Crucial Prognostic Factor Research Articles

Persistent Presence of Postoperative Circulating Tumor Cells is a Poor Prognostic Factor for Patients with Stage I–III Colorectal Cancer after Curative Resection

To detect pre- and postoperative circulating tumor cells (CTCs) in stage I-III colorectal cancer (CRC) patients undergoing curative resection and so identify a subgroup of patients who are at high risk for relapse. Four mRNA molecular markers including human telomerase reverse transcriptase, cytokeratin-19, cytokeratin-20, and carcinoembryonic antigen mRNA were used to detect CTCs in 438 CRC patients underwent curative resection. Out of 438 patients, 80 CRC patients were classified to preoperative (-)/postoperative (-), 221 patients were preoperative (+)/postoperative (-), while 137 patients were preoperative (+)/postoperative (+). Univariately, postoperative relapse was significantly correlated with depth of invasion (P = 0.032), lymph node metastasis (P < 0.001), vascular invasion (P = 0.001), perineural invasion (P = 0.013), and persistent presence of CTCs (P < 0.001). Using a multivariate proportional hazards regression analysis, the presence of lymph node metastasis (P = 0.012; HR, 7.652; 95% CI: 4.162-14.827), vascular invasion (P = 0.033; HR, 4.360; 95% CI: 2.793-10.847), and the persistent presence of CTCs (P < 0.001; HR, 29.486; 95% CI: 10.281-87.792) were demonstrated to be independent predictors for postoperative relapse. Combination of these three independent predictors showed that patients with any one positive predictor had a hazard ratio of sevenfold to develop postoperative relapse (P < 0.001; HR, 7.064; 95% CI: 4.354-11.464). Furthermore, the persistent presence of CTCs was strongly correlated with poorer relapse-free survival rates (all P < 0.001). The promising results of this study suggest that persistent presence of postoperative CTCs may be a crucial prognostic factor adjuvant to conventional tumor markers in CRC patients who have undergone curative resection. Identification of these high-risk patients of persistent CTCs positivity is important and thus could help to define patients for adjuvant therapy with this tumor entity.

The lipoprotein subfraction profile: heritability and identification of quantitative trait loci

The HDL and LDL subclass profile is an emerging cardiovascular risk factor. Yet, the biological and genetic mechanisms controlling the lipoprotein subclass distribution are unclear. Therefore, we aimed 1) to determine the heritability of the entire spectrum of LDL and HDL subclass features and 2) to identify gene loci influencing the lipoprotein subfraction pattern. Using NMR spectroscopy, we analyzed the lipoprotein subclass distribution in 1,275 coronary artery disease patients derived from the Regensburg Myocardial Infarction Family Study. We calculated heritabilities, performed a microsatellite genome scan, and calculated linkage. HDL and LDL subclass profiles showed heritabilities ranging from 23% to 67% (all P < 10(-3)) of traits using univariate calculation. After multivariate adjustment, we found heritabilities of 27-48% (all P < 0.05) for HDL and 21-44% for LDL traits. The linkage analysis revealed a significant logarithm of the odds (LOD) score (3.3) for HDL particle concentration on chromosome 18 and a highly suggestive signal for HDL particle size on chromosome 12 (2.9). After multivariate adjustment, we found a significant maximum LOD score of 3.7 for HDL size. Our study is the first to analyze heritability and linkage for the entire spectrum of LDL and HDL subclass features. Our findings may lead to the identification of genes controlling the lipoprotein subclass distribution.

Mid-Treatment Evaluation of 18-FDG-Positron Emission Tomography/Computed Tomography (PET) as Predictive Value of Response Assessment in Aggressive Non Hodgkin Lymphoma (NHL).

Introduction: The PET is mostly used in staging of NHL patients at diagnosis and as response assessment at the end of treatment. The evaluation by PET after few cycles of chemotherapy may be useful to predict chemosensitivity and then response, progression-free survival and overall survival in this subset of patients. In our study we introduced the PET in the mid-treatment evaluation (PET-2) of aggressive NHL disease.Patients and methods: From June 2004 to December 2006, 25 consecutive aggressive NHL patients were evaluated for this study: 17 males and 8 females respectively with median age of 49 years (range 21–67). We included: 18 Diffuse Large B Cell, 1 anaplastic, 2 mantle cell, and 4 follicular grade III NHL. Patients characteristics were: 11/25 bulky disease; 20/25 intermediate or high IPI risk; 3/25 stage II, 3/25 stage III and 19/25 stage IV. All patients were staged according to standard imaging procedures completed by PET at the diagnosis and at the end of treatment. After 2 or 4 cycles of Rituximab-CHOP-like chemotherapy PET-2 was repeated in all of them.Results: PET-2 demonstrated: 16/25 patients negative and 9/25 patients positive. The conventional and PET restaging performed at the end of treatment were 21/25 negative and 4/25 positive. Among the 16 patients PET-2 negative, 14/16 remained negative at the final PET evaluation and achieved CR, 2/16 became positive with demonstration of progression disease. Among the 9 patients PET-2 positive, 7/9 became negative with achievement of CR. The other 2/9 patients remained positive at the end of therapy: one of them was false positive because of parotid gland carcinoma without NHL involvement. Among 21/25 patients PET negative at the final evaluation, 20/25 patients remained in CR with a median follow-up of 18 months and only one patient negative at the PET-2 and at the final PET demonstrated disease progression. Finally, with a median follow-up of 18 months, FFS was 84% in all pts, 81% in PET-2 negative patients and 89% in PET-2 positive patients respectively.Conclusions: The PET is an important imaging technique for staging and end-treatment evaluation in lymphoma disease, because it can better define CR patients. In Hodgkin disease several studies demonstrated that the early evaluation by PET is a crucial prognostic factor to test chemosensitivity and then to predict favourable outcome. In our study the mid-evaluation of response by this procedure had not so clear predictive value of response assessment, because patients, even if positive at PET-2, can achieve CR at the end of treatment. More large studies are needed to determine the real impact of on-course PET as response assessment in aggressive NHL patients.

Circumferential Margin Involvement Is the Crucial Prognostic Factor after Multimodality Treatment in Patients with Locally Advanced Rectal Carcinoma

After preoperative (radio)chemotherapy, histologic determinants for prognostication have changed. It is unclear which variables, including assessment of tumor regression, are the best indicators for local recurrence and survival. A series of 201 patients with locally advanced rectal cancer (cT3/T4, M0) presenting with an involved or at least threatened circumferential margin (CRM) on preoperative imaging (<2 mm) were evaluated using standard histopathologic variables and four different histologic regression systems. All patients received neoadjuvant radiochemotherapy or radiotherapy. The prognostic value of all factors was tested with univariate survival analysis of time to local recurrence and overall survival. Local recurrence occurred in only 8% of the patients with a free CRM compared with 43% in case of CRM involvement (P < 0.0001). None of the four regression systems were associated with prognosis, not even when corrected for CRM status. However, we did observe a higher degree of tumor regression after radiochemotherapy compared with radiotherapy (P < 0.001). Absence of tumor regression was associated with increasing invasion depth and a positive CRM (P = 0.02 and 0.03, respectively). Assessment of CRM involvement is the most important pathologic variable after radiochemotherapy. Although tumor regression increases the chance on a free CRM, in cases with positive resection margins prognosis is poor irrespective of the degree of therapy-induced regression.

Tethered Spinal Cord Syndrome - The Importance of Time for Outcomes

Tethered spinal cord syndrome is a relatively uncommon disorder of the medullary spine, usually associated with other congenital diseases of the caudal end of the spinal cord. However, it often remains unrecognised and due to its progressive character has serious consequences for those affected. We analysed a group of 22 patients, treated for TTS during the period from 1990 to 2005, focussing on the time period between the onset of symptoms and their treatment. The initial data from the year 1998 already pinpointed this time-lag as a crucial prognostic factor for outcomes. Nine of the 22 treated patients showed an improvement of symptoms, 2 of them ad integrum. Eleven remained unchanged, without further progress and 2 patients worsened after surgery or despite it. Our results showed a direct correlation between the time-lag and the outcome of therapy. The average time span between recognition of disease and operation in those patients whose symptoms improved was about 16.7 months, whereas for those who remained unchanged it was 52.4. In the patients who worsened it was 54 months. Virtually all patients operated within the first year showed a subsequent improvement of symptoms. Only 25 % of patients operated at a later stage achieved some measure of improvement. Time is a relevant factor for success.

Primary hepatoma – guidelines for interdisciplinary treatment

BACKGROUND: Though recent developments in operative and non-operative therapy have added considerably to the therapeutic spectrum for primary hepatoma, there is a need for exact evaluation of their success and guidelines for their application. METHODS: Current therapeutic options for primary hepatoma are rated on the basis of recent publications and results of consensus conferences. RESULTS: According to the Milan criteria only a few patients with hepatocellular carcinoma are eligible for liver transplantation. Early detection of these tumours by surveillance of cirrhotic patients is essential for the success of the transplantation concept. Resection rates for hepatocellular and intrahepatic or hilar cholangiocellular carcinoma amount to about 10–20 %; there is wide consensus that R0-resection is a crucial prognostic factor. For the majority of patients neither transplantation nor resection is an option. For this very delicate patient group, a variety of therapeutic procedures are warranted with effects difficult to compare given the bias of patient selection and the great inter-patient and inter-institutional variability. Especially for procedures with promising results such as radiofrequency ablation, further studies are needed if clinical decisions are to be based on a high level of evidence. CONCLUSIONS: Primary hepatoma should be treated in specialised centres by a team that is truly dedicated to the very special problems of these patients and that holds regular interdisciplinary conferences to optimise the multimodal approach to this disease. Guidelines are helpful for treatment management but must be individually modified and tailored to the specific situation of every single patient.

Preoperative Radiochemotherapy and Radical Resection for Stages II to IV Oral and Oropharyngeal Cancer: Grade of Regression as Crucial Prognostic Factor

Preoperative Radiochemotherapy and Radical Resection for Stages II to IV Oral and Oropharyngeal Cancer: Grade of Regression as Crucial Prognostic Factor

Clinical significance of lymph node dissection in renal cell carcinoma

To identify the role of lymph node dissection in renal cell carcinoma (RCC). A total of 100 patients (66 males, 34 females) were enrolled in the study. The mean age and tumor size were 61.4 years and 5.8 cm, respectively. A total of 41 patients (41%) had tumors <4 cm in diameter. The pathological status was pT1, pT2 and pT3 in 60, 11 and 29 patients, respectively. In total, lymph node metastases were found in seven cases (7%). Of 40 patients with pT1a tumors (tumor size <4 cm), one (2.5%) had lymph node metastasis. Patients with lymph node metastases had significantly larger tumors than those without (8.9 vs 5.5 cm; p<0.05). Regarding patient outcome, 33 (33%) had tumor progression (alive with disease, n=14; disease-specific death, n=19) after a median follow-up period of 54.0 months. In univariate analysis, 15/18 prognostic markers [tumor size, tumor grade, pT, pN and M categories, stage, microscopic venous invasion (V category), microscopic lymphatic invasion (Ly category), pathological tumor infiltration pattern (INF category), plasma fibrinogen, C-reactive protein, immunosuppressive acidic protein, alpha-2 globulin and erythrocyte sedimentation rates at 1 and 2 h] were common significant predictors of tumor progression. A Cox hazard model revealed tumor size, tumor grade and pathological stage to be independent prognostic factors. Tumor size is a crucial prognostic factor for tumor progression, and lymph node dissection may be omitted in T1a tumors.

Preoperative radiochemotherapy and radical resection for stages II to IV oral and oropharyngeal cancer: grade of regression as crucial prognostic factor

The purpose of this study was to assess the prognostic value of histological response to preoperative radiochemotherapy in an established multimodal therapy concept for advanced oral and oropharyngeal cancer. Two hundred and twenty-two patients who underwent preoperative radiochemotherapy (RCT: 50 Gy, mitomycin C and fluorouracil) and radical surgery were retrospectively evaluated. Resected tumours of all patients were histologically analysed and response to RCT was classified in histopathological grades of regression (RG). In a multivariate statistical analysis, RG was compared with established factors regarding their predictive value for overall and disease-specific survival. The 5-year overall survival probability in the different groups of histopathological regression grades were: RG1 (no vital tumour): 73.4%, RG2 (minimal tumour remnants encompassing less than 5%): 72.1%, RG3 (5–50% vital tumour cells): 41.9%, RG4 (more than 50% vital tumour): 37.9%. For disease-specific survival probability no significant differences were found between both groups of “responders” (RG1 and RG2) nor between “non-responders” (RG3 and RG4), whereas responders and non-responders differed significantly from each other (log-rank test; P<0.001). T-classification, N-classification and disease stage, histological grading, tumour site, age, and sex had less prognostic value than RG in a Cox regression model. In the neoadjuvant multimodal therapy concept, histological response to preoperative RCT is a crucial prognostic factor even when surgical R0-resection is accomplished. Thus, non-responders have to be regarded as high-risk patients for recurrence and may benefit from further therapy.

Variables pertinent to successful habilitation of delayed cochlear implantation in prelingual children

It is well known that the duration of deafness is a crucial prognostic factor for the results of a cochlear implant. Nevertheless, this fact does not justify the absolute contraindication of late cochlear implantation in well-selected prelingually deafened children.The aim of this study is to investigate the factors, which might be of relevance to improved speech perception skills, speech and language production skills in this particular group of children. Fifteen children were enrolled in this study; they all had prelingual deafness (mean age at onset of deafness was 1 year). The mean age at implantation was 5.8 years. A hierarchy of listening skills, speech production and spoken language skills were evaluated prior to their receiving the multichannel cochlear implant and at subsequent intervals.Most of the children showed capability to recognize auditory information in a closed-set context, however variable degrees of improvement were reached in open-set speech recognition. They all showed improved speech and language production skills. However, some differences were found between the good and poor performance patients depending on several variables such as motivation and participation of the parents, regularity of attendance, long-term implant experience with consistent use of the device and an aural–oral educational placement.

Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma.

Intrahepatic metastasis via portal vein spread is an important feature and a crucial unfavorable prognostic factor of hepatocellular carcinoma (HCC). To identify the molecular factors for tumor progression, the authors used differential display (DD) to analyze aberrant gene expression in HCC. The goal of the current study was to elucidate the clinicopathologic and prognostic significance of osteopontin (OPN) in HCC progression. OPN mRNA levels, which were increased preferentially in HCC in a DD assay and verified with Northern blotting, were measured in 240 surgically removed, unifocal, primary HCCs using the reverse transcription-polymerase chain reaction at the exponential phase. OPN mRNA expression was correlated with clinicopathologic features, particularly portal vein invasion, early tumor recurrence, and prognosis. Osteopontin mRNA was overexpressed in 133 tumors (55%). The OPN overexpression was associated closely with alpha-fetoprotein elevation (P = 0.001), p53 mutation (P = 0.021), larger tumors (P = 0.002), high-grade HCC (P < 0.001), late-stage HCC (P < 0.001), early tumor recurrence and/or metastasis (P = 0.003), and a lower 10-year survival rate (P = 0.00013). Multivariate analysis revealed that tumor stage and early tumor recurrence were crucial prognostic factors. In early-stage HCC, which has no vascular invasion and a lower early tumor recurrence than late-stage HCC, OPN mRNA overexpression predicted a higher early recurrence rate (P = 0.003). OPN mRNA overexpression was correlated closely with high-grade, late-stage, and early tumor recurrence, which lead to poorer prognosis. Osteopontin overexpression might serve as an unfavorable prognostic factor and a useful marker for predicting early recurrence in early-stage HCC.

Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia

An unmutated germ line configuration of the immunoglobulin variable heavy-chain gene (VH) has emerged to be a crucial adverse prognostic factor in chronic lymphocytic leukemia (CLL) under conventional treatment. The purpose of the present study was to investigate whether the VH mutational status retains its prognostic value in CLL also in the setting of autologous stem cell transplantation (SCT). Therefore, we investigated the mutational status in 58 patients with CLL who underwent myeloablative radiochemotherapy with SCT. Rearranged VH genes were analyzed by multiplex polymerase chain reaction (PCR) and direct sequencing using FR1 family-specific primers and JH consensus primers. Twenty patients (34%) showed less than 98% homology compared with germ line VH sequences and were considered as mutated, whereas 38 patients (66%) had an unmutated VH status (median mutational rate of 0%; range, 0%-1.7%). An unmutated VH configuration was strongly correlated with the presence of short lymphocyte doubling time (P =.003) and high lymphocyte count (P =.005). Time to clinical relapse and time to recurrence of monoclonal B cells as assessed by consensus IgH CDR3 PCR was significantly shorter in the group with unmutated VH genes (2-year probability 19% versus 0%, P =.0008, and 34% versus 9%, P =.0006, respectively). These results show that in CLL, an unmutated VH gene status of the tumor clone remains an adverse prognostic factor after SCT. Nevertheless, the hitherto only 3 deaths and the median treatment-free interval of 49 months in the unmutated cohort suggest a beneficial effect of SCT for this high-risk population in comparison to conventional treatment.

Long-term outcome of gliomas of the visual pathway in type 1 neurofibromatosis

Optic gliomas are frequently associated with neurofibromatosis type 1 (NF1) and belong to the diagnostic criteria of NF1. Different growth rates require differentiated strategies for screening and observation. 29 patients (25 children < 11 years, 4 adults > 18 years) with visual pathway tumors and NF1 were examined neurologically, ophthalmogically, by means of MRI and VEP. Results were set into context with preceding investigations (mean follow up time 6.5 years). 11 children showed a stable condition, 14 an unfavorable process with substantial loss of vision. Children with an unfavorable process showed a lower age at diagnosis (3.2 versus 5.8 years; p < 0.05), more frequently strabism (11/14 versus 1/11; p < 0.05), optic atrophy (12/14 versus 1/11; p < 0.05), pathological VEP (9/9 versus 2/10; p = 0.001), visual field defects (9/9 versus 1/9) and involvement of the optic chiasm (11/14 versus 3/11; p < 0.05) than children with a stable condition. 3 of 4 adults had no visual symptoms despite involvement of the optic chiasm. The crucial prognostic factor is the patient's age at the time of diagnosis. Optic gliomas which become symptomatic in early childhood (< 6 years) grow rapidly and require frequent ophthalmologic investigations and MRI. Tumors diagnosed in late childhood (> 6 years) do not progress, allowing for gradual extension of intervals between ophthalmological investigations.

P-Glycoprotein Expression in De Novo Acute Myeloid Leukemia

Detection of the multidrug resistance P-glycoprotein (PGP) phenotype was performed at the time of diagnosis in 223 patients with acute myeloid leukemia (AML) by flow cytometry using C219 Monoclonal Antibody (MoAb). On the other hand, JSB1 MoAb was tested in 173 of these samples. At onset, PGP was detected in 57.4% of cases with C219 and 75.9% of cases with JSB 1. There was no correlation between PGP expression and sex, age, marrow blast percentage or extramedullary disease. On the contrary, strict correlations were noted either between C219 negativity and FAB M3 subtype or between C219 positivity and FAB M5 group (P = 0.003). Significant correlation was found between PGP phenotype and CD7, as 143 of 223 samples had similar patterns of staining with C219 (P < 0.0001). Finally, there was a close relationship between C219 and JSB1 positivity: all the C219+ cases were positive for JSB1 (P < 0.0001). Concerning the karyotype, most patients with monosomy or del (7) were MDR positive; on the other hand, most patients with t(8;21) or t(15;17) were MDR negative. Rh123 accumulation studies showed a significant decrease of mean fluorescence intensities both in C219 and in JSB1 positive cases in comparison with PGP negative ones (P < 0.001). A significant decrease of remission induction rates (CR) was highlighted both between C219+ and C219− and between JSBT+ and JSB1− cases (32.1% v 62.1% and 32.6% v 73.8%, respectively, with P < 0.0001). The overall survival and the remission duration (CCR) were significantly shorter both in C219+ and in JSB1+ patients with no relationship to age. Furthermore, a higher rate of early relapses was noted among MDR+ when compared with MDR− patients both for C219+ and JSBT cases. The combination (C219− JSB1+) identified a subset of patients with an intermediate prognosis. On multivariate analysis, C219 and JSB1 were confirmed to be independent prognostic factors for achievement of CR, overall survival and CCR. In conclusion, the assessment of MDR phenotype by flow cytometry is a crucial prognostic factor of treatment outcome in AML.

Stage II glottic carcinoma: Prognostic factors and management

Three hundred thirty-six patients with squamous cell carcinoma of the glottic larynx treated at the University of Virginia Medical Center from 1960 through 1977 were reviewed. Seventy patients with T2N0M0 disease, grouped according to the criteria of the American Joint Committee on Cancer, 1978, form the basis of this report. The 5-year actuarial survivals, recurrences, salvages, and prognostic factors were examined. Treatment was radiation, surgery, or a combination of radiation and surgery. Impaired vocal cord mobility in Stage II glottic squamous cell carcinoma is the crucial significant prognostic factor in predicting response to therapy, survival, and response to salvage therapy for recurrences. The 90% 5-year recurrence-free rate with freely mobile cords is comparable to that achieved with Stage I lesions. Impaired mobility resulted in a 5-year recurrence-free rate of 73%, which is comparable to that of T3N0 lesions. We support the concept of reclassifying Stage II disease into Stage IIa (mobile cords) and Stage IIb (impaired mobility). Based on this review and those reported in the literature, we recommend radiation therapy for Stage IIa disease. Surgery results in fewer recurrences and in longer survival than irradiation when the vocal cords are not freely mobile (Stage IIb).