Extent Of Node Involvement Research Articles

Cytoplasmic CXCR4 expression in breast cancer: induction by nitric oxide and correlation with lymph node metastasis and poor prognosis

BackgroundLymph nodes constitute the first site of metastasis for most malignancies, and the extent of lymph node involvement is a major criterion for evaluating patient prognosis. The CXC chemokine receptor 4 (CXCR4) has been shown to play an important role in lymph node metastasis. Nitric oxide (NO) may also contribute to induction of metastatic ability in human cancers.MethodsCXCR4 expression was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels (a biomarker for peroxynitrate formation from NO in vivo) and lymph node status, CXCR4 immunoreactivity, and other established clinico-pathological parameters, as well as prognosis, was analyzed. Nitrite/nitrate levels and CXCR4 expressions were assessed in MDA-MB-231 and SK-BR-3 breast cancer cell lines after induction and/or inhibition of NO synthesis.ResultsCXCR4 staining was predominantly cytoplasmic; this was observed in 50%(56/113) of the tumors. Cytoplasmic CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis. Kaplan-Meier survival curves showed that cytoplasmic CXCR4 expression was associated with reduced disease-free and overall survival. In multivariate analysis, cytoplasmic CXCR4 expression emerged as a significant independent predictor for overall and disease-free survival. Cytoplasmic expression of functional CXCR4 in MDA-MB-231 and SK-BR-3 cells was increased by treatment with the NO donor DETA NONOate. This increase was abolished by L-NAME, an inhibitor of NOS.ConclusionOur data showed a role for NO in stimulating cytoplasmic CXCR4 expression in vitro. Formation of the biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in vivo. In addition, cytoplasmic CXCR4 expression may serve as a significant prognostic factor for long-term survival in breast cancer.

The impact of positive soft tissue surgical margins following radical cystectomy for high-grade, invasive bladder cancer

We evaluate the incidence and risk factors associated with positive soft tissue surgical margins (STSM) and determine the association with various surgical and pathological characteristics and clinical outcomes in patients undergoing radical cystectomy (RC) for bladder cancer. From November 1971 to December 2005, 1,591 patients with primary transitional cell carcinoma (TCC) of the bladder underwent RC, with an extended bilateral pelvic lymphadenectomy and urinary diversion. A positive STSM was defined as tumor identified at the inked perivesical soft tissue surrounding the cystectomy specimen. Data were analyzed according to various clinical and pathologic variables, and survival analysis was performed. A total of 18 patients (1%) demonstrated pathologic evidence of a positive STSM following RC. Positive STSM were significantly associated with lymphovascular invasion, advanced pathologic stage, lymph node involvement, extent of nodal involvement and lymph node density. No patient with an organ-confined primary bladder tumor had a positive STSM, while 3% with extravesical tumor extension demonstrated a positive STSM. Recurrence-free and overall survival at 5 and 10 years for patients with a positive STSM was 29 and 22%, and 29 and 11%, respectively (p < 0.001). A positive STSM increased the risk of recurrence by threefold and the overall risk of death by 2.6 times. Only nine patients (1%) without evidence of nodal involvement had a positive STSM with a worse survival compared to those same pathologic subgroup and negative STSM. Nine patients (2%) with lymph node tumor involvement had positive STSM and also demonstrated significantly worse survival. Although a positive STSM was present in only 1% of patients undergoing a RC for TCC of the bladder, it was found to be an independent risk factor for advanced disease, lymph node involvement and tumor progression with worse survival. A dedicated effort should be made to avoid a positive STSM at the time of RC.

Significance of expression of stromal cell derived factor 1 and CXCR4 in invasive breast cancer

To study the expression of stromal cell derived factor 1(SDF-1)/CXCR4 and their association with clinicopathologic features and lymph node metastasis in invasive breast carcinoma. The expression of SDF-1 was studied by immunohistochemistry and in-situ hybridization. Immunohistochemical study for CXCR4 was also performed. The correlation with various clinicopathologic parameters was analyzed. (1) SDF-1 was mainly expressed in tumor cells and the level of its expression (both membranous and cytoplasmic) in lymph node-positive group was higher than that in lymph node-negative group (P = 0.033). Only cytoplasmic expression correlated with the number of positive lymph node involved by metastasis, TNM tumor stage, histologic grade, tumor dimension and estrogen receptor status (P < 0.05). (2) SDF-1 protein was also detected in the endothelial cells, although its mRNA was rarely detected. SDF-1 staining in lymphatics was associated with positive lymph node (P = 0.005) and SDF-1 staining in blood vessels correlated with stromal lymphocytic reaction (P = 0.001). The extent of nodal involvement was higher in the group with positive SDF-1 staining in blood vessels and with prominent lymphocytic reaction than that in other groups with one or neither of the two features (P < 0.05). (3) On the other hand, CXCR4 was mainly expressed in tumor cells (both nuclear and cytoplasmic); and the level of its expression in lymph node-positive group was higher than that in lymph node-negative group (P = 0.005). Only cytoplasmic expression correlated with the number of positive lymph node involved by metastasis, TNM tumor stage, histologic grade, tumor dimension and HER2 status (P < 0.05). The nuclear expression of CXCR4 was only correlated with progesterone receptor status (P < 0.01). The cytoplasmic expression CXCR4 also positively correlated with SDF-1 expression (P = 0.001). SDF-1 and CXCR4 can serve as biomarkers for diagnosis and prediction of lymph node metastasis, as well as potential therapeutic targets in invasive breast carcinoma. The difference in localization and staining patterns may also carry different significance.

Lymphatic Vessel Activation in Cancer

Most cancerous lesions metastasize through the lymphatic system and the status of regional lymph nodes is the most important indicator of a patient's prognosis. The extent of lymph node involvement with cancer is also an important parameter used for determining treatment options. Although the importance of the lymphatic system for metastasis has been well recognized, traditionally, the lymphatic vessels have not been considered actively involved in the metastatic process. Recent evidence, however, indicates that the activation of the lymphatic system is an important factor in tumor progression to metastasis. Tumor lymphangiogenesis has been associated with increased propensity for metastasis, and lymphatic vessel density has emerged as another promising prognostic indicator. More recently, lymphangiogenesis in the sentinel lymph nodes has been shown to contribute to malignant progression. In addition to its role as a transport system for tumor cells, the lymphatic system may also be more actively involved in metastases by directly facilitating tumor cell recruitment into the lymphatic vessels. This review highlights recent advances in our understanding of the mechanisms by which lymphatic vessels participate in metastasis.

The significance of CXCR4 expression for the prediction of lymph node metastasis in breast cancer patients

OBJECTIVE The chemokine receptor (CXCR4) CXC chemokine receptor 4) plays an important role in cancer metastasis. We therefore studied differential expression of the CXCR4, as well as that of the biomarker HER2, so as to evaluate whether these biomarkers can be used to predict axillary lymph node metastasis in breast cancer patients. METHODS Immunohistochemistry was used to evaluate the CXCR4 and HER2 expressions and to examine the paraffin sections of the breast cancers at various stages. Positive lymph node expression was found in 80 of the cases, and in 7 there was negative expression. RESULTS Compared to the cases with negative lymph nodes, there was a high expression of CXCR4 (26.3% vs. 14.3%, P = 0.013), and an over-expression of HER2 (28.8% vs. 14.3%, P = 0.011). Moreover, there was a direct correlation between the CXCR4 and HER2 expressions and the tumor staging ( P = 0.000) and lymph node metastasis ( P = 0.032). When the two biomarkers, i.e. CXCR4 and HER2, were concurrently labeled, a high expression of one of the biomarkers could be seen in the cases with positive lymph nodes (51.3% vs. 28.6%, P < 0.003). CONCLUSION The chemokine receptor, CXCR4, is a new type biomarker in predicting axillary lymph-node metastasis in breast cancers. Compared with the other markers, such as HER2 etc., assessment of CXCR4 can improve the prediction of the presence and extent of lymph node involvement.

Evaluation of the Use of Prophylactic Cranial Irradiation in Small-Cell Lung Cancer

<h3>Background</h3> Prophylactic cranial irradiation (PCI) is used in patients with small-cell lung cancer (SCLC) to reduce the incidence of brain metastasis after primary therapy. Our purpose was to evaluate the effects of PCI on overall survival (OS) and cause-specific survival. <h3>Patients and Methods</h3> A total of 7995 patients with limited-stage SCLC diagnosed between 1988 and 1997 were retrospectively identified from centers participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Six hundred seventy patients were identified as having received PCI as a component of their first course of therapy. Overall survival and cause-specific survival were estimated by the Kaplan-Meier method, comparing patients treated with or without prophylactic whole-brain radiation therapy. The Cox proportional hazards model was used in the multivariate analysis to evaluate potential prognostic factors. <h3>Results</h3> The median follow-up time was 13 months (range, 1-180 months). Overall survival at 2 years and 5 years was 23% and 11%, respectively, in patients who did not receive PCI. In patients who received PCI, 2-year and 5-year OS was 42% and 19%, respectively (<i>P</i> < 0.001). Cause-specific survival at 2 and 5 years was 28% and 15%, respectively, in patients who did not receive PCI and 45% and 24%, respectively, in patients who did receive PCI (<i>P</i> < 0.001). On multivariate analysis of cause-specific and OS, age at diagnosis, sex, grade, extent of primary disease, size of disease, extent of nodal involvement, and PCI were significant (<i>P</i> < 0.001). The hazard ratios for disease-specific and all-cause mortality were 1.13 and 1.11 for those not receiving PCI, respectively. <h3>Conclusion</h3> Significantly improved overall and cause-specific survival were observed in patients treated with PCI on unadjusted and adjusted analyses. This study concurs with the European experience, which has been published. Prophylactic cranial irradiation should be considered the standard of care in SCLC.

Radicalidad en la cirugía del colangiocarcinoma hiliar (tumor de Klatskin)

In patients with hilar cholangiocarcinoma, long-term survival critically depends on complete tumor resection. Indeed, there are no long-term survivors with positive resection margins. Furthermore, hilar cholangiocarcinoma seems to have a low propensity for distant metastases and adjuvant therapy after surgery has not been shown to have clear clinical benefits. This evidence should be regarded as arguments for extended resections. The question remains of how to achieve an R0 resection. In the last few years greater use of major hepatectomy has increased resectability and has improved long-term results. Concomitant resection of the caudate lobe is recommended as this site is a prime area of local recurrence. Frozen sections should be routinely used to assess the remnant proximal and distal ductal stumps. However, if the proximal remnant is positive, additional ductal resection at the separating limits is not always feasible. Gross portal vein invasion has a negative impact on survival, but should not be a contraindication to resection. Hepatectomy with portal vein resection can offer long-term survival in some patients with advanced hilar cholangiocarcinoma. The incidence of nodal involvement in resected specimens has been reported to range from 30% to more than 50% and there is a correlation between primary tumor extension and nodal involvement. Lymphatic metastases from hilar cholangiocarcinoma appear to spread first to pericholedochal nodes in the hepatoduodenal ligament and then to spread widely toward the posteriorsuperior area around the pancreatic head, portal vein and common hepatic artery. Routine lymphadenectomy should include all these areas. The only factors precluding resection are involvement of celiac, superior mesenteric or para-aortic tumoral nodes. Survival is closely associated with the extent of nodal involvement. The no-touch technique including right trisegmentectomy combined with portal vein resection has been proposed as the surgical procedure of choice for a more radical approach, and as a measure to prevent dissemination of tumor cells during surgery.

Cyclin D-1, Interleukin-6, HER-2/neu, Transforming Growth Factor Receptor-II and Prediction of Relapse in Women with Early Stage, Hormone Receptor-Positive Breast Cancer Treated with Tamoxifen

We hypothesized that amplification or overexpression of HER-2 (c-erbB-2), the Ki-67 antigen (Mib1), cyclin D-1 (CD1), interleukin-6 (IL-6), or the transforming growth factor beta II receptor, (TGFbetaRII), would predict relapse in women with early stage, estrogen (ER) and/or progesterone receptor (PR) positive breast cancer treated with tamoxifen. Conditional logistic regression models and a new novel analytic method - support vector machines (SVM) were used to assess the effect of multiple variables on treatment outcome. All patients had stage I-IIIa breast cancer (AJCC version 5). We paired 63 patients who were disease-free on or after tamoxifen with 63 patients who had relapsed (total 126); both disease-free and relapsed patients were matched by duration of tamoxifen therapy and time to recurrence. These 126 patients also served as the training set for SVM analysis and 18 other patients used as a validation set for SVM. In a multivariate analysis, larger tumor size, increasing extent of lymph node involvement, and poorer tumor grade were significant predictors of relapse. When HER-2 or CD1 were added to the model both were borderline significant predictors of relapse. The SVM model, after including all of the clinical and marker variables in the 126 patients as a training set, correctly predicted relapse in 78% of the 18 patient validation samples. In this trial, HER-2 and CD1 proved of borderline significance as predictive factors for recurrence on tamoxifen. An SVM model that included all clinical and biologic variables correctly predicted relapse in >75% of patients.

A new paradigm in the management of anorectal melanoma: Trans-anal excision with sphincter preservation and sentinel node biopsy

8513 Background: Anorectal melanoma is rare and highly lethal. Historically this disease has often been treated with abdominoperineal (APR) resection and delayed groin dissection for nodal relapse. As an alternative we have investigated trans-anal excision (TAE) with sphincter preservation and lymphatic mapping with sentinel node biopsy (SNB). We compared the outcomes of this more conservative treatment plan between our institutional data (JWCI) and the Surveillance, Epidemiology and End Results (SEER) data. Methods: JWCI prospective melanoma database (1974–2006) and the SEER database (1973–2003) were searched for pts diagnosed with anorectal melanoma (n=60 vs. n=183, respectively). Treatment, types of recurrence, and survival were recorded. Survival was estimated by the Kaplan-Meier method. Results: Lymphoscintography revealed lymphatic drainage to superficial inguinal nodal basin(s) in all cases. Among JWCI pts, the proportion of pts requiring delayed lymphadenectomy was significantly lower when TAE was performed with SNB versus without SNB (10.0% vs. 58.8%; p=0.018). Among JWCI lymphadenectomy specimens, immediate lymphadenectomy for a positive SNB was associated with fewer metastatic lymph nodes than delayed lymphadenectomy for palpable nodal recurrences (1.6 vs. 2.9; p=0.029), suggesting disease progression during observation. Over the past decade, APR rates were 11.5% for JWCI pts and 43.2% for and SEER pts, (p=0.004). JWCI pts and the SEER pts had median survivals of 33 and 17 months, respectively (p=0.009). TAE versus APR did not adversely affect the survival of JWCI pts (39 vs. 23 months; p=0.010) or SEER pts (18 vs. 16 months; p=0.875). Conclusion: Lymphatic mapping with SNB accurately identified the inguinal nodal basin as the most frequently involved basin and reduced the rate of recurrence and extent of nodal involvement. In this study, the largest to analyze surgical treatment and outcomes for pts with anorectal melanoma in the United States, national TAE rates differed from those at a tertiary melanoma center. TAE did not adversely affect survival in either dataset. Therefore, TAE plus SNB is preferred when negative margins can be obtained; APR should be reserved for locally advanced tumors that cannot be removed by TAE. No significant financial relationships to disclose.

Metastatic Cutaneous Squamous Cell Carcinoma: An Update

Squamous cell carcinoma (SCC) is the second most common type of skin cancer in the United States. Cutaneous SCC has the potential to metastasize and cause morbidity and mortality. Our purpose was to review and summarize the literature on metastatic cutaneous SCC, including risk factors for metastasis, data from clinical studies, and current management. Multiple studies confirm that even well-differentiated and small tumors (<2 cm) may metastasize. Over the past two decades, additional literature on the risk factors for metastatic cutaneous SCC, including immunosuppression, has been published. In addition, new staging systems have been proposed that may influence management of these tumors. Chemotherapy regimens are numerous, but remain limited in ability to improve overall survival. Although we know more about the risk factors, survival for patients with metastatic cutaneous SCC depends on extent of nodal involvement. Therefore, emphasis should remain on prevention and aggressive treatment of cutaneous SCC and vigilant observation for signs and symptoms of metastasis.

99mTc-MIBI imaging of cutaneous AIDS-associated Kaposi's sarcoma

Kapoksi's sarcoma (KS) is a common neoplasm complicating acquired immunodeficiency syndrome (AIDS). Skin, mucus membranes, lymph nodes, gastrointestinal tract and lungs may be involved. Kaposi's sarcoma has been demonstrated by scintigraphy, and a (99m)Tc-hexakis-2-methoxy isobutyl isonitrile (MIBI) scan can demonstrate lymphoma and tumors of the brain, nasopharynx, thyroid, parathyroid, lung, breast and kidney. It may also be useful for detecting and delineating the extent of KS. The objective of this study was to determine the efficacy of (99m)Tc-MIBI scanning to demonstrate cutaneous AIDS-associated KS, lymphedema and lymphadenopathy in the extremities. Whole body (99m)Tc-MIBI scans were obtained on 40 patients with AIDS-associated KS. Abnormal uptake of (99m)Tc-MIBI in the skin, subcutaneous soft tissues and lymph nodes was compared with the clinical assessment. The (99m)Tc-MIBI uptake was noted in the cutaneous/subcutaneous KS of the extremities with a sensitivity of 73.53%, a specificity of 96.91% and an accuracy of 91.31%. Abnormal lymph nodes and lymphedema were detected in more patients on (99m)Tc-MIBI scans (33 and 18 patients) than clinical assessment (10 and 12 patients), respectively. Lymphedema of the lower extremity was found in four of 17 patients without any palpable or abnormal lymph node uptake of (99m)Tc-MIBI in the inguinal regions. Follow-up (99m)Tc-MIBI scans after treatment showed no uptake in the skin lesions and decreased uptake in the lymph nodes corresponding to complete clearing on clinical assessment. (99m)Tc-MIBI imaging provides additional information on the extent of lymph node involvement and more precise staging and therapeutic planning. It may be useful as a predictive test or follow up of response of cutaneous KS to treatment.

The benefits and limitations of sentinel lymph node biopsy

The status of the axilla is the single most important prognostic indicator of overall survival in patients with breast cancer. Staging is based on tumor size and on the presence of lymph node metastases. The number of lymph nodes, although prognostic, no longer impacts treatment options. Sentinel lymph node (SLN) mapping and dissection is a more sensitive and accurate technique for nodal evaluation and has been applied to staging of axillary lymph nodes in patients with breast cancer, providing prognostic information, with less surgical morbidity than with axillary lymph node dissection (ALND). When analyzed by an experienced pathologist with serial sectioning and immunohistochemical evaluation, SLN is the most accurate detection tool used in staging of breast cancer. In many centers that use these staging principles, ALND is no longer performed for histologically negative axillary SLNs. In addition, this technique may also be therapeutic because in most patients, the SLN is the only positive axillary node. SLN biopsy is justified in women with ductal carcinoma in situ who have a high risk of invasive carcinoma, such as those with large tumors, a mass, or high-grade lesions. SLN biopsy is performed in the setting of neoadjuvant chemotherapy and demonstrates accurate evaluation of the axilla in 90% of the cases. Women with locally advanced breast cancer may derive great benefit from a minimally invasive approach to the axilla because the extent of nodal involvement is unlikely to change further treatment. For clinically palpable nodes, ALND should be performed for therapeutic and local control. The use of sentinel node mapping in pregnancy is controversial. Vital blue dye is contraindicated in pregnant patients, although some have used radioactive colloid alone to map this subgroup of patients.

High Rate of Lymph-Node Metastasis in Submucosal Esophageal Squamous-Cell Carcinomas and Adenocarcinomas

The application of endoscopic mucosectomy in early esophageal cancer is limited by the presence of lymph-node metastasis. The aim of this prospective study was to analyze the rate of lymph-node involvement relative to the depth of mucosal or submucosal tumor penetration, comparing squamous-cell carcinomas and adenocarcinomas. A total of 60 patients with pT1 esophageal cancer--24 with squamous-cell carcinomas (SCCs) and 36 with adenocarcinomas--were treated with transthoracic en-bloc esophagectomy with two-field lymphadenectomy (n = 50) or transhiatal esophageal resection (n = 10). An average of 30 lymph nodes were examined, and the following characteristics were evaluated: histology, mucosal infiltration, depth of submucosal wall infiltration in three thirds (sm1, sm2, sm3), grading, resection category, ratio of metastatic to resected lymph nodes, and locations of metastatic nodes. The rates of lymph-node metastasis were 0% for the 16 mucosal carcinomas and 45% for the 44 submucosal carcinomas (P < 0.01). There were no significant differences in the extent of lymph-node involvement between submucosal adenocarcinomas (41%) and submucosal SCCs (50%). Sm1 carcinomas were associated with a lower rate of lymph-node metastasis (SCCs 33%, adenocarcinomas 22%) than sm3 carcinomas (SCCs 69%, adenocarcinomas 78%). Two patients (9%) with submucosal SCCs and five patients (23%) with submucosal adenocarcinomas were classified as having stage pM1 lymph. The average lymph-node ratio in patients with pN1 was 0.13 for adenocarcinomas and 0.1 for SCCs (difference not significant). In the multivariate analysis, the parameters mucosal vs. submucosal (P < 0.01) and G1/G2 vs. G3 (P < 0.05) showed a significant impact in relation to metastatic lymph nodes. The most important factor for predicting lymph-node metastasis in early esophageal cancer is the presence of submucosal infiltration. Early adenocarcinomas and SCCs do not differ with regard to their rate of lymphatic involvement. The rate of lymph-node metastasis increases with the depth of submucosal infiltration, but metastases can already occur in sm1 lesions. Submucosal infiltration is a contraindication for endoscopic mucosectomy. Limited surgical procedures without adequate lymphadenectomy do not appear to be appropriate in the treatment of patients with submucosal esophageal carcinomas.

P95HER-2 Predicts Worse Outcome in Patients with HER-2-Positive Breast Cancer

The HER-2 receptor undergoes a proteolytic cleavage generating an NH(2)-terminally truncated fragment, p95HER-2, that is membrane-associated and tyrosine-phosphorylated. We have reported that p95HER-2, but not the full-length receptor, p185HER-2, correlated with the extent of lymph node involvement in patients with breast cancer and its expression was significantly enhanced in nodal metastatic tissue. These facts suggested an important role for p95HER-2 either as a marker or cause of metastasis and poor outcome in breast cancer. In this work, we have studied the prognostic value of p95HER-2 in breast cancer. Primary breast tumor tissues (n = 483) were from surgical resections conducted in hospitals in two different countries: the U.S. (n = 334) and Spain (n = 149). HER-2 protein forms, including p185HER-2 and p95HER-2, were examined in extracts of primary breast tumors by Western blot analysis. The levels of the two forms (high or low) were tested for association with other clinicopathologic factors and for correlation with disease-free survival. The median follow-up was 46 months. A high level of p95HER-2 in primary tumor tissue correlated with reduced 5-year disease-free survival (hazard ratio, 2.55; 95% confidence interval, 2.13-8.01; P < 0.0001). The median time for disease-free survival was 32 versus 139 months in patients with low levels of p95HER-2. In comparison, high levels of the full-length p185HER-2 did not significantly correlate with poor outcome (P > 0.1). Multivariate analysis revealed that high p95HER-2 was an independent predictor of disease-free survival (hazard ratio, 1.59; 95% confidence interval, 1.246-1.990; P = 0.0004). p95HER-2 expression is an independent prognostic factor in breast cancer and defines a group of patients with HER-2-positive breast cancer with significantly worse outcome.

Node dissection in gastric cancer.

Three hundred patients who underwent absolute and relative curative gastrectomy and lymph node dissection for gastric cancer were reviewed with respect to postoperative mortality; proportion of patients with node involvement according to the extent of dissection; number of metastatic nodes dissected according to the extent of dissection; accuracy of macroscopic evaluation of node involvement and microscopic node involvement according to tumour location. If more nodes were dissected the proportion of patients with node involvement and the total number of metastatic nodes increased; conversely within R0 and R3 the extent of dissection did not affect postoperative survival. Finally when the presence and extent of node involvement was only macroscopically evaluated, the patients were classified incorrectly in 9.5 per cent of the N0 group and 20.2 per cent of the N1 group. The data suggest that lymph node dissection may be useful in the treatment of gastric cancer, and within the extent studied the employment of this procedure does not affect the postoperative mortality.

Clinical Dose-Volume Histogram Analysis in Predicting Radiation Pneumonitis in Hodgkin’s Lymphoma

Purpose/Objective: Very few studies have focused exclusively on radiation pneumonitis in Hodgkin’s Lymphoma (HL). A seminal paper from the lung cancer literature (1Graham M.V. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D Treatment for non-small cell lung cancer (NSCLC).IJROBP. 1999; 45: 323-329Google Scholar) predicts for a 13% incidence of grade 2 or greater radiation pneumonitis (RP) if the V20 (volume of lung receiving 20Gy) is 32–40%, increasing to 36% for V20 >40%. Moreover if the mean lung dose (MLD) is >20Gy, the rate of RP was 24%. The objectives of this study were firstly to quantify the incidence of RP in a modern Hodgkin’s Lymphoma cohort; and secondly to attempt to identify a clinically relevant parameter to determine the risk of RP in lymphoma patients. Materials/Methods: From January 2003 to February 2005, 65 consecutive HL patients receiving radical mediastinal radiotherapy (RT) were retrospectively reviewed. Clinical parameters collected included disease stage, site and extent of nodal involvement, smoking status, respiratory co-morbidities, and pulmonary function tests. Treatment parameters including RT dose, field dimensions, RT induced esophagitis, chemotherapy regime (primary and/or salvage), number of cycles, and cumulative bleomycin dosage were reviewed. Results: There were 65 patients (37 females, 28 males) median age 29 years (range 11.9 – 63.1 years). Stage of disease was: IA-IB 11%, IIA 49%, IIB 29%, IIIA-B 8%, IVB 3%. ABVD chemotherapy was given in 86%, with a median of 6 cycles. Post-chemotherapy RT was given in 58 pts, and 7 had RT post autologous stem cell transplant. Median cumulative bleomycin dose was 162 units. Three patients developed bleomycin related pulmonary toxicity, with 2 additional suspected cases. RT dose was 35Gy/20 fractions in 74% (range 15–40Gy). The median V20 was 31.1% (range 0–53%) and mean lung dose (MLD) was 12.4Gy (range 2.9–19.6Gy). No obvious relationship was found between RP and any of the clinical or treatment parameters tested. Actuarial survival at 2 years is 100% with a median follow up of 1.7 years. Two cases of RP occurred at 1.5 and 2.7 months post RT, for an overall incidence of 3%. Both were SWOG grade 2 in severity, occurred in females who received 6 cycles of ABVD, and who experienced progressive disease and underwent RT (dose 35Gy/20 fractions) in the post transplant setting. The first case was in an ex-smoker with IA disease and a 9cm initial mediastinal mass who had developed bleomycin toxicity with a restrictive lung defect (DLCO of 48% predicted) prior to RT. The other case occurred in a non-smoker with IIIB disease and a 12cm mediastinal mass. Both responded clinically to a tapering schedule of prednisone. The RP cases with V20 values of 47% and 41% respectively fell into the highest quartile (range 37–53%), corresponding to a risk of 2/18 (11% among cases in the 4th quartile). Their mean lung doses of 17.6Gy and 16.4Gy were also in the highest quartile (range 14.8–19.6Gy). Conclusions: Despite relatively high V20 values in this cohort, the incidence of radiation pneumonitis was lower than predicted based upon the lung cancer literature. We report that a V20 value of 37% or greater is associated with a RP incidence of 11%, suggesting that a higher V20 cutoff may apply to HL patients. Moreover our study found that a MLD of >15Gy, in comparison to >20Gy in lung cancer, may be used to determine the risk of RP in lymphoma patients, which may in part reflect the lower absolute prescribed RT dose in this setting.

CCR7 and CXCR4 as Novel Biomarkers Predicting Axillary Lymph Node Metastasis in T1 Breast Cancer

The chemokine receptors CCR7 and CXCR4 have been shown to play an important role in cancer metastasis. We therefore studied the differential expression of CCR7 and CXCR4, along with that of the biomarker HER2-neu, to evaluate whether these biomarkers could predict axillary lymph node metastasis in breast cancer. Biomarker expression levels were evaluated using paraffin-embedded tissue sections of lymph node-negative (n = 99) and lymph node-positive (n = 98) T1 breast cancer by immunohistochemical staining. Lymph node-positive tumors showed higher rates of high cytoplasmic CCR7 staining (21.5% versus 8.5%, P = 0.013) and HER2-neu overexpression (21.5% versus 9.3%, P = 0.019) than did lymph node-negative tumors. Similarly, high cytoplasmic CXCR4 expression occurred more commonly in lymph node-positive tumors (11.2% versus 5.1%, P = 0.113). In contrast, predominantly nuclear CXCR4 staining was more likely to be found in lymph node-negative tumors (54.5% versus 37.8%, P = 0.018). Furthermore, cytoplasmic CXCR4 coexpressed with HER2-neu was the only factor associated with involvement of four or more lymph nodes (16.7% versus 1.2%, P = 0.04) among lymph node-positive tumors. When all three biomarkers (CCR7, CXCR4, HER2-neu) were utilized together, 50.0% of lymph node-positive tumors highly expressed one of these biomarkers compared with 18.8% of the lymph node-negative tumors (P < 0.0001). Our results suggest that the chemokine receptor CCR7 is a novel biomarker that can predict lymph node metastases in breast cancer. Utilization of additional markers, such as CXCR4 and HER2-neu, further improves the prediction of the presence and extent of lymph node involvement.

Neoadjuvant Therapy for Rectal Cancer Down-Stages the Tumor but Reduces Lymph Node Harvest Significantly

The impact of neoadjuvant therapy (NAT) for rectal cancer on lymph node yield is not well known. This study evaluates the impact of NAT on tumor regression and lymph node harvest. The subjects were 40 patients with rectal cancer; 20 receiving high-dose, long-course neoadjuvant therapy, and 20 age- and sex-matched controls who did not receive neoadjuvant therapy. Tumor regression (TRG) was graded from 1 to 5 as: TRG1, no residual tumor cells; TRG2, occasional residual tumor cells with marked fibrosis; TRG3, marked fibrosis with scattered tumor cells or groups; TRG4, abundant cancer cells with little fibrosis; TRG5, no tumor regression. We also evaluated the number of lymph nodes retrieved from excised specimens, the size of the largest node, and the extent of lymph node involvement by the tumor. Tumor regression was seen in all patients; as TRG1 in 6 (30%), TRG2 in 2 (10%), TRG3 in 3 (15%), and TRG4 in 9 (45%). The median nodal harvest was 4 (range (0-12) in the NAT group vs 9 (range 1-19) in the control (P = 0.001). The median size of the largest lymph node was 5 mm (range 2-12 mm) in the NAT group vs 9 mm (range 4-15 mm) in the control group (P = 0.004). Tumor-positive nodes were identified in 4 of 17 of the NAT group patients and in 9 of the 20 controls (P = 0.308). Although NAT down-stages rectal cancer, it results in a significantly low yield of lymph nodes, which are also significantly smaller than those in nonirradiated controls. Therefore, surgeons and histopathologists must ensure adequate sampling and accurate staging is done for patients with irradiated rectal cancer.

Resection and Mediastinal Lymph Node Dissection

Mediastinal lymph node assessment is an essential component of the surgical management of lung cancer. Traditionally, a potentially curative resection is considered to involve the complete resection of the primary tumor with microscopically benign resection margins, and a systematic dissection of lymphatic drainage to accessible mediastinal nodes. Defining the extent of lymph node involvement is important for accurate staging and prognostic guidance. Accurate lymph node assessment also guides the decision to use

Statistical Interaction in the Survival Analysis of Early Breast Cancer using Registry Data: Role of Breast Conserving Surgery and Radiotherapy

To identify subgroup effects that might influence the survival results of postoperative radiotherapy. Women selected from the Surveillance, Epidemiology, and End Results database, aged 40-69 years, with non-metastasized T1-T2 breast carcinoma, in whom axillary lymph node dissection was performed. Subgroup analyses were performed using proportional hazards models with interactions. Joint significance of subgroups was evaluated with the Wald test. Event was death from any cause. Statistically significant interactions were found between type of surgery (breast-conserving [BCS] or mastectomy [ME]), radiotherapy [RT], T stage, and extent of nodal involvement, but not between treatments and nodal examination. For each treatment combination, ME-no RT, ME+RT, BCS-no RT, BCS+RT, the mortality hazard ratios were respectively: 1, 1.12, 1.11, 0.78 in T1, 0-3 positive nodes; 2.45, 2.77, 2.71, 1.92 in T2, 4+ nodes; 1.31, 1.38, 1.33, 1.19 in T2, 0-3+ nodes; and 3.41, 2.79, 3.44, 2.40 in T2, 4+ nodes. The corresponding joint tests showed: in the absence of radiotherapy, no significant survival disadvantage for breast-conserving surgery vs mastectomy; with radiotherapy, significant survival advantage for breast-conserving surgery irrespective of stage and for mastectomy in T2, 4+ nodes. For mastectomy in less advanced stages receiving radiotherapy, excess breast cancer deaths suggested undocumented adverse selection. The corresponding result was considered inconclusive. The analyses found subgroup effects that should be taken into account to interpret treatment results in breast cancer.