Subsequent Development Of Distant Metastases Research Articles

Comprehensive Evaluation of Quality of Life in Penile Cancer Patients following Surgical Treatment

Background: Penile cancer (PC) is a highly aggressive disease, with a significant tendency for lymphatic spreading and subsequent development of distant metastases. The mutilating nature of PC surgical treatment has profound implications on the patient’s body integrity and self-image, sexual life and intimacy, voiding and mental health. The aim of our study was to comprehensively evaluate PC patients’ post-treatment quality of life (QoL), sexual activity, self-esteem, fatigue and fear of disease recurrence. (2) Methods: A cross-sectional study was conducted at the Clinic of Urology, University Clinical Centre of Serbia, and included 31 PC patients. Data were collected by means of a questionnaire. (3) Results: The average score on the Global health status scale was 67.2 out of 100 (ranging from 16.7 to 100), and the SD was 22.5. Hierarchical linear regression analysis showed that demographic characteristics, Hospital Anxiety and Depression scale (HADS) anxiety and depression scores, total Multidimensional Fatigue Inventory, Fear of cancer recurrence and Rosenberg scores and erectile function score explained a total of 78.2% of the variance in the global health status/QoL scale of PC patients. (4) Conclusions: Efforts should be made not only to increase the survival of PC patients after surgical treatment but also to enable the best possible level of QoL in the post-operative period.

Abstract PD15-01: Snord67 promotes lymph node metastasis through U6-mediated alternative splicing in breast cancer

Abstract Background: While the presence of lymph node (LN) metastases in solid tumor malignancies is clinically significant and associated with increased risk for distant metastases, there is little evidence that lymphatic metastasis is distinct from hematogenous dissemination. Recent studies showed that cancer cells in LNs can directly give rise to distant metastases, but the mechanisms behind how cancer cells exit lymph nodes to establish distant metastases is still unknown. Materials and Methods: We developed an immunocompetent mouse model of lymph node metastasis using the 4T1 murine breast cancer cell line. In this model, 4T1 cells micro-surgically injected into axillary lymph nodes (AxLN) are capable of spontaneously establishing distant metastases. We then performed microarray analyses of subclones derived from MFP tumors, AxLN-injected tumors (AxLN), and lung metastases that arose from AxLN-injected tumors (AxLN-LuM) to evaluate for non-coding RNAs (ncRNAs) that were differentially expressed in AxLN tumors. Results: Microarray analyses of ncRNAs expressed in MFP, AxLN, and AxLN-LuM subclones showed that a class of ncRNAs, small nucleolar RNAs (snoRNAs), were enriched in AxLN tumors compared to MFP and AxLN-LuM. We identified the snoRNA SNORD67 as a key regulator of LN metastasis. Knockout of SNORD67 by both CRISPR and antisense oligonucleotide (ASO) resulted in significantly decreased LN tumor growth and subsequent development of distant metastases. This was at least in-part due to loss of targeted 2’-O-methylation of the small nuclear RNA U6, a component of the spliceosome. RNA-Seq analyses revealed distinct alternative splicing in SNORD67 knockouts. Using rapid autopsy breast cancer cases, we found that matched primary tumor and LN metastases revealed similar alternatively spliced genes, including several genes with previously described cancer-promoting splice variants. Conclusions: Small nucleolar RNAs (snoRNAs) have long been regarded as “housekeeping genes”, important for ribosomal biogenesis and protein synthesis. However, there is increasing evidence that this largely ignored class of non-coding RNAs (ncRNAs) also have wide-ranging, non-canonical functions in diseases, including cancer. SnoRNAs have been shown to have both oncogenic and tumor suppressor roles, yet whether snoRNAs regulate metastasis is unknown. Here we show that expression of certain snoRNAs are enriched in lymph node (LN) metastases in a micro-surgical, immune-competent mouse model of breast cancer. Moreover, our results show that SNORD67 is critical for growth of LN metastases and subsequent spread to distant metastases, and suggest that snoRNA-guided modifications of the spliceosome represent a previously unappreciated, yet targetable pathway in cancer. Citation Format: Yvonne Chao, Yinzhou Zhu, Hannah J Wiedner, Yi-Hsuan Tsai, Lily Wilkinson, Alessandro Porrello, Amanda ED Van Swearingen, Lisa Carey, Jimena Giudice, Christopher L Holley, Chad V Pecot. Snord67 promotes lymph node metastasis through U6-mediated alternative splicing in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-01.

The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation

EPHB6 is a metastasis inhibitory gene that is frequently decreased or deficiency in non-small cell lung cancer (NSCLC), which contributed to the subsequent development of distant metastasis. These suggested the possibility that reactivation of EPHB6 might prevent the metastasis of NSCLC. Nevertheless, EPHB6 expression might also promote cancer cell growth and inhibit cell apoptosis by activating Akt and ERK pathway, apart from inhibition of migration and invasion. In the present study, we developed a novel quinazolin-4(3H)-one analog (DFX24) as a potential PI3Kα inhibitor, which inhibited both cell proliferation and metastasis of NSCLC cell lines. Investigation to the molecular mechanisms revealed DFX24 inhibited the cell growth and metastasis via inhibition of PI3Kα and ERK activity, as well as the increase in EPHB6 expression. In addition, DFX24 also induced cell cycle arrest and tumor cell apoptosis by inhibiting PI3K/Akt pathway and activating mitochondria-dependent pathway, respectively. These findings suggested that DFX24 might be considered as a novel drug candidate and may provide a potential therapy for NSCLC.

The clinical value of peripheral immune cell counts in pancreatic cancer.

Elevated neutrophil-lymphocyte ratio (NLR) is linked to poor overall survival (OS) in pancreatic cancer. We aim to investigate the association of the various hematologic markers, in particular NLR among others, with distant metastases, a common feature in pancreatic cancer. Clinical data from 355 pancreatic cancer patients managed at King Hussein Cancer Center (Amman-Jordan) have been reviewed. We examined the relationship between absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute eosinophilic count (AEC), absolute monocytic count (AMC), NLR, monocyte to lymphocyte ratio (MLR) and platelet to lymphocyte ratio (PLR) with the presence of baseline distant metastases and OS. Receiver Operating Characteristic (ROC) curve analysis was plotted to identify the NLR optimum cutoff value indicative of its association with distant metastases. On univariate and multivariate analyses patients whom on presentation had high NLR (≥3.3) showed more baseline distant metastases compared to patients with low NLR (<3.3), (p-value: <0.0001 and <0.0001, respectively). Patients with high baseline ANC (≥5500/μL), AMC (≥600/μL), MLR (≥0.3) had more baseline distant metastases in comparison to patients with lower values (p-value: 0.02, 0.001, and <0.0001, respectively). High ANC, NLR, MLR, and PLR and low ALC were associated with poorer OS, (p-value: <0.0001, <0.0001, <0.0001, 0.04, and 0.01, respectively). This study presents additional evidence of the association of some of the hematologic markers; in particular ANC, NLR, AMC, and MLR, with baseline distant metastases and poor outcome in pancreatic cancer. Whether these immune phenomena can help in identifying patients at higher risk for the subsequent development of distant metastases is unknown.

Carcinoid Tumors of the Rectum

This study aims to describe recent experience with rectal carcinoids in European and North American centers. While considered indolent, the propensity of carcinoids to metastasize can be significant. Rectal carcinoid patients were identified from prospective databases maintained at 9 institutions between 1999 and 2008. Demographic, clinical, and histologic data were collated. Median follow-up was 5 years (range, 0.5-10 years). Two hundred two patients were identified. The median age was 55 years (range, 31-81 years). The majority of tumors were an incidental finding (n = 115, 56.9%). The median tumor size was 10 mm (range, 2-120 mm). Overall, 93 (49%) tumors were limited to the mucosa or submucosa, 45 (24%) involved the muscularis propria, 29 (15%) extended into the perirectal fat, and 6 (3%) reached the visceral peritoneum. The primary treatment modalities were endoscopic resection (n = 86, 43%) and surgical extirpation (n = 102, 50%). Forty-one patients (40%) underwent a high anterior resection, whereas 45 (44%) underwent anterior resection with total mesorectal excision. Seven patients (7%) underwent Hartman's procedure, 7 (7%) underwent abdomino-perineal resection, and 6 (6%) had transanal endoscopic microsurgery, whereas 4 (4%) patients underwent a transanal excision. Multiple variable logistic regression analysis demonstrated that tumor size greater than 10 mm and lymphovascular invasion were predictors of nodal involvement (P = 0.006 and < 0.001, respectively), whereas the presence of lymph node metastases and lymphovascular invasion was associated with subsequent development of distant metastases (P = 0.033 and 0.022, respectively). The presence of nodal metastases has a profound effect upon survival, with a 5-year survival rate of 70%, and 10-year survival of 60% for node positive tumors. Patients with distant metastases have a 4-year survival of 38%. Tumor size greater than 10 mm and lymphovascular invasion are significantly associated with the presence of nodal disease, rendering mesorectal excision advisable. Transanal excision is adequate for smaller tumors.

The EPHB6 Receptor Tyrosine Kinase Is a Metastasis Suppressor That Is Frequently Silenced by Promoter DNA Hypermethylation in Non–Small Cell Lung Cancer

Loss of EPHB6 receptor tyrosine kinase expression in early-stage non-small cell lung carcinoma (NSCLC) is associated with the subsequent development of distant metastasis. Here, we analyzed the regulation and function of EPHB6 in lung cancer metastasis. The expression levels of EPHB6 were compared among normal lung tissue (n = 9), NSCLC without metastasis (n = 39), and NSCLC with metastasis (n = 39) according to the history of the patients. In addition, EPHB6 expression levels of matched tumor-normal pairs from 24 NSCLC patients were analyzed. The promoter DNA methylation status and its association with the expression levels of EPHB6 were determined among 14 pairs of tumor-normal samples. Metastatic potential of EPHB6 was assessed in vitro and in vivo in a metastasis mouse model. Overexpression and RNA interference (RNAi) approaches were used for analysis of the biological functions of EPHB6. EPHB6 mRNA and protein levels were significantly reduced in NSCLC tumors compared with matched normal lung tissue. Decreased EPHB6 expression levels were associated with an increased risk for metastasis development in NSCLC patients. Loss of expression correlated with EPHB6 hypermethylation. EPHB6 expression was induced by 5-aza-2'-deoxycytidine treatment in an NSCLC cell line. Restoration of EPHB6 expression in lung adenocarcinoma cells increased adhesion and decreased migration. Reexpression of EPHB6 in lung cancer cells almost entirely abolished metastasis formation in non obese diabetic (NOD)/severe combined immunodeficient mice. Taken together, these analyses show that EPHB6 is a metastasis inhibitory gene that is frequently silenced by hypermethylation of its promoter in NSCLC.

Survivin Is a Potential Mediator of Prostate Cancer Metastasis

We examined whether Survivin expression is associated with an increased risk of metastasis in prostate cancer. A total of 205 patients with T1 (23%) and T2 (77%) prostate cancer were treated with conventional external beam radiation therapy from 1991 to 1993 at the Massachusetts General Hospital. Of the patients, 62 had adequate and suitable-stained tumor material for Survivin analysis. Median follow-up was 102 months (range, 5-127 months). Distant failure was determined on the basis of clinical criteria. In preclinical studies, replication-deficient adenovirus encoding phosphorylation-defective Survivin Thr34→Ala dominant-negative mutant pAd-S(T34A) or short hairpin RNA (shRNA) was used to inhibit Survivin in prostate cancer models, and the cell motility, morphology, and metastasis were investigated. Our correlative data on men with early-stage (T1/T2) prostate cancers treated at Massachusetts General Hospital by definitive radiotherapy indicated that overexpression of Survivin (positive staining in ≥10% cells) was associated with a significantly increased risk for the subsequent development of distant metastasis (p = 0.016) in the univariate analysis. In the multivariate analysis, overexpression of Survivin remained an independent predictor of distant metastasis (p = 0.008). The inhibition of Survivin dramatically inhibited invasiveness of prostate cancer cells in the in vitro invasion assay and spontaneous metastasis in the Dunning prostate cancer in vivo model. Furthermore, attenuation of Survivin resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. This study suggests that Survivin may be a potentially important prognostic marker and promising therapeutic target in metastatic prostate cancer.

Twist, an independent prognostic marker for predicting distant metastasis and survival rates of esophageal squamous cell carcinoma patients

The transcription factor Twist plays a key role in cancer metastasis. The present study aimed at investigating clinical Twist expression in patients with esophageal squamous cell carcinoma (ESCC) in order to correlate the Twist levels with the patients' survival rates and their other clinical parameters. Immunohistochemical staining using polyclonal Twist antibody was performed on paraffin embedded specimens of 112 ESCC patients and non-neoplastic esophageal epithelium used as a control. The overall staining intensity was analyzed along with clinicopathologic data and prognosis of ESCC. Twist expression was significantly higher in ESCC than in non-neoplastic oesophageal epithelium (P < 0.001). The Twist expression directly correlated with distant metastasis after esophagectomy (P = 0.001). Kaplan-Meier estimate in conjunction with the log-rank test revealed an inverse proportion relationship between postoperative survival rates of the patients and their Twist expression levels (log-rank, P < 0.001). In addition, Cox mono-variate analysis revealed that T/N classification, pTNM stage, distant metastasis and Twist expression were significantly correlated with mortality risk of patients after operation (P < 0.05). By Cox multi-variate analysis, Twist expression (risk ratio = 2.394; P < 0.001) and N classification were identified as the independent prognostic factors of patient survival. In conclusion, upregulated Twist expression in the primary ESCC significantly correlates with the high risk of subsequent development of distant metastasis and low postoperative survival rates; the latter was not significantly correlated with patients' age, gender, tumor location and differentiation. Twist may serve as an independent prognostic marker for predicting development of distant metastasis in ESCC patients and their survival.

Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study)

Aim To evaluate the prognostic and predictive importance of detection of melanoma cells in peripheral blood using reverse transcriptase polymerase chain reaction (RT-PCR) in stage III cutaneous melanoma patients after sentinel or regional lymph node dissection. Patients and methods Serial testing for tyrosinase and Mart-1/Melan-A transcripts in peripheral blood was performed every 6 months over a maximum period of 60 months in a subset of patients enrolled in EORTC 18991 phase 3 trial, comparing pegylated interferon-α-2b with observation. Univariate and multivariate analyses were performed to estimate the role of RT-PCR as prognostic and predictive factor for distant metastasis-free survival (DMFS). Results Among 299 patients who underwent RT-PCR analyses, 109 (36.5%) had at least one positive sample, either at time of randomisation ( N = 17) or subsequently ( N = 92). The cumulative rate of positive results was similar in the two treatment groups, as the DMFS from first RT-PCR positivity. RT-PCR result, positive versus negative, at a given time point, had no prognostic impact on subsequent DMFS. Cox time-dependent analysis indicated a significantly higher risk of developing distant metastasis in patients with a positive sample as compared to those with a negative one: hazard ratio (HR) of 2.23 (95% confidence interval (CI), 1.40–3.55; p < .001). These results were comparable in the 2 treatment groups, indicating that RT-PCR assessment was not predictive for treatment outcome. Conclusion Detection of circulating tumour cells by RT-PCR for tyrosinase and Mart-1/Melan-A was a time-dependent moderate prognostic factor for subsequent development of distant metastasis in stage III melanoma patients.

Predictive value of bone marrow accumulation of Tc-99m tetrofosmin for subsequent development of distant metastases in breast cancer

We evaluated the predictive value of bone marrow accumulation of technetium (Tc)-99m tetrofosmin in patients with breast cancer for distant metastases in comparison with conventional prognostic factors such as clinical stage, tumor size, axillary lymph node (Node) status, and estrogen receptor (ER) status. Bone marrow scans with Tc-99m tetrofosmin were performed on 64 patients with breast cancer who had no clinical evidence of distant metastases. Accumulation in the femoral marrow was classified into four patterns, no detectable, lower, higher, and intensively higher. Higher or intensively higher pattern was interpreted as abnormal. Thirty-six patients with abnormal accumulation (marrow-positive group) and 28 patients without abnormal accumulation (marrow-negative group) were enrolled in the follow-up study. The mean length of observation after scans was approximately 3 years. The predictive value of femoral marrow status and conventional prognostic factors for distant metastases was evaluated by statistical analysis. Univariate analysis showed a significantly higher incidence of subsequent bone metastases (36%>4%; P<0.005), and distant metastases (69%>18%; P<0.001) in the marrow-positive group when compared with the marrow-negative group. Conventional prognostic factors except tumor size were also significantly associated with the development of distant metastases; 77% in clinical stage 3>39% in clinical stages 1, 2, P<0.05; 64% in Node-positive>29% in Node-negative, P<0.01; and 70% in ER negative>27% in ER positive, P<0.005. These conventional factors were not significantly associated with bone metastases. The Cox proportional hazard ratio for bone metastases was markedly higher in femoral marrow status (hazard ratio=11.07). The distant metastases-free survival was significantly reduced in ER negative (P<0.0005), Node-positive (P=0.0215), and clinical stage 3 patients (P=0.0163). On the other hand, a more marked difference was observed in the femoral marrow status (P<0.0001). The hazard ratio for distant metastases was 2.44 in clinical stage, 2.74 in tumor size, 2.74 in Node, and 3.68 in ER, which were each independent prognostic factors associated with distant metastases. However, femoral marrow status was markedly associated with distant metastases (hazard ratio=5.27). Bone marrow accumulation of Tc-99m tetrofosmin can be a promising prognostic factor independent of conventional prognostic factors for predicting development of not only bone metastases but also distant metastases in breast cancer.

Upregulation of Twist in oesophageal squamous cell carcinoma is associated with neoplastic transformation and distant metastasis

Background: The antiapoptotic and epithelial–mesenchymal transition activities of Twist have been implicated in the neoplastic transformation and the development of metastasis, respectively. Upregulation of Twist, described in several types of...

Patterns of disease recurrence influenced by hematogenous tumor cell dissemination in patients with cervical carcinoma of the uterus.

The presence of isolated tumor cells (ITC) in the bone marrow at the time of primary diagnosis indicates an increased risk for subsequent development of distant metastases in various solid tumors. This study evaluates the prevalence and prognostic significance of ITC in patients with primary carcinoma of the cervix uteri. We immunocytochemically analyzed bone marrow aspirates of 130 patients with newly diagnosed carcinoma of the cervix uteri for the presence of cytokeratin(CK)-positive cells from May 1994 to January 2001. We used a quantitative immunoassay with the monoclonal anti-CK antibody A45-B/B3 and evaluated 2 x 10(6) bone marrow cells per patient. Patients were followed prospectively for a median of 43 (range, 1-85) months. Isolated tumor cells were found in the bone marrow of 38 patients (29%). The presence of ITC did not correlate with the International Federation of Gynecology and Obstetrics (FIGO) tumor stage (P = 0.61), pelvic and paraaortal lymph node involvement (P = 0.41), histopathologic grading (P = 0.67), the histologic type of the carcinoma (P = 0.93), invasion of lymph nodes (P = 0.93) and blood vessels (P = 0.92), or with menopausal status (P = 0.17). The bone marrow status at the time of primary diagnosis did not correlate with the overall survival as estimated by Kaplan-Meier analysis (P = 0.30). However, distant metastases occurred in 5% of the patients (n = 5) with negative bone marrow status and in 15% of the patients (n = 6) with positive bone marrow status (P = 0.054). The median distant disease-free survival period was 78 months (95% confidence interval 73-82) in patients with negative bone marrow status and 72 months (95% CI 61-82) in patients with positive bone marrow status (P = 0.051). Multivariate analysis revealed the presence of ITC as a significant, independent risk factor for the subsequent development of distant metastases (relative risk 3.6, P = 0.046). Despite the locoregional predominance of cervical carcinoma at the time of primary diagnosis, the presence of ITC in the bone marrow indicates an increased risk for the development of distant metastases. This information may prove useful to stratify patients for systemic treatment.

The Systemic Progression of Human Cancer: A Focus on the Individual Disseminated Cancer Cell—The Unit of Selection

The metastatic progression of solid tumors is discussed controversially. Because metastasis is usually lethal, it appears as an end point of successive cellular changes. This has led to the prevailing interpretation that genetic changes, in addition to those present in the most advanced clone of the primary tumor, are required to initiate invasion, dissemination, and growth at anatomically distant sites. It has become possible to detect and analyze single disseminated cancer cells at ectopic sites long before metastasis can be diagnosed by standard clinical techniques. Because the finding of single disseminated cancer cells correlates with the subsequent development of distant metastasis, these cells have been identified as the precursors of metastasis. Their direct molecular-genetic characterization, however, shows that dissemination occurs very early in the process of accumulation of genetic changes and suggests that metastases may seldom be derived from the dominant clone of the primary tumor. In contrast, it appears that cancer cell evolution explores a multitude of variant cells from which systemic cancer can develop independently. This review integrates data derived by different approaches into a model of systemic cancer progression.

Distant metastases in head and neck cancer patients who achieved loco-regional control.

One of the reasons for failure in patients with head and neck carcinoma who achieve locoregional control with treatment is the appearance of distant metastases. The objective of this study was to evaluate the frequency of distant metastases in this group of patients and to determine the relative role of several prognostic factors in the subsequent development of distant metastases. Retrospective study from a database that collects the information prospectively in a cohort of patients with head and neck carcinoma. Patients and Methods The study was carried out in 1244 patients with oral cavity, pharyngeal, or laryngeal carcinoma who achieved locoregional control. We evaluated the frequency of distant metastases and the influence of different variables in their appearance. Five percent of patients with locoregional control had distant metastases. In the univariate study, the variables that influenced the appearance of distant metastases were tumor site, T stage, N stage, and histologic differentiation. On multivariate analysis, the variables that increased the risk of distant metastases were N stage, T stage, and the location of the tumor at the hypopharynx and the supraglottis. Five percent of patients with oral cavity, pharyngeal, or laryngeal carcinomas who achieved locoregional control died as a consequence of the development of distant metastases. The factors that significantly increased the risk of distant metastases in this group of patients were the advanced local and regional extension of the tumor and the location at the hypopharynx or supraglottis.

Prognostic implications of response to preoperative infusional chemoradiation in locally advanced rectal cancer

Background and purpose: To evaluate the influence of response to preoperative infusional chemoradiation on outcome parameters among patients with locally advanced rectal cancer. Materials and methods: Preoperative chemoradiotherapy, 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m 2 per day), was given to 117 patients. As determined by pretreatment endorectal ultrasound (EUS), 96% of cases were Stage T3, and 51% had EUS evidence of perirectal adenopathy. Surgery was performed approximately 6 weeks after chemoradiation therapy. Postoperatively adjuvant systemic therapy, consisting of 400–425 mg/m 2 of 5-fluorouracil plus 20 mg/ m 2 leucovorin for 5 days, was administered every 28 days for six cycles. Outcome parameters of local control (LC), freedom from distant metastases (DMC), disease-free survival (DFS) and cancer specific survival (CSS) were evaluated relative to primary tumor characteristics. Results: The final post-treatment pathological tumor stages were complete response in 27%, Tis-2 N0 in 26%, T2 N1 in 5%, T3 N0 in 21%, T3 N1 in 15%, T4 N0 in 5% and T4 N1 in 1%. Down-staging occurred in 61% of cases. The pretreatment primary tumor size only influenced rates of local control ( P<0.03) and had no other influence on outcome parameters. Pretreatment evidence of perirectal lymph node involvement had no impact on outcome parameters. Pathologic evidence of nodal involvement did affect DMC ( P<0.002) and DFS ( P<0.003). Pathologic evidence of response did influence freedom from the development of distant metastases ( P<0.004). On pairwise analysis this relationship held only when responders were compared to non-responders. No difference was observed based on the level of downstaging at the primary tumor. Correspondingly, DFS was improved when non-responders were compared to downstaged patients ( P<0.01). Response to preoperative chemoradiation failed to affect rates of LC or CSS. For the group as a whole, adjuvant chemotherapy improved only CSS ( P<0.03). Adjuvant chemotherapy was given to 74 patients, 36 of whom had responded to preoperative chemoradiation. Improvements were only seen in DFS ( P<0.03) when down-staged patients were compared to the non-responders who received adjuvant chemotherapy. In addition, the DFS rates were lower in the non-responder group who received adjuvant chemotherapy even when they were compared to down-staged patients who did not receive adjuvant chemotherapy ( P<0.04). Conclusion: Consistent with other reports, disease free survival and subsequent development of distant metastases is reduced in the more than 60% of patients who respond to preoperative infusional chemoradiation. Evidence of response appears more significant than the degree of response. At present, no impact is seen on cancer specific survival rates. Consideration should be given for strategies that base selection of subsequent adjuvant chemotherapy on response to preoperative chemoradiation.

Ipsilateral breast tumor recurrence as a predictor of distant disease: implications for systemic therapy at the time of local relapse.

To evaluate the prognostic significance of ipsilateral breast tumor recurrence (IBTR) with respect to the subsequent development of distant metastasis. Between January 1970 and December 1989, 973 patients with invasive breast cancer were treated with conservative surgery and radiation therapy at Yale-New Haven Hospital. The median follow-up time as of December 1993 was 8.6 years. A number of prognostic factors were tested as possible predictors of distant metastases, including whether a patient experienced IBTR. IBTRs were broken down by time to recurrence to determine whether the breast recurrence-free interval had any prognostic relevance with respect to the development of distant metastasis. As of December 1993, out of the entire population of 973 patients, 73 patients had developed IBTR and 134 had developed distant metastases. The overall actuarial survival rate at 10 years was .71 +/- .02, with a 10-year actuarial breast recurrence-free rate of .84 +/- .02 and a 10-year distant metastasis-free rate of .77 +/- .02. The overall distant metastasis rate was higher in patients who experienced IBTR compared with patients who had never experienced IBTR. Furthermore, the time to IBTR had a significant effect on distant metastases. Of 32 patients who developed an IBTR within 4 years of original diagnosis, 16 (50%) developed distant metastases. In contrast, of 41 patients who developed later breast relapses (> 4 years from original diagnosis), only seven (17%) developed distant metastases (P < .01). Of 32 patients who developed early breast relapse, the 5-year survival rate following breast relapse was .50 +/- .01, compared with a 5-year post-breast relapse survival rate of .78 +/- .10 among 41 patients with later breast relapses (P < .05). It appears that early IBTR is a significant predictor for distant metastases. Whether early breast tumor relapse is a marker for or cause of distant metastases remains a controversial and unresolved issue. Implications for adjuvant systemic therapy at the time of breast relapse are discussed.

Clinical significance of routine pre-cystectomy bone scans in patients with muscle-invasive bladder cancer.

To evaluate the clinical significance of bone scans taken routinely before total cystectomy in patients with bladder cancer of clinical stage > or = T2. Of 227 consecutive patients with stage > or = T2 bladder cancer diagnosed between 1980 and 1990 but with no clinical suspicion of bone metastases, 91 had a pre-cystectomy bone scan performed at the Norwegian Radium Hospital. The medical records of these patients were reviewed to examine the subsequent development of distant metastases and survival. Of the 91 patients, 37 (41%) developed skeletal bone metastases after cystectomy, unrelated to the clinical T category. In 35 patients, the pre-cystectomy bone scan showed pathological uptake of isotope which was interpreted by the specialist in nuclear medicine as suspicious of (13 patients) or probably caused by (22 patients) skeletal metastases. In either circumstance, the clinician decided that total cystectomy was precluded, particularly as most of the changes could be explained radiologically as being degenerative. In the individual patient, there was no clinically useful correlation between the findings on the pre-cystectomy bone scan and the clinical course of disease, nor if serum alkaline phosphatase (SAP) level was included as an additional predictive factor. However, although not statistically significant, the follow-up of all patients revealed an association between the degree of change on the pre-cystectomy bone scan and the subsequent development of skeletal metastases and cancer-corrected survival. Unless further investigations, particularly magnetic resonance imaging (MRI), can be performed, the findings of a routine pre-operative bone scan are usually unable to identify patients with bladder cancer of stage > or = T2 who will not be cured by total cystectomy. An increased level of SAP did not improve the predictive accuracy of a pre-cystectomy bone scan. However, the results indicate that future clinical research should be directed at combining the findings of bone scans and MRI in the search for micrometastases.

Does node location affect the incidence of distant metastases in head and neck squamous cell carcinoma?

An analysis of 455 patients with head and neck carcinomas and clinically positive neck nodes who were treated with radiation therapy alone to their primary tumors (with or without a neck dissection) was conducted to determine the relative role of several prognostic factors in the subsequent development of distant metastases (DM). The factors analyzed were N stage, node location (upper neck only vs. lower with or without upper neck), T stage, primary site (oral cavity, oropharynx, nasopharynx, hypopharynx, supraglottic larynx), modified AJCC stage, and neck treatment. All patients were treated between 1964 and 1985 and had a minimum follow-up of 2 years. The N stage and node location were the most significant prognostic factors in the subsequent development of distant metastases. The incidence of distant metastases increased with increasing neck stage (N1, 11%; N2, 18%; N3, 27%), and in four of five neck stages (N2B being the exception), the incidence of distant metastases was greater for those patients with metastatic adenopathy in the lower neck. The incidence of distant metastases by modified AJCC stage was 12 111 (11%) for Stage III, 34 146 (23%) for Stage IVA, and 41 198 (19%) for Stage IVB. The primary site and T stage had little influence on the subsequent development of distant metastases. A multivariate analysis of the clinical factors confirmed the importance of neck stage and node location in estimating the probability of distant metastases. Control of disease above the clavicles and the addition of a neck dissection also significantly affected the chance of developing distant metastases.

5-Year survival of patients with periaortic nodal metastases in clinical stage IB and IIA cervical carcinoma

From 1969 to 1981 thirty-six patients with stage IB and IIA cervical carcinoma were identified at pretherapy surgical staging laparotomy with histologically documented metastatic disease to the periaortic lymph nodes. All patients underwent a periaortic node dissection and all patients completed a course of extendedfield radiotherapy in a postoperative setting. No major radiotherapeutic complications were encountered. The 5-year actuarial survival rate was 50%, with a median survival time of 29 months. The median time to recurrence was 10 months, while the median duration of survival following a recurrence was 7 months. Seventy-five percent of all recurrences occurred at distant sites. These data demonstrate that survival may be favorably influenced by employing extended-field radiotherapy in those patients with early-clinical-stage cervical cancer and periaortic nodal metastases. The subsequent development of distant metastases after such a treatment regimen emphasizes the need for adjuvant cytotoxic chemotherapy to enhance overall survival.

Pharyngeal carcinoma and natural killer cell activity

An evaluation of natural killer cell activity was performed in 42 patients with pharyngeal carcinoma. Compared with age- and sex-matched control subjects, the cancer patients expressed significantly lower cytotoxicity against K562 target cells (68 ± 8 lytic units versus 99 ± 8 lytic units, p < 0.01), with 52 percent of the patients expressing deficient activity (below 1 standard deviation of the mean activity of the control population). The probability of deficient activity was greater in these patients than observed in patients with cancer of other head and neck sites. Although natural killer cell activity was lower in patients who drank alcohol or had nodal metastases, no single clinical factor was predictive of deficient cytotoxic response. Prospective longitudinal evaluation (mean = 12 months) of these pharyngeal cancer patients demonstrated that deficient natural killer cell activity measured before treatment identified a population with a significantly increased risk for the development of distant metastases. Distant metastases developed in 7 of 18 patients (39 percent) with deficient natural killer cell activity. In contrast, none of the 16 patients with normal natural killer cell function had evidence of distant disease at last follow-up (p < 0.01). Deficient natural killer cell activity exists in patients with pharyngeal cancer and is an independent marker for the subsequent development of distant metastases.