Outcomes of surgical resection and intraoperative electron radiotherapy for patients with para-aortic recurrences of gastrointestinal and gynecologic malignancies.

BACKGROUND: Para-aortic lymph node (PALN) metastases from primary pelvic malignancies are often treated with resection, but recurrence is common. We report toxicity and oncologic outcomes for patients with PALN metastases from gastrointestinal and gynecologic malignancies treated with resection and intraoperative electron radiotherapy (IORT). METHODS: We retrospectively identified patients with recurrent PALN metastases who underwent resection with IORT. All patients were included in the local recurrence (LR) and toxicity analyses. Only patients with primary colorectal tumors were included in the survival analysis. RESULTS: There were 26 patients with a median follow up of 10.4 months. The rate of para-aortic local control (LC) was 77% (20/26 patients) and the rate of any cancer recurrence was 58% (15/26 patients). Median time from surgery and IORT to any recurrence was 7 months. The LR rate for those with positive/close margins was 58% (7/12 patients) versus 7% (1/14 patients) for those with negative margins (p = 0.009). 15% (4/26 patients) developed surgical wound and/or infectious complications, 8% (2/26 patients) developed lower extremity edema, 8% (2/26 patients) experienced diarrhea, and 19% (5/26 patients) developed an acute kidney injury. There were no reported nerve injuries, bowel perforations, or bowel obstructions. For patients with primary colorectal tumors (n = 19), the median survival (OS) was 23 months. CONCLUSIONS: We report favorable LC and acceptable toxicity for patients receiving surgical resection and IORT for a population that has historically poor outcomes. Our data show disease control rates similar to literature comparisons for patients with strong risk factors for LR, such as positive/close margins.

Un análisis general de la prolisil-oxidasa circulante en pacientes no isquémicos con una insuficiencia cardiaca común con fracción de eyección conservada / A global assessment of circulating prolysyl oxidase in nonischemic patients with garden-variety heart failure with preserved ejection fraction

Introducción y objetivos: La enzima lisil-oxidasa se expresa al alza en el miocardio de pacientes con cardiopatía hipertensiva. Se propone investigar si los pacientes con insuficiencia cardiaca y fracción de eyección conservada de origen hipertensivo-metabólico (ICFEc-HM) presentaban también concentraciones elevadas de prolisil-oxidasa circulante (pLOXc) y las posibles consecuencias de ello. Métodos: Se cuantifican las concentraciones de pLOXc de 85 pacientes no isquémicos con ICFEp-HM en estadio C y se comparan con las de 51 controles sanos. Se evaluaron además las correlaciones entre las concentraciones de pLOXc y ciertos parámetros de rigidez miocárdica, productos del ciclo del colágeno y citocinas fibrogénicas, así como el valor predictivo de la concentración plasmática de la proenzima a 1 año de seguimiento. Resultados: Se detectaron valores aumentados de pLOXc y se encontró que se correlacionaban con los cocientes E/E' y las constantes de rigidez que se calcularon. El subgrupo de pacientes con disfunción diastólica de tipo 1 mostró una correlación negativa solo entre la pLOXc y el péptido natriurético cerebral, mientras que en los pacientes con un patrón diastólico restrictivo se demostró una fuerte correlación entre la pLOXc y la galectina-3. El análisis de Kaplan-Meier reveló que las concentraciones de pLOXc > 52,20 ng/ml incrementaron ligeramente el riesgo de desenlace fatal (test de log rank= 4,45; p = 0,034). Al aplicar la regresión de COX, se obtuvo que la pLOXc es un significativo predictor independiente de muerte u hospitalización por descompensación de la ICFEp-HM (HR = 1,360; IC95%, 1,126-1,638; p = 0,046). Conclusiones: Los pacientes con ICFEp-HM sintomática tienen altas concentraciones séricas de pLOXc, lo cual se asocia con índices de llenado diastólico restrictivo. Tales concentraciones representan un factor de riesgo moderado de mal pronóstico. A lo largo de la historia natural de la ICFEp-HM, se ha constatado que las concentraciones de pLOXc al principio se correlacionan negativamente con las de péptido natriurético cerebral, y después tienen correlación positiva con las de galectina-3, a medida que se desarrolla una disfunción diastólica avanzada

Introduction and objectives: Lysyl oxidase is overexpressed in the myocardium of patients with hypertensive cardiomyopathy. We aimed to explore whether patients with hypertensive-metabolic heart failure with preserved ejection fraction (HM-HFpEF) also have increased concentrations of circulating prolysyl oxidase (cpLOX) and its possible consequences. Methods: We quantified cpLOX concentrations in 85 nonischemic patients with stage C, HM-HFpEF, and compared them with those of 51 healthy controls. We also assessed the correlations of cpLOX with myocardial stiffness parameters, collagen turnover products and fibrogenic cytokines, as well as the predictive value of plasma proenzyme levels at 1-year of follow-up. Results: We detected raised cpLOX values and found that they correlated with calculated E/E' ratios and stiffness constants. The subgroup of patients with type I diastolic dysfunction showed a single negative correlation between cpLOX and B-type natriuretic peptide whereas patients with a restrictive diastolic pattern showed a strong correlation between cpLOX and galectin-3. Kaplan-Meier analysis revealed that cpLOX > 52.20 ng/mL slightly increased the risk of a fatal outcome (log-rank = 4.45; P = .034). When Cox regression was used, cpLOX was found to be a significant independent predictor of cardiovascular death or hospitalization due to the decompensation of HM-HFpEF (HR, 1.360; 95%CI, 1.126-1.638; P = .046). Conclusions: Patients with symptomatic HM-HFpEF show high cpLOX serum levels associated with restrictive diastolic filling indices. These levels represent a moderate risk factor for poor clinical outcome. Throughout the natural history of HM-HFpEF, we observed that cpLOX concentrations were initially negatively correlated with B-type natriuretic peptide but positively correlated with galectin-3 as advanced diastolic dysfunction developed

A Global Assessment of Circulating Prolysyl Oxidase in Nonischemic Patients With Garden-variety Heart Failure With Preserved Ejection Fraction.

INTRODUCTION AND OBJECTIVES: Lysyl oxidase is overexpressed in the myocardium of patients with hypertensive cardiomyopathy. We aimed to explore whether patients with hypertensive-metabolic heart failure with preserved ejection fraction (HM-HFpEF) also have increased concentrations of circulating prolysyl oxidase (cpLOX) and its possible consequences. METHODS: We quantified cpLOX concentrations in 85 nonischemic patients with stage C, HM-HFpEF, and compared them with those of 51 healthy controls. We also assessed the correlations of cpLOX with myocardial stiffness parameters, collagen turnover products and fibrogenic cytokines, as well as the predictive value of plasma proenzyme levels at 1-year of follow-up. RESULTS: We detected raised cpLOX values and found that they correlated with calculated E/E' ratios and stiffness constants. The subgroup of patients with type I diastolic dysfunction showed a single negative correlation between cpLOX and B-type natriuretic peptide whereas patients with a restrictive diastolic pattern showed a strong correlation between cpLOX and galectin-3. Kaplan-Meier analysis revealed that cpLOX > 52.20 ng/mL slightly increased the risk of a fatal outcome (log-rank = 4.45; P = .034). When Cox regression was used, cpLOX was found to be a significant independent predictor of cardiovascular death or hospitalization due to the decompensation of HM-HFpEF (HR, 1.360; 95%CI, 1.126-1.638; P = .046). CONCLUSIONS: Patients with symptomatic HM-HFpEF show high cpLOX serum levels associated with restrictive diastolic filling indices. These levels represent a moderate risk factor for poor clinical outcome. Throughout the natural history of HM-HFpEF, we observed that cpLOX concentrations were initially negatively correlated with B-type natriuretic peptide but positively correlated with galectin-3 as advanced diastolic dysfunction developed.

Combined Aortic Valve Replacement and Renal Cell Carcinoma Thrombectomy.

Although nephrectomy for renal cell carcinoma with inferior vena cava invasion is a common procedure, it is rare to have level IV invasion necessitating cardiopulmonary bypass (CPB). Furthermore, it is exceptionally rare to perform cardiac surgery concomitantly with this resection. We report a case in which an aortic valve replacement was done in the same surgical setting as a level IV thrombectomy. We have demonstrated that although it can be difficult to manage the coagulopathy post-CPB, this can be successfully accomplished with adequate prior preparation and a coordinated team effort.

Mass-forming cholangiocarcinoma and adenocarcinoma of unknown primary: can they be distinguished on liver MRI?

PURPOSE: To determine MR features suggestive of mass-forming cholangiocarcinoma (CCA) or liver metastases of adenocarcinoma of unknown primary (AUP), and to compare the ability of two experienced radiologists to establish the correct diagnosis. MATERIALS AND METHODS: 61 patients with CCA or AUP, with MRIs were placed into two groups: population 1, 28 patients with certain diagnosis of either CCA or AUP; and population 2, 33 patients with uncertain diagnosis. Using population 1 with known diagnosis, two investigators formulated imaging criteria for CCA or AUP, which represented phase 1 of the study. In phase 2, two independent radiologists categorized the patients in populations 1 and 2 as CCA or AUP using the formulated criteria. This categorization was compared with the patient medical records and pathologist review. Findings were tested for statistical significance. RESULTS: In phase 1, solitary lesion, multifocal lesions with dominant lesion, capsule retraction, and porta hepatis lymphadenopathy were features of CCA; multifocal lesions with similar size, and ring enhancement were features of AUP. The number of lesions, capsule retraction, and early tumor enhancement pattern were observed to be significant features (P < 0.05). In phase 2, agreement between the two radiologists was good (k = 0.663). For population 1, the agreement was good (k = 0.659), and was fair for population 2 (k = 0.293). Concordance between the two radiologists, medical record, and the pathologist was found in 41/61 (67%) patients. CONCLUSION: Distinctive features of CCA and AUP are identifiable on MRI images, which may aid the radiologist to establish the correct diagnosis.

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.

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.

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 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.

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.

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.

Utility of the omentum in pelvic floor reconstruction following resection of anorectal malignancy: patient selection, technical caveats, and clinical outcomes.

This study assesses the usefulness of the omentum in the reconstruction of complex perineal defects, following abdominoperineal resection or pelvic exenteration, for anorectal malignancy. Between 2000 and 2008, 70 patients (mean age: 59 years) with anorectal malignancy underwent abdominoperineal resection (n = 57) or pelvic exenteration (n = 13) and were reconstructed by primary repair alone (n = 13), primary repair with omentum (n = 16), myocutaneous flap alone (n = 28), or myocutaneous flap with omentum (n = 13). Patients with and without omental flaps were compared by Student t test and chi2 analysis. Omental flaps were based on a single pedicle, tunneled in the retrocolic plane lateral to the ligament of Treitz, and transposed across the sacrum to the pelvic floor. In total, 29 patients had pelvic floor and perineal reconstruction with the omentum, and 41 patients had reconstruction without the omentum. Incidence of major pelvic complications (abscess, urinoma, deep vein thrombosis, flap dehiscence, hernia, bowel obstruction, fistula) was greater in the "no omentum" group (25/41 patients, 61%), compared with the "omentum" group (6/29 patients, 21%) (P < 0.01). No differences were observed regarding age, stage, incidence of radiotherapy, blood loss, length of stay, or mortality. Use of the omentum as a primary flap, or in combination with a myocutaneous flap, in the reconstruction of complex perineal defects, is associated with a decreased incidence of postoperative complications, strongly supporting the use of the omentum in pelvic floor reconstruction.

A phase I study of bortezomib in combination with standard 5-fluorouracil and external-beam radiation therapy for the treatment of locally advanced or metastatic rectal cancer.

BACKGROUND: Standard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation. PATIENTS AND METHODS: Patients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m2/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies. RESULTS: Nine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m2 dose level. There was no clear evidence of suppression of nuclear factor-kappaB target gene expression in biopsy samples. CONCLUSION: The MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.

Radiosensitization of epidermal growth factor receptor/HER2-positive pancreatic cancer is mediated by inhibition of Akt independent of ras mutational status.

PURPOSE: Epidermal growth factor receptor (EGFR) family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations. EXPERIMENTAL DESIGN: Expression of EGFR family members in pancreatic cancer lines was assessed by quantitative reverse transcription-PCR. Cell growth inhibition was determined by MTS assay. The effects of inhibition of EGFR family receptors and downstream signaling pathways on in vitro radiosensitivity were evaluated using clonogenic assays. Growth delay was used to evaluate the effects of nelfinavir on in vivo tumor radiosensitivity. RESULTS: Lapatinib inhibited cell growth in four pancreatic cancer cell lines, but radiosensitized only wild-type K-ras-expressing T3M4 cells. Akt activation was blocked in a wild-type K-ras cell line, whereas constitutive phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was seen in lines expressing mutant K-ras. Overexpression of constitutively active K-ras (G12V) abrogated lapatinib-mediated inhibition of both Akt phosphorylation and radiosensitization. Inhibition of MAP/ERK kinase/ERK signaling with U0126 had no effect on radiosensitization, whereas inhibition of activated Akt with LY294002 (enhancement ratio, 1.2-1.8) or nelfinavir (enhancement ratio, 1.2-1.4) radiosensitized cells regardless of K-ras mutation status. Oral nelfinavir administration to mice bearing mutant K-ras-containing Capan-2 xenografts resulted in a greater than additive increase in radiation-mediated tumor growth delay (synergy assessment ratio of 1.5). CONCLUSIONS: Inhibition of EGFR/HER2 enhances radiosensitivity in wild-type K-ras pancreatic cancer. Nelfinavir, and other phosphoinositide 3-kinase/Akt inhibitors, are effective pancreatic radiosensitizers regardless of K-ras mutation status.

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.

Continuous elimination of Pb2+, Cu2+, Zn2+, H+ and NH4 + from acidic waters by ionic exchange on natural zeolites.

A study of breakthrough curves for cations usually found in acid mine drainage (Pb(2+), Cu(2+), Zn(2+) and H(+)) and municipal wastewater (NH(4)(+)) have been conducted on some natural zeolitic tuffs. The zeolitic tuffs used in this study are: three zeolitic tuffs from Cayo Formation, Guayaquil (Ecuador), characterized by X-ray diffraction as clinoptilolite (sample CLI-1) and heulandite (samples HEU-1 and HEU-2)-rich tuffs, and two zeolitic tuffs from Parnaiba Basin, Belem do Pará (Brazil), characterized as stilbite-rich tuffs (samples STI-1 and STI-2). The clinoptilolite sample CLI-1 shows an exceedingly good exchange capacities for Pb(2+) and NH(4)(+) as received, and also a very high exchange capacity for Cu(2+) and Zn(2+) when conditioned with 2M sodium chloride, with much higher values than those reported in the literature for other clinioptilolite ores. A general order of effective cation exchange capacity could be inferred from breakthrough curves on these zeolitic tuffs: CLI-1 > HEU-2 > HEU-1 > STI-2. Since it is true for most of the cations studied.

Preoperative tyrosine kinase inhibition as an adjunct to debulking nephrectomy.

OBJECTIVES: Since the introduction of tyrosine kinase inhibitors (TKI), treatment of metastatic renal cell carcinoma (RCC) has undergone dramatic changes. However, the use of TKI therapy in adjunctive settings remains to be defined. We present a single-institution experience of patients who received preoperative TKI before nephrectomy for metastatic or unresectable disease. METHODS: The records of 9 patients with locally advanced or metastatic RCC treated with TKI therapy before nephrectomy at the University of North Carolina were reviewed. All procedures and radiographic images were performed at 1 institution. The cases were surveyed for the effect of TKI on tumor burden and surgical approach and timing. RESULTS: The patients received systemic therapy with either sorafenib or sunitinib before proceeding to nephrectomy on clinical trials for metastatic disease or as the standard of care. The surgery was well tolerated by all patients, without an apparent effect from TKI therapy on the surgical technique or complications. Responses were observed in the primary tumor, as well as in the metastatic sites. CONCLUSIONS: Neoadjuvant TKI therapy can induce responses in the primary tumor and has the potential advantage of cytoreduction when administered before nephrectomy for RCC. This setting also potentially provides an opportunity to evaluate the TKI responsiveness of patients with metastatic disease. However, prospective trials evaluating adjunctive surgical approaches to locally advanced and metastatic RCC are needed to determine the significant benefits of TKI therapy and to define the optimal agent, timing of therapy, and disease stage to derive benefit for preoperative therapy.

Short preoperative treatment with erlotinib inhibits tumor cell proliferation in hormone receptor-positive breast cancers.

PURPOSE: To administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity. PATIENTS AND METHODS: Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ER alpha. RESULTS: In drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade