Independent Prognostic Influence Research Articles

Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis

Fluorescence in situ hybridization (FISH) has become a powerful technique for prognostic assessment in multiple myeloma (MM). However, the existence of associations between cytogenetic abnormalities compels us to re-assess the value of each abnormality. A total of 260 patients with MM at the time of diagnosis, enrolled in the GEM-2000 Spanish transplant protocol, have been analyzed by FISH in order to ascertain the independent influence on myeloma prognosis of IGH translocations, as well as RB and P53 deletions. Survival analyses showed that patients with t(4;14), RB or P53 deletions had a significantly shorter survival than patients without these abnormalities. However, patients with RB deletions without other abnormalities in FISH analysis, displayed a similar outcome to those patients without genetic changes by FISH (46 vs 54 months, P=0.3). In the multivariate analysis the presence of t(4;14), RB deletion associated with other abnormalities, age >60 years, high proportion of S-phase cells and advanced stage of the disease according to the International Staging System retained their independent prognostic influence. In summary, RB deletion as a sole abnormality does not lead to a shortening in the survival of MM patients, whereas t(4;14) confers the worst prognosis in MM patients treated with high-dose chemotherapy.

Smoking Compromises Cause-specific Survival in Patients with Operable Colorectal Cancer

Aims To assess whether active smoking compromises survival in patients with colorectal cancer. Materials and methods We studied a regionally based cohort of 284 consecutive patients referred to the Tayside Cancer Centre for consideration of adjuvant treatment after curative surgery for colorectal cancer. Results Cause-specific survival was significantly worse ( P = 0.0015) in patients who were actively smoking at the time of their first post-operative visit. The absolute difference in 5-year cause-specific survival (active smokers vs the rest) was 21%. In adjusted multi-variate analysis of patients after pathologically complete (R0) resection, the hazard ratio was 2.55 (95% confidence interval 1.40–4.64) in active smokers compared with non-smokers. T stage, number of positive nodes and co-morbidity score were also of independent prognostic influence. Conclusions Persistent smoking was, in this small series, an important and independent predictor of cancer-related death after surgery for cancer of the large bowel. Because smoking and deprivation are related, some of the adverse effects of deprivation upon survival in this group of patients may be explained by smoking behaviour.

Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patients.

Although multiple myeloma (MM) is predominantly a disease of the elderly, few studies have focused on the identification of prognostic factors in this group of patients. Four hundred twenty five MM patients >65 years were uniformly treated with chemotherapy (MP or VCMP/VBAD). Multivariate analysis identified 4 factors with independent unfavorable prognostic influence: high percentage of S-phase bone marrow plasma cells (>2.5%); elevated beta(2) microglobulin (B2M) (>4 mg/L); age >80 years old; and LDH serum levels (above normal limit). The S-phase value was the most powerful independent prognostic factor to discriminate subgroups of patients with different prognosis. Thus, 3 main risk categories could be identified according to S-phase values: </=1%, 1-3% and >3%, with median survivals of 34, 22 and 12 months, respectively (p < 0.0001). Our study also proved the value for elderly patients of the recently developed International Score System (ISS) based on B2M and albumin. Furthermore, the number of S-phase cells helped to subdivide the ISS III Group identifying a subset of patients with very poor prognosis defined by an additional high S-phase, who displayed a median survival of only 8 months. These results demonstrate that elderly patients can be accurately classified according to prognosis, which may be particularly valuable when comparing the efficacy of new treatment strategies. Moreover, our results underline the high prognostic value of proliferative activity of PC, a parameter that should be considered in routine laboratory investigations of MM.

Prognostic Factors, Pattern of Recurrence and Survival in a Danish Bladder Cancer Cohort Treated with Radical Cystectomy

A cohort of 248 consecutive patients with bladder cancer undergoing radical cystectomy between 1992 and 98 was retrospectively followed from diagnosis until death. Prognostic factors, pattern of recurrence and survival were analysed. Pathological T and N, angiolymphatic and perineural invasion had an independent prognostic influence on survival. Patients without muscle-invasive tumour (Ta, T1) had a good prognosis, whereas patients with primarily superficial tumour progressing to muscle-invasive tumour had a significantly poorer outcome. Forty-six percent of these patients developed recurrences in the follow-up period, with a median time from recurrence to death of 5 months. The 5-year disease-specific survival for all 248 patients was 57%. Patients with pT4b or N+ all died within 3 years. Patients with positive lymph nodes or T4b were not curable with cystectomy alone. Patients with advanced T or with perineural/vessel invasion are in need of improved treatment options. Patients with superficial tumours at high risk of progression should be offered early cystectomy.

Methylation is an inactivating mechanism of the p16 gene in multiple myeloma associated with high plasma cell proliferation and short survival

In order to gain further insights into the role of the p16 gene in cell cycle regulation and the prognostic implications of its inactivation, we investigated the methylation status of the p16 gene in 98 untreated patients using a polymerase chain reaction assay based on the inability of some restriction enzymes to digest methylated sequences. Forty-one patients showed a p16 methylated gene (42%). The percentage of S-phase plasma cells (PC) in these patients was almost three times higher than in those with an unmethylated p16 gene (4.16% +/- 3.37%vs 1.5% +/- 1.41%, P < 0.001). The presence of p16 methylation also correlated with both elevated beta2-microglobulin serum levels and high C-reactive protein values. Patients with a p16 methylated gene had shorter overall and progression-free survival than those patients without p16 methylation. However, this feature did not retain independent prognostic influence on multivariate analysis, probably due to its association with the S-phase PC, which had more potent statistical significance in the Cox model. These findings showed methylation of the p16 gene was a frequent event inMM patients at diagnosis, and was associated with an increased proliferative rate of plasma cells and a poor prognosis, indicating an important role for p16 gene in the cell cycle regulation of multiple myeloma tumour cells, and thus in the clinical outcome of the disease.

Prognostic index for cutaneous melanoma: an analysis after follow-up of 2715 patients.

In 2715 of 4524 patients with cutaneous melanoma treated surgically between 1968 and 1992 prognostic parameters were analysed for their value in predicting the occurrence of first progression. All of the 2715 patients developed only one invasive cutaneous melanoma during the follow-up period. Data concerning tumour thickness and mitotic index (maximum number of mitoses per square millimetre) of the cutaneous melanomas were determined. Between the characteristics age, tumour thickness, mitotic index, prognostic index (PI), sex, site of tumour, melanoma subtype and Clark level, the value of the mitotic index, as a prognostic parameter independent of tumour thickness, and the combination of mitotic index and tumour thickness were evaluated. The development of the first metastases was documented during a mean follow-up of 7.5 years. The majority of first recurrences occurred at regional lymph nodes and attempts have been made to identify those patients at risk of developing metastatic disease. The most effective parameters proved to be tumour thickness and mitotic index. For both parameters an independent prognostic influence was shown. The prognostic index, defined as the product of tumour thickness and number of mitoses per square millimetre, was re-evaluated and confirmed. A new modified prognostic index, defined as the product of square tumour thickness and mitotic index, proved to be even more useful for defining a subgroup of patients who are at risk of developing metastases and, therefore, might benefit from adjuvant therapy.

Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning

Objective: This study was undertaken to investigate the value of the ground-glass opacity (GGO) area found on high-resolution computed tomography (HRCT) scanning as a preoperative prognostic indicator. Patients and methods: We studied 104 patients with small-sized lung adenocarcinoma, 20 mm or less in diameter, between 1995 and 1999. Three independent radiologists semi-quantitatively scored the extent of GGO on HRCT as greater than or less than 50%. Three independent pathologists semi-quantitatively scored the extent of the bronchioloalveolar carcinoma (BAC) component of the tumor on histologic examination as greater than or less than 50%. As no relapse occurred in patients with GGO greater than 50%, multivariate analysis of this prognostic factor was not possible. Results: Fifty patients were scored as having both BAC and GGO greater than 50%, 36 as both BAC and GGO less than 50%, and 16 as BAC greater than 50% and GGO less than 50%. In only two patients (1.9%), BAC less than 50% was overestimated on HRCT as GGO greater than 50%. The sensitivity and specificity of GGO to BAC were 76 and 95%, respectively. The 3 year-relapse-free survival rates in each group of 52 patients with GGO greater than and less than 50% were 100 and 72%, respectively, after a median follow-up of 24 months. Univariate analysis indicated that both GGO and BAC areas were significantly correlated with cancer relapse ( P=0.005 and P=0.002). The multivariate analysis revealed an independent prognostic influence of the BAC area on relapse-free survival ( P=0.015, relative risk=0.07). Conclusions: To date there has been no relapse among the 52 patients with GGO greater than 50%. This novel classification based on the semiquantitative analysis of GGO area on HRCT should become an useful independent preoperative indicator when deciding on operative procedure, and to predict the potential of relapse in patients with small adenocarcinoma arising from the peripheral lung.

Esophageal cancer: the mode of lymphatic tumor cell spread and its prognostic significance.

Data on skip metastases and their significance are lacking for esophageal cancer. This issue is important to determine the extent of lymphadenectomy for esophageal resection. In this study we examined the lymphatic spread in esophageal cancer by routine histopathology and by immunohistochemistry. A total of 1,584 resected lymph nodes were obtained from 86 patients with resected esophageal carcinoma and evaluated by routine histopathology. Additionally, frozen tissue sections of 540 lymph nodes classified as tumor-free by routine histopathology were screened for micrometastases by immunohistochemistry with the monoclonal antibody Ber-EP4. The lymph nodes were mapped according to the mapping scheme of the American Thoracic Society modified by Casson et al. Forty-four patients (51%) had pN1 disease, and 61 patients (71%) harbored lymphatic micrometastases detected by immunohistochemistry. Skip metastases detected by routine histopathology were present in 34% of pN1 patients. Skipping of micrometastases detected by immunohistochemistry was found in 66%. The presence of micrometastases was associated with a significantly decreased relapse-free and overall survival (56.0 v 10.0 months and > 64 v 15 months, P <.0001 and P =.004, respectively). Cox regression analysis revealed the independent prognostic influence of micrometastases in lymph nodes. Lymph node skipping had no significant independent prognostic influence on survival. Histopathologically and immunohistochemically detectable skip metastases are a frequent event in esophageal cancer. Only extensive lymph node sampling, in conjunction with immunohistochemical evaluation, will lead to accurate staging. An improved staging system is essential for more individualized adjuvant therapy.

Deletion of 11q23 is a frequent event in the evolution of MYCN single-copy high-risk neuroblastomas.

Deletions of the long arm of chromosome 11 are frequently identified in human neuroblastomas. We screened 394 primary neuroblastomas and 52 tumor-derived cell lines with a panel of 11q and 11p polymorphic markers to determine the frequency of chromosome 11 allelic deletion, and to differentiate partial deletions of chromosome 11q (unb[11q] LOH) from whole chromosome loss. Allelic deletion occurred most frequently at cytogenetic band 11q23 and was detected in 161 primary neuroblastomas (41%) and 18 cell lines (35%). Eighty-seven tumors (22%) had unb[11q] LOH with a heterogeneous distribution of deletion breakpoints. Unb[11q] LOH was highly correlated with age > 1 year at diagnosis (P = 0.008), stage 4 disease (P = 0.001), unfavorable Shimada histopathology (P < 0.001), and assignment to a high-risk therapeutic protocol (P < 0.001), and was inversely correlated with MYCN amplification (P = 0.018). Patients whose tumors showed unb[11q] LOH were less likely to survive (P < 0.001), but there was only a trend towards an independent prognostic influence in multivariate analyses. Thus, structural rearrangements resulting in unb[11q] LOH commonly occur during the malignant evolution of high-risk neuroblastomas with single-copy MYCN.

Prognostic Relevance of a Histological Grading System Using MIB-1 for Adult Soft-Tissue Sarcoma

Several histological grading systems have been proposed and found as strong indicators of outcome in soft-tissue sarcomas. However, a putative independent prognostic influence of recently developed biological and molecular markers remains to be established. This study investigated the prognostic relevance of a histological grading system based on the assessment of proliferative activity in adult soft-tissue sarcomas of the extremities, trunk, head, and neck. Tissue blocks from 95 of 108 patients without distant metastases or regional lymph node involvement were available. Immunohistochemical staining for MIB-1 and p53 was done on paraffin-embedded sections. All clinicopathologic and immunohistochemical variables and patient survival were assessed using univariate and multivariate analyses. Variables included histological grading based on the modified Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system using the MIB-1 score for the estimation of the proliferative potential of the tumors. Variables associated with overall survival were tumor site in the trunk, head and neck, mitosis count, necrosis, MIB-1 score, FNCLCC grade, modified FNCLCC grade using the MIB-1 score, and stage (all p values <0.05). In multivariate analysis, the modified grade proved to be the most significant predictor of shortened overall survival, in addition to tumor site in the trunk, head, and neck. Overexpression of p53 did not correlate with increased risk of tumor mortality. Using MIB-1 to replace mitosis counts in the FNCLCC system improves grading of soft-tissue sarcomas, and this in conjunction with other important factors appear to be more accurate prognostic factors for survival, and for patient selection in investigational adjuvant treatment trials.

Long-term results of early gastric cancer accomplished in a European institution by Japanese-type radical resection.

BACKGROUND: Long-term survival following Japanese-type radical surgery for 130 consecutively performed early gastric cancers (EGC) in a single Austrian institution between January 1, 1984 and May 31, 1998 was analyzed in terms of long-term survival, postoperative morbidity, and mortality.METHODS: Extended D2 lymphadenectomy as defined by the JRSGC was performed in 129 patients with EGC. The surgical process was consistent as nearly all patients were operated on by only two surgeons. Overall survival and factors influencing survival were analyzed with particular regard to the depth of tumor infiltration, histological type, tumor grading, Lauren classification, tumor diameter, macroscopic appearance, localization, and lymph node involvement.RESULTS: Of 678 gastric cancer patients surgically treated in the mentioned period, 130 patients (19.2%) were qualified as EGC. In 70 patients the tumor was limited to the mucosa and in 60 patients the tumor had not yet invaded the submucosa. The percentage of patients with positive lymph nodes increased from 2.9% with mucosal invasion to 21.7% with submucosal tumor involvement. The overall 5- and 10-year observed survival rate, postoperative mortality not excluded, was 74.6% and 62.1%, respectively, and 91.1% and 91.1%, respectively, when calculated as tumor specific. The 5- and 10-year observed survival rate of tumors limited to the mucosa was 77.2% and 72.1%, respectively, and 98.1% and 98.1%, respectively, when calculated as tumor specific. The respective values for submucosal invasion were 71.6% and 51.7%, and 82.7% and 82.7%. Postoperative complications occurred in 17 patients (13.1%) and postoperative hospital mortality totaled 1.5% (2/130). In multivariate analysis, only lymph node metastases were found to have independent prognostic influence on survival ( P < 0.001; hazard ratio, 8.25).CONCLUSION: Japanese-type radical lymph node dissection for EGC in a European surgical institution yielded long-term survival nearly identical to that reported repeatedly by Japanese authors. Postoperative morbidity and mortality was not sacrificed by our comparatively radical surgical approach.

In reply

We appreciate the comments of Marcus and Clarf-ield in reference to our study published in the January issue of the Journal. Standard deviation of the patients age in each group was as follows: 15.2 years for the group less than 65 years of age and 7.9 years for the group 65 years and older. When the “old” group was subdivided further into two categories, 65 to 74 years and 75 years and older, mortality of patients in relation to age and functional status continues to show the influence of impaired functional status on outcome (Table 1). On the other hand, all consecutive patients with a positive blood culture for Gram-negative and Gram-positive bacilli during the study period were included in the prospective study, as were patients with AIDS. However, although AIDS was more common in the younger group, the mortality of AIDS patients was higher in the most disabled. In our opinion, functional status is a better prognostic factor than age because it indicates the severity of comorbidity independent of the comorbid process itself. AIDS is a comorbid process with independent prognostic influence, but impaired functional status acts as a confounder.

The prognostic importance of peritoneal involvement in colonic cancer: A prospective evaluation

BACKGROUND & AIMS: Prognostic parameters specific to the colon have been somewhat neglected compared with the rectum. This study was instituted to assess the influence of local peritoneal involvement (LPI) on pelvic and intraperitoneal recurrence and prognosis in an unselected, prospective series of colonic cancer resections. METHODS: Meticulous examination of 412 resections included evaluation of the relation of the tumor to the peritoneal surface. Histological assessment was as follows: 1, peritoneal involvement absent (81 resections, 20%); 2, inflammatory reaction with tumor close but not present at the surface (89 resections, 22%); 3, peritoneal surface unequivocally infiltrated (112 resections, 27%); and 4, peritoneal involvement with ulceration and tumor cells lying apparently free in the peritoneum (130 resections, 32%). RESULTS: LPI showed strong independent prognostic influence in both curative surgery groups and in all patients. In multivariate analysis in curative surgery, LPI was the most powerful prognostic indicator. It was significantly associated with palliative surgery, extent of local spread, and mucinous subtype and predicted cases with subsequent intraperitoneal recurrence and/or persistence. CONCLUSIONS: LPI is a common event in colonic cancer and is a consistent predictor of subsequent intraperitoneal recurrence. It is an important independent pathological prognostic parameter and may supersede other parameters in current usage in colonic cancer prognosis. (Gastroenterology 1997 Apr;112(4):1096-102)

Lymphoid cell distribution as prognostic factor in carcinoma of the uterine cervix.

Pretreatment assessment of blood lymphoid cells was performed in 44 patients with carcinoma of the cervix and in 19 healthy controls. White blood cells were determined by routine differential counting, and T-lymphocyte subsets and monocytes were quantitated using monoclonal antibodies. Increase in monocyte numbers, as determined by the 1D5 antibody, was seen in the cancer patients, especially in the group with advanced disease. No change in T-lymphocyte subpopulations could be found. During the 5-year follow-up period, 17 patients had a recurrence or died of cancer. The best prognostic information was obtained from conventional clinical parameters, e.g. stage, tumor size and lymph node status. Increased numbers of granulocytes and monocytes were found in advanced stage disease but had no independent prognostic influence. In pelvic lymph node biopsies taken from patients undergoing Wertheim-Meigs operation the T-helper/T-suppressor ratio was higher and the monocyte number lower than in peripheral blood. No correlation could be detected between node cell distribution and the prognosis. It is concluded that immunological testing, as performed in this study, elicits very little new prognostic information.

The clinical features and prognosis of rhabdomyosarcoma: Follow-up studies on pediatric tumors from the Japanese pediatric tumor registry 1971–1980. Part II

A retrospective study was conducted on 126 patients with rhabdomyosarcoma enrolled in the Japanese Pediatric Tumor Registry between 1971 and 1980. The age of the patients ranged from less than 1 year to 15 years, and the male to female ratio was 1.3:1.0. Primary sites included the pelvis (37.3 per cent), abdomen (23.8 per cent), head and neck (21.4 per cent), thorax (9.5 per cent), extremities (6.4 per cent) and unknown (1.6 per cent). According to the staging system of the Japanese Society of Pediatric Surgeons, the extent of disease was classified into stages Ia (26.2 per cent of the total); Ib (14.6 per cent); II (12.6 per cent), III (29.1 per cent) and IV (17.5 per cent). The clinical stage was significantly correlated with survival outcome in this series (p less than 0.05). Age, sex, histology and primary site per se had no independent prognostic influence on tumor-free survival. With regard to treatment modalities, surgery was performed in 94.0 per cent of the patients, and radiotherapy at a mean dose of 37 Gy, and/or multi-agent chemotherapy in 41.7 per cent and 80.0 per cent, respectively. The patients who underwent total excision had a better survival outcome than those who did not (p less than 0.05). Combination chemotherapy such as VAC was more commonly administered in the latter study period. The overall 2-year tumor-free survival rate (2YTFSR) significantly improved from 24.0 per cent in the former period between 1971 and 1975 to 48.7 per cent in the latter period between 1976 and 1980 (p less than 0.05).

Influence of mucinous components on survival in colorectal adenocarcinomas: a multivariate analysis.

Of 534 resected colorectal adenocarcinomas, 165 (31%) contained some mucinous components; these represented the main part of the tumour in 67 (13%). Of the mucin containing tumours, 63 (38%) were in the right colon compared with 50 (13%) of the non-mucinous ones (p less than 0.001). Patients with predominantly mucinous tumours were significantly older than those with non-mucinous tumours, and they tended to present with tumours at a more advanced stage. A multivariate analysis did not show any significant independent prognostic influence of the mucinous component except when this had a predominantly signet ring cell pattern.

Neuroblastoma: influence of age at diagnosis, stage, tumor site, and sex on prognosis.

A study of a consecutive series of 99 children with neuroblastoma seen at two major Toronto hospitals between 1951 and 1971 is reported. The children who were aged 24 months or less at diagnosis showed an overall two-year survival rate of 59 percent. Analysis, including fitting of a log-linear model, showed that increased probability of survival was associated with younger age at onset, nonadrenal site, and lower staging and the each of these factors acted independently. The sex of the child had no prognostic effect. This study thus extends earlier work by demonstrating the independent prognostic influence of site of tumor. The implications for treatment policy are discussed.

Clinical pattern and course of disease in primary biliary cirrhosis based on an analysis of 236 patients

A prospective study of the clinical pattern and course of primary biliary cirrhosis based on the data of 236 patients (211 females, 25 males) in an international randomized trial has been performed mainly using life-table technique. The median follow-up period has been 18 mo. After the entry into the study, at which time the median duration of symptoms was 2.1 yr, the estimated 5-yr increase in the cumulative percentage of patients was for pruritus from 75% to 95%, jaundice 59% to 82%, hepatomegaly 54% to 86%, pigmentation 54% to 85%, xanthomas 27% to 50%, GI bleeding 17% to 46%, ascites 7% to 49%, and vertebral collapse 3% to 20%. The frequency of cirrhosis increased from 30% to 82% in 4 yr. The mitochondrial antibody titer showed a high rate of progression with time. In analysis of subgroups, age, histologic stage, and particularly the serum bilirubin level were important prognostic factors. Sex, duration of symptoms, and character of first symptom or sign had no independent prognostic influence. The most important indication of seriously proressive course was rapid development of severe cholestasis independent of the histologic stage.