryngeal carcinoma, and the patients have a relatively good prognosis. Many patients retained their larynx intact. Recurrence after primary radiotherapy can be treated by surgery, with a high success rate even in advanced stages. Development of second primary cancer is a growing problem.

Adolescent↗

Quality of life after curative radiotherapy in Stage I non-small-cell lung cancer.

PURPOSE: The aim of this study was to investigate changes in quality of life (QOL) among medically inoperable Stage I non-small-cell lung cancer (NSCLC) patients treated with curative radiotherapy. PATIENTS AND METHODS: The study sample was composed of 46 patients irradiated for Stage I NSCLC. Quality of life was assessed before, during, and after radiotherapy using the European Organization for the Research and Treatment of Cancer QLQ-C30 and QLQ-LC13. Changes in symptom and QOL scores over time were evaluated with a repeated measurement analysis of variance using the mixed effect modeling procedure, SAS Proc Mixed. Twenty-seven patients were treated only at the primary site, whereas for 19 patients, the regional lymph nodes were included in the target volume as well. RESULTS: The median follow-up time of patients alive was 34 months. The median survival was 19.0 months. None of the locally treated patients developed regional recurrence. A significant, gradual increase over time was observed for dyspnea, fatigue, and appetite loss. A significant, gradual deterioration was observed also for role functioning. No significant changes were noted for the other symptoms or the functioning scales. Significantly higher levels of dysphagia, which persisted up to 12 months, were observed in those in which the regional lymph nodes were treated, as compared to the locally treated patients. Radiation-induced pulmonary changes assessed with chest radiograph were more pronounced in the group treated with locoregional radiotherapy. CONCLUSIONS: After curative radiotherapy for Stage I medically inoperable NSCLC, a gradual increase in dyspnea, fatigue, and appetite loss, together with a significant deterioration of role functioning, was observed, possibly because of pre-existing, slowly progressive chronic obstructive pulmonary disease and radiation-induced pulmonary changes. Taking into account the low incidence of regional recurrences after local irradiation, the higher incidence and severity of radiation-induced changes, and the higher levels of dysphagia persisting up to 12 months, local irradiation of the primary tumor without elective irradiation of the regional lymph nodes may be the most appropriate treatment for patients with small, peripherally located tumors.

Adult↗

Curative radiotherapy for primary orbital lymphoma.

PURPOSE: To review our institutional experience with primary orbital lymphoma and determine the prognostic factors for survival, local control, and distant metastases. In addition, we also analyzed the risk factors for complications in the radiotherapeutic management of this tumor. METHODS AND MATERIALS: Between 1973 and 1998, 47 patients (29 women [62%] and 18 men [38%], median age 69 years, range 32-89) with Stage IAE orbital lymphoma were treated with curative intent at one department. Five had bilateral orbital involvement. The tumor was located in the eyelid and extraocular muscles in 23 (44%), conjunctiva in 17 (33%), and lacrimal apparatus in 12 (23%). The histologic features according to the World Heath Organization classification of lymphoid neoplasms was follicular lymphoma in 25, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in 8, diffuse large B-cell lymphoma in 12, mantle cell lymphoma in 6, and peripheral T-cell lymphoma in 1. For the purposes of comparison with the existing literature on orbital lymphomas, the grading system according to the Working Formulation was also recorded. The histologic grade was low in 33 (63%), intermediate in 18 (35%), and high in 1 (2%). All patients were treated with primary radiotherapy alone. The median dose for low-grade tumors was 3000 cGy (range 2000-4020); the median dose for intermediate and high-grade tumors was 4000 cGy (range 3000-5100). A lens-sparing approach was used in 19 patients (37%). Late complications for the lens and cornea were scored according to the subjective, objective, management, and analytic (SOMA) scale of the Late Effects of Normal Tissue (LENT) scoring system. The median follow-up was 55 months (range 6-232). RESULTS: The local control rate was 100% in the 52 orbits treated. The 5-year overall survival and relapse-free survival rate was 73.6% and 65.5%, respectively. Tumor grade and location did not predict for overall survival or relapse-free survival. Seven patients (15%) developed distant recurrence (brain 2, extremity 2, mediastinum 1, liver 1, and retroperitoneum 1). One patient (2%) developed cervical node metastasis. The 5- and 10-year cataract-free survival rate was 56.7% and 32.9%, respectively. Of the 12 lens complications, 8 were LENT Grade 1 and 4 were Grade 3 toxicity. Only male gender predicted for an increased risk of cataract formation. Radiotherapy dose and technique did not predict for cataract formation; however, none of the patients who underwent the lens-sparing technique developed Grade 3 lens toxicity or required surgical correction. Of the nine corneal events, two were Grade 1, four Grade 2, and three were Grade 3 toxicity. Ten dry eyes were recorded; all were mild, and no patient had severe dry eye syndrome. Neovascular glaucoma was seen in 1 patient. No injury to the retina or optic nerve was reported. CONCLUSION: Radiotherapy alone is a highly effective modality in the curative management of primary orbital lymphoma. Most complications were minimal and did not require medical or surgical intervention. Although the use of the lens-sparing technique did not influence the incidence of cataractogenesis, we continue to recommend this approach whenever possible, because our experience indicates a higher grade of toxicity occurs and a higher incidence of corrective surgery is needed in patients treated without lens protection.

Adult↗

Curative surgical resection following reirradiation for recurrent rectal cancer.

PURPOSE: In spite of adjunctive radiation and chemotherapy, 10 to 25% of patients with resected rectal cancer develop local recurrence in the pelvis. This study evaluates the potential for curative surgical resection of residual disease following reirradiation for recurrent rectal cancer. METHODS AND MATERIALS: Thirty-nine patients with recurrent adenocarcinoma of the rectum following prior adjunctive therapy underwent reirradiation of the pelvis with concurrent intravenous infusion of 5-fluorouracil. Median time to recurrence following initial treatment was 18 months. Prior radiation doses to the pelvis ranged from 40 to 66 Gy with a median of 50.4 Gy. Reirradiation doses ranged from 20 Gy to 49.2 Gy with a median total dose of 36 Gy. Eight to 12 weeks following reirradiation patients underwent surgical resection of disease. Thirty-one patients had gross total resection of tumor. RESULTS: Patients have been followed for 24 months to 75 months after reirradiation for recurrent rectal cancer with a median follow-up of 3 years. Reirradiation was well tolerated, with seven patients requiring a significant treatment break. Early termination of reirradiation occurred in five patients because of diarrhea, moist desquamation, or mucositis. No surgical mortality was observed. Postoperatively, two patients developed delayed wound healing. Late complications included six patients who developed small bowel obstruction with three patients developing a bowel fistula. The median survival of patients is 45 months, with a 5-year actuarial survival of 24%. Actuarial local control at 5 years was 45%. The rate of distant metastases was 17%. CONCLUSION: Selected patients with rectal cancer who develop recurrent disease following previous adjuvant therapy can undergo successful curative surgical resection following reirradiation/chemotherapy with significant long-term survival.

Adenocarcinoma↗

Family caregiver quality of life: differences between curative and palliative cancer treatment settings.

To compare the impact of cancer caregiving in curative and palliative settings on family caregiver quality of life (QOL), 267 family caregivers of cancer patients receiving curative treatment were compared to 134 family caregivers of cancer patients receiving palliative treatment through hospice. Both groups completed a demographic profile in addition to two self-report QOL questionnaires. Patient performance status and disease site were also recorded. Family caregivers of patients receiving palliative care had significantly lower QOL scores and lower scores on physical health. Hierarchical multiple regressions showed that after accounting for patient performance status, treatment status accounted for no additional significant variability in QOL scores. After accounting for caregiver level of education, treatment status accounted for no additional significant variability in physical health. These results suggest that the lower QOL scores of caregivers in the palliative setting are a reflection of the patients' poorer performance status. The lower physical health scores of caregivers in the palliative setting appear to be a reflection of their lower educational level. Additional research is needed to evaluate the influence of specific demands of caregiving and emotional distress of the caregiver on caregiver QOL.

Adult↗

Cancer of the esophagus and gastro-esophageal junction: potentially curative therapies.

The definition of potential curative tumors of the esophagus and gastro-esophageal junction remains problematic. This is due to a lack of accuracy in clinical staging despite recent advances in CT, endoscopic ultrasonography (EUS), positron emission tomography scan and minimally invasive staging modalities. As a result much controversy persists regarding indications for surgery and extent of resection and lymphadenectomy. Today surgery with curative option results in five-year survival of over 30%. Multimodality regimens, especially neoadjuvant chemoradiotherapy, seem to be beneficial in patients with a complete response on pathologic staging. Other indications are investigational and should be studied within carefully monitored study protocols. In early carcinoma T(is)-T(1a) endoluminal ablation technique seem to open promising perspectives provided of discrimination between T(is)-T(1a) and T(1b) can be made by the use of 20mhz EUS probes.

Adenocarcinoma↗

Association between preoperative plasma CEA levels and the prognosis of gastric cancer following curative resection. Tumor Marker Committee, Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan.

A large-scale retrospective study was undertaken to evaluate the association between preoperative plasma carcinoembryonic antigen (CEA) levels and the prognosis of 2768 gastric cancer patients who underwent curative gastrectomy between 1983 and 1984 at 66 leading medical institutions in Japan Postoperative follow-up was at least 5 years. Preoperative plasma CEA levels were also analysed against other prognostic factors. Preoperative plasma CEA levels showed strong correlations to the degree of lymph node metastasis (P < 0.001), TNM stage (P = 0.004) and the histopathology of the gastric cancer (P < 0.001). Preoperative CEA levels were also evaluated against survival, after being adjusted for the effect of clinically important factors by multivariate analysis. Patients with lower preoperative plasma CEA levels survived significantly longer than patients with higher CEA levels (P = 0.0001). This analysis demonstrates that curatively resected gastric cancer patients with higher preoperative plasma CEA levels have a poorer prognosis than those with lower levels, despite the adjustment for the effects of major prognostic factors.

Adolescent↗

Curative effect of picroliv on primary cultured rat hepatocytes against different hepatotoxins: an in vitro study.

Picroliv, the standardized active principle from the plant Picrorhiza kurrooa showed significant curative activity in vitro in primary cultured rat hepatocytes against toxicity induced by thioacetamide (200 microg/mL), galactosamine (400 microg/mL), and carbon tetrachloride (3 microl/mL). Activity was assessed by determining the change in hepatocyte viability and rate of oxygen uptake and other biochemical parameters (GOT, GPT, and AP). The toxic agents alone produced a 40-62% inhibition of cell viability and a reduction of biochemical parameters after 24 h of incubation at 37 degrees C which (on removal of the toxic agents) was reversed after further incubation for 48 h. Incubation of damaged hepatocytes with picroliv exhibited a concentration- (1-100 microg/mL) dependent curative effect in restoring altered viability parameters. The results warrant the use of this in vitro system as an alternative for in vivo assessment of hepatoprotective activity of new agents.

Animals↗

Longterm effects of hepatic arterial interleukin-2-based immunochemotherapy after potentially curative resection of colorectal liver metastases.

BACKGROUND: Our previous study of hepatic arterial infusion of interleukin-2 (IL-2)-based immunochemotherapy demonstrated a high response rate of patients with unresectable liver metastases. In this study, we applied this therapy to the prevention of liver recurrence in patients who underwent potentially curative resection of liver metastases. STUDY DESIGN: A pilot study was conducted of 18 patients with liver metastases from primary colorectal cancer who underwent potentially curative liver resection followed by adjuvant immunochemotherapy. The regimen consisted of a weekly hepatic arterial infusion of IL-2 (1.4-2.1 X 10(6) U) and 5-fluorouracil (250 mg) and a bolus of mitomycin C (2-4 mg) for 6 months. RESULTS: Among 18 patients, 14 are still alive with a median postoperative survival of 52 months (as of April 1998). The 5-year overall survival rate was 75%. Although recurrent cancer developed in 6 of the 18 patients, no patients had recurrence in the residual liver. This complete prevention of liver recurrence is believed to have contributed to the high 5-year survival rate (75%) as compared with the survival rate of patients treated with surgery alone (average, 30%-40%) or with several other forms of adjuvant therapy. CONCLUSIONS: Interleukin-2-based immunochemotherapy is useful in combination with liver resection for the prevention of liver recurrence in colorectal cancer patients with liver metastases. A multicenter randomized trial is recommended.

Adult↗

Hematopoietic cell transplantation from related and unrelated donors after minimal conditioning as a curative treatment modality for severe paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder caused by a somatic mutation of the X-linked phosphatidylinositol glycan class A gene. Allogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning is the only curative treatment; however, it is associated with high treatment-related mortality. Here, we report on allogeneic HCT for PNH after minimal conditioning. Seven adult patients with high-risk PNH underwent peripheral blood HCT from HLA-A-, -B-, -C-, -DRB1-, and -DQB1-matched related (n = 2) and unrelated (n = 5) donors. Conditioning included fludarabine 30 mg/m(2)/d on days -4 to -2 and 2 Gy of total body irradiation on day 0. After HCT, patients were given immunosuppressive therapy with oral cyclosporine starting on day -3 and mycophenolate mofetil starting on day 0. All 7 patients attained durable engraftment. After 28 days, a median of 77% (range, 53%-96%) T-cell donor chimerism was found in bone marrow and peripheral blood. T-cell chimerism increased to 91% (range, 76%-100%) on day +180 and to 100% in all surviving patients after 12 months. All 7 patients attained complete remissions of their disease. Four patients are alive 13 to 38 months after HCT. Three patients died of treatment-related mortality, 1 because of complications after acute pancreatitis and multiorgan failure, 1 because of infection related to chronic graft-versus-host disease (GVHD), and 1 because of bleeding after liver biopsy for late subacute/chronic GVHD. Allogeneic HCT from related and unrelated donors after minimal conditioning is a new and potentially curative option for patients with advanced PNH.

Adolescent↗

Mechanism of interferon alpha on inhibition of metastasis and angiogenesis of hepatocellular carcinoma after curative resection in nude mice.

The aim of this study was to examine the mechanism of interferon alpha (IFN-alpha) on inhibition of metastasis and recurrence of hepatocellular carcinoma (HCC). Nude mice bearing human HCC xenografts with high metastatic potential (LCI-D20) underwent curative resection of tumors on postimplant day 11. IFN-alpha was begun the next day at different dosages given subcutaneously for 35 consecutive days; normal saline solution was injected into the control mice. The mice were killed 48 hours after the final treatment, and the parameters were evaluated. The HCC intrahepatic recurrence rate, the size of the recurrent lesions, the rate of lung metastasis, the serum vascular endothelial growth factor level, and the microvessel density (immunohistochemistry) were as follows: 100%, 2136+/-794 mm(3)(mean+/-standard deviation), 100%, 265.7+/-154.7 pg/ml, and 144+/-37/HP, respectively, in the control mice, whereas these same values were 62.5%, 89+/-45 mm(3), 12.5%, 53.3+/-9.9 pg/ml, and 86+/-25/HP, respectively, in the IFN-alpha 1.5 x 10(7)U/kg treatment group (P<0.05) and 26.7%, 46+/-21 mm(3), 0%, 65.2+/-17.9 pg/ml, and 39+/-14/HP in the IFN-alpha 3 x 10(7)U/kg treatment group, respectively (P<0.05). However, a significant difference was not found in the serum levels of basic fibroblast growth factor among the control and IFN-alpha treatment groups. IFN-alpha inhibits metastasis and recurrence of human HCC after curative resection in nude mice mediated by antiangiogenesis through downregulating expression of vascular endothelial growth factor but not basic fibroblast growth factor.

Angiogenesis Inhibitors↗

Helicobacter pylori as a prognostic indicator after curative resection of gastric carcinoma: a prospective study.

BACKGROUND: The effect of Helicobacter-pylori status on survival after curative resection for gastric adenocarcinoma is unknown. We aimed to follow-up patients who were positive or negative for infection with H pylori who had curative (ie, R0) resection for gastric adenocarcinoma to assess differences in relapse-free survival and overall survival. METHODS: Before surgery, we assessed the H pylori status of 166 patients who had R0 resection for gastric adenocarcinoma between 1992 and 2002 with bacterial culture, histological analyses (ie, staining with haematoxylin and eosin and with Warthin-Starry), and serological analyses. FINDINGS: At a median follow-up of 53.0 months (range 1-146), relapse-free survival was 56.7 months (95% CI 4.7-108.7) and overall survival was 61.9 months (13.0-110.9) in patients positive for H pylori, compared with 19.2 months (12.7-25.6) and 19.2 months (7.1-31.3), respectively, in patients negative for H pylori (p=0.0009 for difference in relapse-free survival between groups, and p=0.0017 for difference in overall survival between groups). In multivariate analyses, H pylori was an independent prognostic factor for relapse-free survival (hazard ratio 2.16 [95% CI 1.33-3.49]) and overall survival (2.00 [1.22-3.27]). Depth of tumour invasion (2.60 [1.66-4.08]), lymph-node metastasis (2.11 [1.25-3.57]), and patient age 67.5 years or older (1.75 [1.11-2.75]) were also independent prognostic factors for overall survival. INTERPRETATION: Tumour-specific immune responses might be downregulated in patients who are negative for H pylori, and these patients should be followed up carefully because of a poor outlook.

Adenocarcinoma↗

Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente).

BACKGROUND: Several studies have investigated the possible role of the adjuvant chemotherapy after curative resection for gastric cancer failing to show a clear indication; previous meta-analyses suggested small survival benefit of adjuvant chemotherapy, but the statistical methods used were open to criticisms. MATERIALS AND METHODS: Randomised trials were identified by means of Medline and CancerLit and by selecting references from relevant articles. Systematic review of all randomised clinical trials of adjuvant chemotherapy for gastric cancer compared with surgery alone, published before January 2000, were considered. Pooling of data was performed using the fixed effect model. Death for any cause was the study endpoint. The hazard ratio and its 95% confidence intervals (95% CI), derived according to the method of Parmar, were the statistics chosen for summarising the relative benefit of chemotherapy versus control. RESULTS: Overall 20 articles (21 comparisons) were considered for analysis. Three studies used single agent chemotherapy, seven combination of 5-fluorouracil (5-FU) with anthracyclin, ten combination of 5-FU without anthracyclines. Information on 3658 patients, 2180 deaths, was collected. Chemotherapy reduced the risk of death by 18% (hazard ratio 0.82, 95% CI: 0.75-0.89, P < 0.001). Association of Anthracyclines to 5-FU did not show a statistically significant improvement when compared with the effect of the other regimens. CONCLUSIONS: Chemotherapy produces a small survival benefit in patients with curatively resected gastric cancer. However, taking into account the limitations of literature based meta-analyses, adjuvant chemotherapy is still to be considered as an investigational approach.

Antineoplastic Combined Chemotherapy Protocols↗

The role of CA-242 and CEA in surveillance following curative resection for colorectal cancer.

This study was undertaken to evaluate the role of a new tumour marker, CA-242, alone or in combination with CEA in the practical management of colorectal cancer patients after potentially curative resection. A cohort of 149 patients who had undergone 'curative' surgery was followed up according to an intensive protocol in order to detect recurrent disease. Over a median tumour marker follow-up period of 24 months there were 25 recurrences in 24 patients. Both CEA and CA-242 alone detected half the local recurrences. The sensitivity of CEA was 84% for distant or mixed recurrence compared with 64% for CA-242. An abnormality of either CEA or CA-242 enabled detection of five out of six local recurrences and 17 out of 19 distant or mixed recurrences with a median lead time of 5 months for each marker. Both markers were elevated concurrently in only one local and 11 distant recurrences. While CA-242 alone is not superior to CEA, their combined use (either abnormal) has a high sensitivity (88%), specificity (78%) and negative predictive value (97%); this may be useful in reducing unnecessary investigations in follow-up programmes and as a guide to the initiation of further treatment for recurrent disease.

Adult↗

p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer.

This study was undertaken to determine the value of tumour microvessel density (MVD) and the expression of p53 and vascular endothelial growth factor (VEGF) as prognostic markers in patients with gastric cancer operated on for cure. In all, 156 patients with curatively resected gastric cancer constituted the basis of this blinded retrospective evaluation. Patients were treated with either surgery alone (n=53) or surgery plus adjuvant chemotherapy (n=103). Tumour MVD, p53 expression, and VEGF expression were assayed using immunohistochemical techniques. After a mean follow-up of 43 months, 64 (41%) patients had died and 55 (35%) patients developed tumour recurrence. Positive correlations between MVD and both p53 (P=0.005) and VEGF (P=0.005) expression were observed. Both MVD >/=100 (P=0.05) and positive VEGF expression (P<0.02) were associated with shorter disease-free survival, and positive VEGF expression (P=0.01) was also associated with shorter overall survival. Multivariate analysis confirmed that, in addition to the pathological tumour stage, lymph node ratio, the extent of lymphadenectomy and perineural invasion, p53 expression, and VEGF expression were independently associated with both disease-free survival (P<0.0005 and 0.02, respectively) and overall survival (P<0.02 and 0.01, respectively). Finally, patients whose tumours did not show p53 expression had a survival benefit compared to those expressing p53 when treated with adjuvant chemotherapy (P=0.01). This investigation demonstrates that p53 expression and VEGF expression are independent prognostic factors for both disease-free survival and overall survival in patients with curatively resected gastric cancer, and that p53 status may also influence response to chemotherapy.

Adult↗

The relationship between the preoperative systemic inflammatory response and cancer-specific survival in patients undergoing potentially curative resection for renal clear cell cancer.

The relationship between tumour stage, grade (Fuhrman), performance status (ECOG), a combined score (UCLA Integrated Staging System, UISS), systemic inflammatory response (elevated C-reactive protein concentration), and cancer-specific survival was examined in patients undergoing potentially curative resection for renal clear cell cancer (n=100). On univariate survival analysis, sex (P=0.050), tumour stage (P=0.001), Fuhrman grade (P<0.001), UISS (P<0.001), C-reactive protein (P=0.002) were significant predictors of survival. On multivariate analysis with sex, UISS and C-reactive protein entered as covariates, only UISS (HR 2.70, 95% CI 1.00-7.30, P=0.050) and C-reactive protein (HR 4.00, 95% CI 1.21-13.31, P=0.024) were significant independent predictors of survival. The presence of a preoperative systemic inflammatory response predicts poor cancer-specific survival in patients who have undergone potentially curative resection for renal clear cell cancer.

C-Reactive Protein↗

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies.

The chronological history of the important discoveries leading to our present understanding of the essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia (CML) are first reviewed, focusing in particular on abnormalities that are responsible for the massive myeloid expansion. CML is an excellent target for the development of selective treatment because of its highly consistent genetic abnormality and qualitatively different fusion gene product, p210(bcr-abl). It is likely that the multiple signaling pathways dysregulated by p210(bcr-abl) are sufficient to explain all the initial manifestations of the chronic phase of the disease, although understanding of the circuitry is still very incomplete. Evidence is presented that the signaling pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate with cytokines to increase the proportion of stem cells that are activated and thereby increase recruitment into the committed progenitor cell pool, and that this increased activation is probably the primary cause of the massive myeloid expansion in CML. The cooperative interactions between Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between multiple cytokines that are normally required for the activation of stem cells, while at the same time causing numerous subtle biochemical and functional abnormalities in the later progenitors and precursor cells. The committed CML progenitors have discordant maturation and reduced proliferative capacity compared to normal committed progenitors, and like them, are destined to die after a limited number of divisions. Thus, the primary goal of any curative strategy must be to eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of killing the majority of actively proliferating early CML progenitors with minimal effects on normal progenitors. However, like their normal counterparts, most of the CML primitive stem cells are quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later. An outline of a possible curative strategy is presented that attempts to take advantage of the subtle differences in the proliferative behavior of normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl. Leukemia (2003) 17, 1211-1262. doi:10.1038/sj.leu.2402912

Antineoplastic Agents↗