Intraoperative electron radiation therapy as an important treatment modality in retroperitoneal sarcoma.

BACKGROUND: Local recurrence (LR) rates in patients with retroperitoneal sarcoma (RPS) are high, ranging from 40% to 80%, with no definitive studies describing the best way to administer radiation. Intraoperative electron beam radiation therapy (IOERT) provides a theoretical advantage for access to the tumor bed with reduced toxicity to surrounding structures. The goal of this study was to evaluate the role of IOERT in high-risk patients. METHODS: An institutional review board approved, single institution sarcoma database was queried to identify patients who received IOERT for treatment of RPS from 2/2001 to 1/2009. Data were analyzed using the Kaplan-Meier method, Cox regression, and Fisher Exact tests. RESULTS: Eighteen patients (median age 51 y, 25-76 y) underwent tumor resection with IOERT (median dose 1250 cGy) for primary (n = 13) and recurrent (n = 5) RPS. Seventeen patients received neoadjuvant radiotherapy. Eight high-grade and 10 low-grade tumors were identified. Median tumor size was 15 cm. Four patients died and two in the perioperative period. Median follow-up of survivors was 3.6 y. Five patients (31%) developed an LR in the irradiated field. Three patients with primary disease (25%) and two (50%) with recurrent disease developed an LR (P = 0.5). Four patients with high-grade tumors (57%) and one with a low-grade tumor (11%) developed an LR (P = 0.1). The 2- and 5-y OS rates were 100% and 72%. Two- and 5-y LR rates were 13% and 36%. CONCLUSIONS: Using a multidisciplinary approach, we have achieved low LR rates in our high-risk patient population indicating that IOERT may play an important role in managing these patients.

A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease. METHODS AND FINDINGS: We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7-10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group. CONCLUSIONS: Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets. Please see later in the article for the Editors' Summary.

Postoperative hypocalcemia after parathyroidectomy for renal hyperparathyroidism in the era of cinacalcet.

Chronic kidney disease is often accompanied by hyperparathyroidism. Cinacalcet, a recent addition to the medical armamentarium, has proven efficacious. It is unclear whether cinacalcet use has any impact on the postoperative course in patients progressing to surgery. The records of 77 patients operated on for renal hyperparathyroidism were reviewed. Sixty-three were treated before the use of cinacalcet and 14 after. Ten subtotal and 67 total parathyroidectomies were performed. Mean nadir serum calcium was similar (6.6 +/- 1.3 vs 6.2 +/- 1.4 mg/dL). More patients taking cinacalcet preoperatively required intravenous calcium postoperatively (62%) than those treated before its use (41%), although this did not reach statistical significance (P = 0.09). In those undergoing total parathyroidectomy, cinacalcet use preoperatively (n = 11) led to a lower postoperative nadir calcium (5.8 +/- 1.7 vs 6.6 +/- 1.3 mg/dL) as compared with those who did not receive it (n = 56) (P = 0.05). This translated to a greater need for intravenous calcium infusion postoperatively (72 vs 38%) (P = 0.03). These data suggest a somewhat more aggressive postoperative course in patients who fail calcimimetic and require surgery. This may be useful to inform physicians and patients of expectations postoperatively, although it is not likely to alter management.

A pilot study of early 18F-FDG PET to evaluate the effectiveness of radiofrequency ablation of liver metastases.

OBJECTIVE: The objective of our study was to collect pilot data about the use of FDG PET within hours after radiofrequency ablation (RFA) of liver metastases. CONCLUSION: Total photopenia on early PET can potentially be regarded as a macroscopic tumor-free margin; focal uptake can be regarded as macroscopic residual tumor.

Successful minimally invasive parathyroidectomy for primary hyperparathyroidism without using intraoperative parathyroid hormone assays.

BACKGROUND: The need for intraoperative parathyroid hormone (iPTH) assays in minimally invasive parathyroidectomy (MIP) remains controversial. We report the results of MIP performed without the use of iPTH assays. METHODS: This was a single-institution retrospective review of patients with primary hyperparathyroidism treated with MIP between October 1, 1998, and December 31, 2002. RESULTS: Seventy-seven patients were studied. The mean preoperative calcium level was 11.4 mg/dL. All patients had a normal calcium level postoperatively (range, 7.4-10.2 mg/dL, mean, 9.1 mg/dL). Three patients (4%) required re-exploration for various reasons including the development of a second adenoma, secondary hyperparathyroidism, and discordant pathology. All 3 patients initially were eucalcemic. CONCLUSIONS: Our success rate of 96% using a combination of preoperative sestamibi scans, intraoperative gamma probe localization, and selective frozen pathology is consistent with the published success rates using iPTH assays of 95% to 100%. We conclude that MIP can be performed successfully without using iPTH assays.

Axillary lymph node count is lower after neoadjuvant chemotherapy.

BACKGROUND: Retrieval of fewer than 10 lymph nodes at axillary dissection (ALND) for breast cancer can represent anatomic variation or inadequate dissection. We postulated that despite aggressive ALND, a lower lymph node count is more frequent after neoadjuvant chemotherapy. METHODS: Patients who received neoadjuvant chemotherapy followed by ALND were compared with patients who received surgery first. All patients received a level I and II ALND at a single institution by one of the breast surgeons. The number of nodes retrieved at ALND was dichotomized into categories (< 10 and > or = 10), and compared using Fisher exact test. RESULTS: A total of 143 neoadjuvant and 170 surgery-first patients were studied. Patients treated with neoadjuvant chemotherapy were significantly more likely to have fewer than 10 lymph nodes retrieved at ALND than were the surgery-first patients (19/143 or 13% vs. 6/170 or 4%, P = .003). CONCLUSIONS: A low lymph node count is more common in patients after treatment with neoadjuvant chemotherapy and should not be assumed to represent an incomplete ALND.

Microsatellite instability testing in colorectal carcinoma: choice of markers affects sensitivity of detection of mismatch repair-deficient tumors.

PURPOSE: Microsatellite instability (MSI) is found in 10% to 15% of sporadic colorectal tumors and is usually caused by defects in DNA mismatch repair (MMR). In 1997, a panel of microsatellite markers including mononucleotide and dinucleotide repeats was recommended by a National Cancer Institute workshop on MSI. We investigated the relationship between instability of these markers and MMR protein expression in a cohort of sporadic colorectal cancer patients. EXPERIMENTAL DESIGN: Paraffin sections of normal and tumor tissue from 262 colorectal cancer patients were examined for MSI status by PCR amplification and for MMR protein expression using antibodies against hMLH1, hPMS2, hMSH2, and hMSH6. RESULTS: Twenty-six (10%) of the patients studied had tumors with a high level of MSI (MSI-H). The frequencies of MSI were the same in African-American and Caucasian patients. Each of the MSI-H tumors had mutations in both mononucleotide and dinucleotide repeats and had loss of MMR protein expression, as did two tumors that had low levels of MSI (MSI-L). These two MSI-L tumors exhibited mutations in mononucleotide repeats only, whereas eight of the other nine MSI-L tumors had mutations in just a single dinucleotide repeat. There was not a statistically significant difference in outcomes between patients whose tumors were MMR-positive or MMR-negative, although there was a slight trend toward improved survival among those with MMR-deficient tumors. CONCLUSIONS: The choice of microsatellite markers is important for MSI testing. Examination of mononucleotide repeats is sufficient for detection of tumors with MMR defects, whereas instability only in dinucleotides is characteristic of MSI-L/MMR-positive tumors.

Experienced radio-guided surgery teams can successfully perform minimally invasive radio-guided parathyroidectomy without intraoperative parathyroid hormone assays.

Minimally invasive parathyroidectomy is an accepted treatment option for primary hyperparathyroidism. The need for intraoperative parathyroid hormone assays (iPTH) to confirm adenoma removal remains controversial. We studied minimally invasive radio-guided parathyroidectomy (MIRP) performed using preoperative sestamibi localization studies, intraoperative gamma detection probe, and the selective use of frozen section pathology without the use of iPTH. This is a single institution review of patients with primary hyperparathyroidism treated with MIRP by surgeons experienced in radio-guided surgery between October 1, 1998 and July 15, 2005. Information was obtained by reviewing computer medical records as well as contacting primary care physicians. Factors evaluated included laboratory values, pathology results, and evidence of recurrence. One hundred forty patients were included with a median preoperative calcium level of 11.3 mg/dL (range, 9.6-17) and a PTH level of 147 pg/mL (range, 19-5042). The median postoperative calcium level was 9.3 mg/dL. All patients were initially eucalcemic postoperatively except for one who had normal parathyroid levels. However, five (4%) patients required re-exploration for various reasons. Of the failures, one was secondary to the development of secondary hyperparathyroidism, and therefore would not have benefited from iPTH, one had thyroid tissue removed at the first operation, and three developed evidence of a second adenoma. One of these three patients had a drop in PTH level from 1558 pg/mL preoperatively to 64 pg/mL on postoperative Day 1, indicating that iPTH would not have prevented this failure. Thus, only three (2.1%) patients could have potentially benefited from the use of iPTH. MIRP was successful in 96 per cent of patients using a combination of preoperative sestamibi scans, intraoperative localization with a gamma probe, and the selective use of frozen pathology. This correlates with reported success rates of 95 per cent to 100 per cent using iPTH. We conclude that minimally invasive parathyroidectomy can be successfully performed without using iPTH assays.

Staged sentinel lymph node biopsy before mastectomy facilitates surgical planning for breast cancer patients.

BACKGROUND: In patients with breast cancer who choose mastectomy with immediate reconstruction, the sentinel lymph node (SLN) status on permanent histology may complicate treatment if a metastasis is found. The purpose of this study was to determine how performing an SLN biopsy (SLNB) before the definitive operation would influence subsequent surgical procedures. METHODS: Our SLN database was searched for patients who underwent staged SLNB with subsequent mastectomy between 2001 and 2004. RESULTS: Twenty-five patients with 27 breast cancers underwent SLNB before mastectomy. Of them, 9 of 27 (33%) were node positive. All 9 patients underwent modified radical mastectomy. Three node-positive patients did not undergo immediate reconstruction. Of the remaining 6 node-positive patients, 5 underwent reconstruction with autologous tissue rather than a tissue expander. In contrast, 6 of 16 (37%) node-negative patients underwent reconstruction with a tissue expander. CONCLUSIONS: Staged SLNB assists in selecting the appropriate operation in patients who are considering immediate reconstruction.

Dysregulation of annexin I protein expression in high-grade prostatic intraepithelial neoplasia and prostate cancer.

PURPOSE: To determine expression levels of annexin I (lipocortin I) in patient-matched benign prostatic epithelium (BPE), high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate cancer (CaP). EXPERIMETNAL DESIGN: Annexin I protein expression was examined with a standard immunohistochemical protocol in 69 radical prostatectomy specimens, 45 of which also contained HGPIN. Immunostained sections were scored visually by a genitourinary pathologist and mean optical density was measured with digital image analysis. Real-time fluorescence quantitative PCR was used to measure expression levels of annexin I mRNA in patient-matched CaP and BPE from 14 snap-frozen, radical prostatectomy specimens. RESULTS: Annexin I protein expression was reduced in 91% (41/45) of HGPIN lesions and 94% (65/69) of invasive CaP compared with BPE in the same histological section when assessed visually. Mean absorbance was reduced significantly (P < 0.05) in 97.7% (44/45) of HGPIN lesions and 98.5% (68/69) of CaP glands compared with BPE. In 79% of cases (11/14; P < 0.05), mRNA expression was reduced in CaP as compared with patient-matched BPE. Annexin I mRNA and protein expression levels did not correlate with Gleason grade, pathological stage, or race. CONCLUSIONS: Down-regulation of annexin I protein expression is a common finding in HGPIN and CaP, suggesting that annexin I dysregulation may be an important early event in CaP initiation. Because mRNA levels are reduced in a high proportion of cases, one likely mechanism for annexin I dysregulation occurs at the level of gene transcription. Results of these studies support a valuable role for a molecular profiling approach to CaP research.

Human epidermal receptor-2 expression in prostate cancer.

PURPOSE: Efforts to conclusively establish that human epidermal receptor (HER)-2 overexpression is important to androgen-dependent carcinoma of the prostate (AD-CaP) or to progression to androgen independence (AI-CaP) have failed because of variability in tissue procurement, antibodies, immunostaining procedures, and assessment methods. However, because some in vitro and animal model data correlate HER-2 overexpression with progression to androgen independence, trials of agents that target the HER-2 receptor are under way. To clarify human tumor findings, we studied HER-2 expression at the gene (DNA), mRNA, and protein levels in well-characterized CaP specimens. EXPERIMENTAL DESIGN: Fifty AD-CaP and 25 AI-CaP specimens from similar numbers of Caucasian and African Americans were immunostained for HER-2 receptor. HER-2 mRNA levels were measured using real-time fluorescence quantitative PCR in patients for whom frozen specimens were available. HER-2 amplification was evaluated using fluorescent in situ hybridization. RESULTS: HER-2 receptor immunostained in 52% of androgen-dependent and one (4%) androgen-independent tumor. HER-2 immunostaining was not related to age, race, serum prostate-specific antigen levels, or pathologic stage and Gleason grade. HER-2 overexpression was not detected in AI-CaP at the mRNA or gene level. Mean HER-2 mRNA expression was higher (P < 0.05) in AD-CaP than AI-CaP (22,080 versus 15,496 HER-2 copies). HER-2 was not amplified in any of 20 AD-CaP or 19 AI-CaP specimens. CONCLUSIONS: HER-2 protein and message overexpression and HER-2 amplification were not found in AI-CaP.

Cytokeratin immunohistochemical validation of the sentinel node hypothesis in patients with breast cancer.

No standard method for handling and histopathologic examination of the sentinel node (SN) exists. We hypothesized that a focused examination of all nodes with serial sectioning and cytokeratin immunohistochemical staining would confirm the SN as the node most likely to harbor metastasis. Intraoperative lymphatic mapping and sentinel lymphadenectomy using blue dye and (99m)technetium-labeled sulfur colloid were performed. All nodes were stained with H&E. All tumor-free nodes underwent additional sectioning and staining with H&E and an immunohistochemical stain. Routine H&E examination detected SN metastases in 27.6% of cases. Occult SN metastases were identified in 12.7% of cases. None of the 724 non-SNs examined contained occult metastases. The SN false-negative rate was zero. This study confirms histopathologically that the SN has biologic significance as the axillary node most likely to harbor metastatic tumor Standardization of the handling, sectioning, and staining of the SN is necessary as lymphatic mapping and sentinel lymphadenectomy become integrated into the care of patients with breast cancer

High-resolution axillary ultrasound is a poor prognostic test for determining pathologic lymph node status in patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer.

BACKGROUND: The purpose of this study was to evaluate the efficacy of high-resolution axillary ultrasound in detecting axillary lymph node metastases after neoadjuvant chemotherapy in patients with locally advanced breast cancer. METHODS: Fifty-three patients with stage II or III breast cancer undergoing neoadjuvant chemotherapy who had a physical examination, high-resolution axillary ultrasound, and axillary lymph node dissection from January 1999 to September 2003 were included in this study. RESULTS: The positive predictive value of the postchemotherapy ultrasound for predicting pathologic nodal involvement was 83%, but the negative predictive value was only 52%. Postchemotherapy physical examination was also poor at predicting pathologic nodal involvement with a positive predictive value of 93% and a negative predictive value of only 58%. CONCLUSIONS: A negative post-neoadjuvant chemotherapy high-resolution axillary ultrasound or physical examination does not predict pathologic node status, and this test has limited value in this setting.

The EGF receptor family--multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4.

The EGF Receptor (EGFR), the first transmembrane receptor tyrosine kinase cloned and sequenced, and its closely related family members HER2, HER3, and HER4, play myriad roles in mammalian growth and development. Receptor activation involves ligand binding to separate receptors followed by formation of active dimers. These receptors can signal as homodimers or they can subtly alter signaling output by heterodimerizing with other family members. Adding complexity, these receptors with varying specificity bind at least 10 ligands from two ligand families, the EGF and neuregulin/heregulin families. This signaling system's impact on human neoplasia is underscored by the following: i.) EGFR is overexpressed or activated by autocrine or paracrine growth factor loops in at least 50% of epithelial malignancies; ii.) HER2 is amplified and dramatically overexpressed in approximately 20%-25% or breast cancers; iii) HER3 and HER4 are variably expressed in breast and other cancers. Overexpression and/or activation of EGFR, HER2 and HER3 has been correlated with poor tumor prognosis; antibody and small molecule inhibitors of their activity are being tested as therapy in cancer patients. However, the signaling complexity engendered by four interacting receptors and ten ligands makes it difficult to definitively measure receptor signaling output in human tumors and even makes mechanistic studies of the family's role in normal physiology and neoplastic transformation a challenge. In spite of the literature's emphasis on growth control, activation by some EGF receptor family member ligands can produce tumor cell differentiation, characterized by growth cessation and differentiation gene product synthesis. The present work delineates a role for HER4 in breast cancer cell differentiation and demonstrates that HER4 is both necessary and sufficient to produce an anti-proliferative signal. These

Utilization and morbidity associated with placement of a feeding jejunostomy at the time of gastroesophageal resection.

BACKGROUND: The purpose of the study was to evaluate the utilization and morbidity associated with feeding jejunostomy tubes (JT) placed at the time of gastroesophageal resection (GER). METHODS: Under institutional review board approval, a prospective database of patients undergoing GER from January 2004 to September 2010 was reviewed. Data analyzed included patient demographics, postoperative complications, JT use, and JT specific complications. Fisher's exact tests explored associations with utilization of a JT following resection. RESULTS: Seventy-three patients (51 men, 22 women, median age of 59) underwent placement of a JT at the time of GER (total gastrectomy = 28, Ivor-Lewis = 28, subtotal gastrectomy = 8, proximal gastrectomy = 6, and transhiatal esophagectomy = 3) of both malignant (97%) and benign (3%) disease processes. Twenty-one JT specific complications (11 minor and 10 major) were identified. Reoperation was required in the management of two complications (small bowel obstructions), while all other complications were easily managed by an interventional radiologist (n = 8), bedside procedure (n = 5), or did not require intervention (n = 6). Eighty-six percent of patients were discharged tolerating a postgastrectomy diet, 10% nothing per orem, and 4% a liquid diet. Inpatient enteral nutrition (EN) was initiated in 68%, but continued on discharge in only 54% secondary to failure to thrive (54%), dysphagia (21%), anastomic leak (15%), chyle leak (3%), esophagostomy (3%), and duodenal stump leak (3%). The mean time to discontinuance of EN and removal of the JT was 44 days (range, 4-203) and 71 days (range, 15-337) respectively. Although only 13% (n = 5) of patients requiring adjuvant therapy were utilizing their JT at the commencement of therapy, 75% (n = 21) required EN during its course. The median time to adjuvant therapy was found to be slightly longer in those who required outpatient EN versus those who did not (61 vs. 90 days, p = 0.08). However, the median time to adjuvant therapy did not differ between those who were and were not receiving EN at the time of adjuvant therapy commencement (80 vs. 92 days, p = 0.2). Age (p = 0.4), number of co-morbidities (p = 0.2), preoperative percent body weight loss (p = 0.9), and clinical stage (p = 0.8) were not significantly associated with outpatient JT use. Patients who suffered a postoperative complication were most likely to require EN (p = 0.002), an association that strengthened as the number of complications increased (p = 0.0008). Although not statistically significant, a trend towards increased outpatient EN was noted in patients who underwent transhiatal esophagectomy and total gastrectomy (p = 0.06). CONCLUSIONS: JT placement carries a considerable morbidity in patients undergoing GER. However, because it is difficult to preoperatively ascertain who will need prolonged EN, the routine placement of a JT is recommended, particularly in those who will likely require adjuvant therapy or are at high risk for postoperative complications. Despite patient desires for early removal of an unused JT, caution should be taken if adjuvant therapy is being considered.

Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy.

BACKGROUND: KRAS mutations may predict poor response to radiotherapy. Downstream events from KRAS, such as activation of BRAF, AKT and ERK, may also confer prognostic information but have not been tested in rectal cancer (RC). Our objective was to explore the relationships of KRAS and BRAF mutation status with p-AKT and p-ERK and outcomes in RC. METHODS: Pre-radiotherapy RC tumor biopsies were evaluated. KRAS and BRAF mutations were assessed by pyrosequencing; p-AKT and p-ERK expression by immunohistochemistry. RESULTS: Of 70 patients, mean age was 58; 36% stage II, 56% stage III, and 9% stage IV. Responses to neoadjuvant chemoradiotherapy: 64% limited, 19% major, and 17% pathologic complete response. 64% were KRAS WT, 95% were BRAF WT. High p-ERK levels were associated with improved OS but not for p-AKT. High levels of p-AKT and p-ERK expression were associated with better responses. KRAS WT correlated with lower p-AKT expression but not p-ERK expression. No differences in OS, residual disease, or tumor downstaging were detected by KRAS status. CONCLUSIONS: KRAS mutation was not associated with lesser response to chemoradiotherapy or worse OS. High p-ERK expression was associated with better OS and response. Higher p-AKT expression was correlated with better response but not OS.

Utilization of interventional radiology in the postoperative management of patients after surgery for locally advanced and recurrent rectal cancer.

The surgical management of locally advanced primary rectal cancer and locally recurrent rectal cancer requires complex operations frequently resulting in complicated postoperative courses. We sought to evaluate the utilization of interventional radiologic (IR) procedures in the management of postoperative complications. Under Institutional Review Board approval, a prospective database of colorectal cancer patients undergoing resection from July 1999 to January 2010 was analyzed. Data collected included demographics, operative procedure, complications, length of stay, and IR utilization. Fisher's exact tests and logistic regression explored associations with necessitating an IR procedure during the postoperative period. Continuous variables were analyzed using Wilcoxon rank sum tests. One hundred and one patients underwent surgery and 66 received intraoperative electron radiotherapy (IOERT). Primary procedures included pelvic exenteration (n = 35), abdominoperineal resection (n = 25), low anterior resection (n = 23), paraaortic node dissection (n = 7), resection of isolated pelvic/retroperitoneal tumor (n = 7), and colectomy (n = 4). Sixty-two patients required multivisceral resection including partial/total cystectomy (n = 30), small bowel resection (n = 25), oophorectomy (n = 15), vaginectomy (n = 12), hysterectomy (n = 12), hepatectomy (n = 3), and nephrectomy (n = 3). Seventeen partial sacral resections and 47 pelvic sidewall resections were also required. One hundred and thirty-eight complications were identified in 72 patients, 30 of which required a procedural intervention. Twenty-seven IR procedures were performed including drainage of fluid collections (n = 14), nephrostomy tube placement (n = 8), arterial embolization (n = 2), inferior vena cava filter placement (n = 2), and pleural drainage (n = 1). Only three reoperations were required, none related to failure of IR procedures. There were no deaths. Estimated blood loss > 2000 mL (P = 0.002), IOERT (P = 0.03), and incomplete resection (P = 0.02) were found to be associated with postoperative IR utilization. Surgery for locally advanced primary rectal cancer and locally recurrent rectal cancer is associated with significant morbidity but low mortality. IR procedures play a significant role in the postoperative management of these patients and may decrease the need for reoperation.

Nuclear factor κ-light chain-enhancer of activated B cells is activated by radiotherapy and is prognostic for overall survival in patients with rectal cancer treated with preoperative fluorouracil-based chemoradiotheraphy.

PURPOSE: Rectal cancer is often clinically resistant to radiotherapy (RT) and identifying molecular markers to define the biologic basis for this phenomenon would be valuable. The nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) is a potential anti-apoptotic transcription factor that has been associated with resistance to RT in model systems. The present study was designed to evaluate NF-κB activation in patients with rectal cancer undergoing chemoradiotherapy to determine whether NF-κB activity correlates with the outcome in rectal cancer patients. METHODS AND MATERIALS: A total of 22 patients underwent biopsy at multiple points in a prospective study and the data from another 50 were analyzed retrospectively. The pretreatment tumor tissue was analyzed for multiple NF-κB subunits by immunohistochemistry. Serial tumor biopsy cores were analyzed for NF-κB-regulated gene expression using reverse transcriptase polymerase chain reaction and for NF-κB subunit nuclear localization using immunohistochemistry. RESULTS: Several NF-κB target genes (Bcl-2, cellular inhibitor of apoptosis protein [cIAP]2, interleukin-8, and tumor necrosis factor receptor-associated-1) were significantly upregulated by a single fraction of RT at 24 h, demonstrating for the first time that NF-κB is activated by RT in human rectal tumors. The baseline NF-κB p50 nuclear expression did not correlate with the pathologic response to RT. However, an increasing baseline p50 level was prognostic for overall survival (hazard ratio, 2.15; p = .040). CONCLUSION: NF-κB nuclear expression at baseline in rectal cancer was prognostic for overall survival but not predictive of the response to RT. Larger patient numbers are needed to assess the effect of NF-κB target gene upregulation on the response to RT. Our results suggest that NF-κB might play an important role in tumor metastasis but not to the resistance to chemoradiotherapy.

Subcutaneous Metastatic Adenocarcinoma: An Unusual Presentation of Colon Cancer - Case Report and Literature Review.

Subcutaneous metastasis from a visceral malignancy is rare with an incidence of 5.3%. Skin involvement as the presenting sign of a silent internal malignancy is an even rarer event occurring in approximately 0.8%. We report a case of a patient who presented to her dermatologist complaining of rapidly developing subcutaneous nodules which subsequently proved to be metastatic colon cancer, and we provide a review of the literature.