Nipple viability after nipple-sparing mastectomy in patients with prior circum-areolar incisions.

Nipple-areola-sparing mastectomy (NSM) is becoming more commonplace as it offers a more esthetic breast appearance while still appropriately treating malignancy. However, patients with prior circum-areolar incisions are often considered at risk for nipple viability. The authors present a case series of all patients undergoing NSM at their institution between 2012 and 2016. Eighteen consecutive female nonsmoking patients underwent 32 NSMs. None of the patients had reconstructive failures including those relating to the nipple-areola complex (NAC), such as nipple necrosis. NSM is therefore feasible in cases with prior circum-areolar incisions. These patients can be safely reconstructed with both prosthetic devices and autologous tissue.

Implications of Internal Mammary Lymph Node Sampling During Microsurgical Breast Reconstruction.

INTRODUCTION: Internal mammary lymph node (IMN) chain assessment for breast cancer is controversial; however, current oncologic data have shed new light on its importance. Metastatic involvement of the IMN chain has implications for staging, prognosis, treatment, and survival. Here, we analyzed our data gathered during sampling of the IMN and the oncologic treatment changes that resulted from our findings. METHODS: A retrospective chart review was performed on 581 patients who underwent free-flap breast reconstruction performed by the senior author. All dissected IMNs were submitted for pathological examination. Patient demographics, oncologic data, and the results of IMN sampling were reviewed. RESULTS: 581 patients undergoing 981 free flaps were identified. A total of 400 lymph node basins were harvested from 273 patients. Of these, nine had positive IMNs. Two of these nine patients had positive IMNs of the contralateral nonaffected breast. Five patients had positive axillary lymph nodes. Four patients had multifocal tumors, one of which was bilateral. Seven patients had an increase in cancer stage as a result of having positive IMNs. Six patients had a change in treatment: two patients required additional chemotherapy, one received adjuvant radiation therapy, and three necessitated both supplemental chemotherapy and radiation. CONCLUSIONS: Opportunistic biopsy of the IMN while dissecting the recipient vessels is simple and results in no added morbidity. We recommend that biopsy of the IMN chain be performed whenever internal mammary vessels are dissected for microsurgical anastomosis in breast cancer patients. Positive IMN involvement should encourage thorough oncological workup and treatment reevaluation. LEVEL OF EVIDENCE IV: Case series.

Targeting the urokinase plasminogen activator receptor with a monoclonal antibody impairs the growth of human colorectal cancer in the liver.

BACKGROUND: Urokinase plasminogen activator receptor (uPAR) expression has been shown to correlate with poor prognosis in colorectal cancer (CRC). The authors hypothesized that targeting uPAR, a receptor involved in cell proliferation, migration, invasion, adhesion, and angiogenesis, would impair the growth of CRC in the liver, the most common site of metastasis. METHODS: Human CRC cell lines were examined for uPAR expression by Western blot analysis. The in vitro effects of the uPAR monoclonal antibody (MoAb) (ATN-658) were tested in proliferation and migration assays. For in vivo studies, human HCT116 CRC cells were injected directly into the livers of mice in 2 separate studies, the first to determine the effect of therapy with ATN-658 on small-volume disease (therapy begun on Day 4), and a second study to determine the effect of therapy on established disease (therapy begun on Day 12). Mice were randomized to receive either nonspecific immunoglobulin G MoAb (control) or ATN-658, and were sacrificed 1 month after tumor implantation. RESULTS: uPAR was expressed by all CRC cell lines studied. In vitro, ATN-658 had minimal effect on CRC proliferation in monolayers, but significantly decreased CRC cell migration. In vivo, ATN-658 lead to significant reductions in tumor growth versus control when initiated either 4 or 12 days after tumor implantation (-65% vs control [P < or = .05] and -85% vs control [P < or = .05]). ATN-658 significantly inhibited in vivo tumor cell proliferation in both studies. CONCLUSIONS: uPAR MoAb therapy impaired CRC tumor growth in the liver in both small-volume and large-volume disease models.

Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition.

5-Fluorouracil (5FU) and oxaliplatin are standard therapy for metastatic colorectal cancer (CRC), but the development of chemoresistance is inevitable. Because cancer stem cells (CSC) are hypothesized to be chemoresistant, we investigated CSC properties in newly developed chemoresistant CRC cell lines and sought to identify targets for therapy. The human CRC cell line HT29 was exposed to increasing doses of 5FU (HT29/5FU-R) or oxaliplatin (HT29/OxR) to achieve resistance at clinically relevant doses. Western blotting and flow cytometry were done to determine molecular alterations. The insulin-like growth factor-I receptor (IGF-IR) monoclonal antibody (mAb) AVE-1642 was used to inhibit signaling in vitro and in vivo using murine xenograft models. HT29/5FU-R and HT29/OxR showed 16- to 30-fold enrichment of CD133(+) cells and 2-fold enrichment of CD44(+) cells (putative CRC CSC markers). Resistant cells were enriched 5- to 22-fold for double-positive (CD133(+)/CD44(+)) cells. Consistent with the CSC phenotype, resistant cells exhibited a decrease in cellular proliferation in vitro (47-59%; P < 0.05). Phosphorylated and total IGF-IR levels were increased in resistant cell lines. HT29/5FU-R and HT29/OxR cells were approximately 5-fold more responsive to IGF-IR inhibition relative to parental cells (P < 0.01) in vitro. Tumors derived from HT29/OxR cells showed significantly greater growth inhibition in response to an IGF-IR mAb than did parental cells (P < 0.05). Chemoresistant CRC cells are enriched for CSC markers and the CSC phenotype. Chemotherapy-induced IGF-IR activation provided for enhanced sensitivity to IGF-IR-targeted therapy. Identification of CSC targets presents a novel therapeutic approach in this disease.

Neuropilin-2-mediated tumor growth and angiogenesis in pancreatic adenocarcinoma.

PURPOSE: Neuropilin-2 (NRP-2) is a coreceptor for vascular endothelial growth factor (VEGF) on endothelial cells. NRP-2 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells relative to nonmalignant ductal epithelium. This study determined the role of NRP-2 in PDAC cells. EXPERIMENTAL DESIGN: NRP-2 expression was reduced in PDAC cells with stable short-hairpin RNA (shRNA) transfection. Western blotting was done to evaluate signaling intermediates. Migration and invasion studies were carried out in Boyden chambers. Anchorage-independent growth was assessed by soft-agar colony formation. In vivo growth was evaluated using murine subcutaneous and orthotopic xenograft models. Immunohistochemical analysis evaluated in vivo proliferation and angiogenesis. RESULTS: shRNA-NRP-2 decreased NRP-2 levels without affecting neuropilin-1 levels. Akt activation was decreased in clones with reduced NRP-2 (shRNA-NRP-2). shRNA-NRP-2 cells showed decreased migration, invasion, and anchorage-independent growth compared with control cells. In vitro proliferation rates were similar in control- and shRNA-transfected cells. Subcutaneous and orthotopic xenografts from shRNA-transfected cells were significantly smaller than those resulting from control-transfected cells (P < 0.05). Furthermore, shRNA-NRP-2 tumors exhibited less cellular proliferation and decreased microvascular area relative to control tumors (P < 0.05). Constitutive expression of the angiogenic mediator Jagged-1 was reduced in shRNA-NRP-2 cells, whereas vascular endothelial growth factor levels were unchanged. CONCLUSION: Reduction of NRP-2 expression in PDAC cells decreased survival signaling, migration, invasion, and ability to grow under anchorage-independent conditions. In vivo, reduction of NRP-2 led to decreased growth of xenograft tumors and decreased vascular area, which was associated with decreased Jagged-1 levels. NRP-2 is a potential therapeutic target on PDAC cells.

Endoglin (CD105): a marker of tumor vasculature and potential target for therapy.

Endoglin (CD105) is an accessory protein of the transforming growth factor-beta receptor system expressed on vascular endothelial cells. Mutation of the endoglin gene is associated with hereditary hemorrhagic telangiectasias, or Osler-Weber-Rendu syndrome, and has been studied extensively in the context of this disease. The expression of endoglin is elevated on the endothelial cells of healing wounds, developing embryos, inflammatory tissues, and solid tumors. Endoglin is a marker of activated endothelium, and its vascular expression is limited to proliferating cells. Recent studies identified endoglin expression in several solid tumor types, with the level of expression correlating with various clinicopathologic factors including decreased survival and presence of metastases. Attempts to target endoglin and the cells that express this protein in tumor-bearing mice have yielded promising results.

Effect of molecular therapeutics on liver regeneration in a murine model.

PURPOSE: Unresectable metastatic colorectal cancer (CRC) can be rendered resectable with systemic chemotherapy in approximately 20% of cases. Most patients with metastatic CRC receive chemotherapy with the addition of targeted therapy with anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR) antibodies. We sought to determine whether anti-VEGF receptor (VEGFR) or anti-EGFR therapy would impair liver regeneration after partial hepatectomy (PH) in mice. MATERIALS AND METHODS: Mice underwent either 66% PH or sham laparotomy. In the first experiment, mice in the PH group were randomly assigned to receive daily intraperitoneal injections of monoclonal antibodies (MoABs) to murine VEGFR-2 or nonspecific MoABs (control). In the second experiment, mice in the PH group were randomly assigned to receive intraperitoneal injections of antimurine EGFR or nonspecific (control) MoABs. In both experiments, therapy was initiated the day before surgery and continued until the mice were killed on day 5. Livers were collected and processed. RESULTS: Anti-VEGFR-2 therapy slightly impaired liver regeneration and hepatic cell proliferation compared with control. Hematoxylin and eosin staining showed no differences in liver morphology. CD105 staining showed decreased levels of activated endothelium in livers in the VEGFR-2 MoAB group. VEGFR-2 MoAB therapy decreased the levels of the cell cycle regulators cyclin D1 and cyclin D3 and the regenerative cytokine interleukin-6. Anti-EGFR therapy had no effect on liver regeneration or cellular proliferation. CONCLUSION: Anti-VEGFR-2 therapy slightly impaired liver regeneration in this murine model, whereas anti-EGFR therapy had no effect on liver regeneration.

Melanoma adrenal metastasis: natural history and surgical management.

BACKGROUND: Few data exist regarding melanoma metastasis to the adrenal gland. We reviewed our experience to determine the natural history of this condition and the appropriate role for surgical intervention. METHODS: A retrospective review of melanoma patients with adrenal metastasis was performed. Clinical presentation, surgical treatment, and survival were determined. RESULTS: One hundred fifty-four patients with adrenal metastasis were identified. The median survival for the entire group was 6.4 months and was negatively impacted by the presence of synchronous metastasis or an elevated LDH. Twenty-two patients underwent surgery including 20 patients rendered disease free, either by adrenalectomy alone (14) or adrenalectomy with concomitant metastectomy (6). Patients who underwent surgery had an improved survival compared with those managed nonoperatively (P < .0001). CONCLUSIONS: Patients with melanoma adrenal metastasis have a poor prognosis. Surgical treatment should be considered only in highly selected patients, such as those with limited extra-adrenal metastatic disease who can be rendered disease free.

Sentinel lymph node evaluation does not improve staging accuracy in colon cancer.

BACKGROUND: Lymph node involvement is an important prognostic factor in colorectal cancer. Sentinel lymph node (SLN) evaluation for assessing lymph node status in colorectal cancer remains controversial. Here we evaluated the sensitivity, predictive value, and accuracy of SLN evaluation for determining lymph node status in resectable colon cancer. METHODS: A prospective phase 2 cohort study of SLN evaluation in colon cancer was conducted from September 1998 to April 2006. Patients underwent resection and SLN mapping with 1% isosulfan blue and (m99)Tc sulfur colloid injection. SLNs were evaluated by hematoxylin and eosin (HE) staining and, if findings were negative, by additional thin HE sections and immunohistochemical (IHC) staining for pancytokeratin and MOC31. Overall survival for patients with IHC-positive disease was evaluated by Kaplan-Meier analysis and the log rank test. RESULTS: SLNs were identified in 119 (99%) of the 120 patients eligible for the study. Median number of SLNs identified was 4 (range, 0-13). Forty-nine patients (40%) had nodal metastases on HE. The SLN accurately identified nodal metastases in 29 (59%) of these 49 patients and was negative for metastases in 22 patients (41%). SLNs in eight patients (7%) were negative by HE but positive by IHC staining. Positive IHC status did not affect survival after a median follow-up of 33 months (P = .41). CONCLUSIONS: The low sensitivity and high false-negative rate of SLN evaluation does not support this technique for improving the accuracy of nodal staging for patients with colon cancer. The significance of IHC-positive SLNs remains uncertain.

Functional significance of vascular endothelial growth factor receptors on gastrointestinal cancer cells.

Vascular endothelial growth factor (VEGF) has been shown to be the major mediator of physiologic and pathologic angiogenesis. VEGF was initially thought to be an endothelial cell specific ligand, but recently, VEGF has been shown to mediate tumor cell function via activation of receptors on tumor cells themselves. Here, we review the expression patterns and binding profiles of the VEGF receptors and their ligands on gastrointestinal tumor cells. Furthermore, we describe the current knowledge in regards to the function of these receptors on tumor cells. Elucidating the function of VEGF receptors on tumor cells should help us to better understand the potential mechanisms of action of anti-VEGF therapies.

Toxicity and outcomes associated with surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with sarcomatosis.

BACKGROUND: Treatment of peritoneal recurrence following surgical resection of intra-abdominal sarcomas presents a significant challenge to clinicians. Historically, treatment with systemic chemotherapy has been ineffective and surgical resection alone has not been durable. We prospectively evaluated the feasibility of cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin (CDDP) alone or in combination with mitoxantrone (MITOX) for the treatment of sarcomatosis. METHODS: Two phase I trials of HIPEC were conducted (1998-2003). Eligible patients with evidence of sarcomatosis underwent cytoreductive surgery followed by HIPEC. In the first trial, CDDP dosing was established as 90 mg/m2 with a perfusate time of 90 minutes and temperature of 41 degrees C. In the second trial, MITOX (20 mg/m2) was instilled following perfusion with CDDP. Toxicity, efficacy, and quality of life (QOL) were evaluated. RESULTS: A total of 28 patients were enrolled in the two trials. We noted a higher overall toxicity score and complication rate with combination CDDP/MITOX versus CDDP alone and shorter overall survival duration (5.5 months vs 16.9 months, respectively). In addition, local recurrence rates were similar in both groups (CDDP 79% vs CDDP/MITOX 68%). As expected, QOL scores at 6-8 weeks following HIPEC were 15-25% lower than the baseline scores; however, they returned to baseline at 3-6 months. CONCLUSIONS: Although the HIPEC technique is feasible for patients with sarcomatosis, it is associated with significant toxicity and limited clinical benefit. Combination CDDP/MITOX failed to demonstrate any benefit over CDDP alone; moreover, there was an increase in toxicity.

Preoperative evaluation of pancreatic cystic lesions: cost-benefit analysis and proposed management algorithm.

BACKGROUND: This study was performed to develop a management algorithm that accurately predicts the necessity of operative intervention and results in significant cost savings for patients with cystic pancreatic tumors. METHODS: We reviewed 60 patients treated between 1992 and 2003. Accuracy rates of tests used to differentiate benign from premalignant and malignant cysts were calculated. A management algorithm was generated that incorporated clinical presentation, radiologic findings, and selective use of endoscopic procedures. This algorithm was tested for predictive accuracy, and savings between actual management and proposed management were compared. RESULTS: There was an average of 3 preoperative tests performed per patient. Endoscopic procedures included endoscopic retrograde cholangiopancreatography in 21 patients and endoscopic ultrasound in 25 patients. A cyst fluid carcinoembryonic antigen (CEA) level of 158 ng/mL or greater had an accuracy rate of 87.5% that was significantly higher than endoscopic retrograde cholangiopancreatography (72%), endoscopic ultrasound morphology (45%), or endoscopic ultrasound cytology (66.7%). There was no combination of tests that provided greater accuracy than cyst fluid CEA level alone (P < .05). The management algorithm had a positive predictive value of 81%. The average actual cost of radiographic and endoscopic procedures was dollar 8,080 per patient. The proposed cost based on the algorithm was dollar 6,677 with a savings of dollar 1,403 per patient (P = .009). CONCLUSIONS: In patients with clinical symptoms or radiographic findings of mucinous or malignant tumors, further testing is excessive. Of endoscopic tests available, the cystic fluid CEA level most accurately predicts the presence of a mucinous neoplasm. A management algorithm based on presenting symptoms, radiographic findings, and cyst fluid CEA level provides a guideline for the evaluation of cystic lesions in the most cost-efficient manner while ensuring proper care.