The replication-competent oncolytic herpes simplex mutant virus NV1066 is effective in the treatment of esophageal cancer

BACKGROUND: The oncolytic herpes simplex-1 virus, NV1066, is a replication-competent virus that has been engineered to infect and lyse tumor cells selectively and to carry a transgene for enhanced green fluorescent protein (EGFP). The purpose of this study was to determine viral cytotoxicity in an esophageal cancer cell line and to determine whether EGFP expression could be used as a marker of viral infection. METHODS: BE3 esophageal adenocarcinoma cells were infected with NV1066 in vitro to determine cell kill and viral replication. EGFP expression was assessed by flow cytometry. The in vivo anti-tumor activity of NV1066 was tested in subcutaneous and intraperitoneal xenograft models. EGFP expression was localized in vivo by fluorescent microscopy and fluorescent laparoscopy. RESULTS: NV1066 effectively replicated within and killed BE3 cells in vitro and in vivo. EGFP expression identified infected tumor cells. After NV1066 treatment in vivo, EGFP expression localized to the tumor. In an intraperitoneal tumor model, EGFP could be visualized endoscopically using a laparoscope with a fluorescent filter. CONCLUSIONS: NV1066 has oncolytic activity against the BE3 cell line and may be a useful therapy against esophageal cancer. EGFP expression localizes the virus and may help to identify tumor deposits in vivo. Oncolytic activity with NV1066 against gastrointestinal cancers may potentially be tracked by endoscopy.     

Virally-directed fluorescent imaging (VFI) can facilitate endoscopic staging

Background Replication-competent, tumor specific herpes simplex virus NV1066 expresses green fluorescent protein (GFP) in infected cancer cells. We sought to determine the feasibility of GFP-guided imaging technology in the intraoperative detection of small tumor nodules. Methods Human cancer cell lines were infected with NV1066 at multiplicities of infection of 0.01, 0.1 and 1. Cancer cell specific infectivity, vector spread and GFP signal intensity were measured by flow cytometry and time-lapse digital imaging (in vitro); and by use of a stereomicroscope and endoscope equipped with a fluorescent filter (in vivo). Results NV1066 infected all cancer cell lines and expressed GFP at all MOIs. GFP signal was significantly higher than the autofluorescence of normal cells. One single dose of NV1066 spread within and across body cavities and selectively infected tumor nodules sparing normal tissue. Tumor nodules undetectable by conventional thoracoscopy and laparoscopy were identified by GFP fluorescence. Conclusion Virally-directed fluorescent imaging (VFI) is a real-time novel molecular imaging technology that has the potential to enhance the intraoperative detection of endoluminal or endocavitary tumor nodules. R. Huq: Molecular Cytology Core Facility Presented at the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) meeting, Fort Lauderdale, FL, USA, 13–16 April 2005     

Lymphatic mapping and sentinel lymphadenectomy for breast cancer.

OBJECTIVE: The authors report the feasibility and accuracy of intraoperative lymphatic mapping with sentinel lymphadenectomy in patients with breast cancer. SUMMARY BACKGROUND DATA: Axillary lymph node dissection (ALND) for breast cancer generally is accepted for its staging and prognostic value, but the extent of dissection remains controversial. Blind lymph node sampling or level I dissection may miss some nodal metastases, but ALND may result in lymphedema. In melanoma, intraoperative lymph node mapping with sentinel lymphadenectomy is an effective and minimally invasive alternative to ALND for identifying nodes containing metastases. METHODS: One hundred seventy-four mapping procedures were performed using a vital dye injected at the primary breast cancer site. Axillary lymphatics were identified and followed to the first ("sentinel") node, which was selectively excised before ALND. RESULTS: Sentinel nodes were identified in 114 of 174 (65.5%) procedures and accurately predicted axillary nodal status in 109 of 114 (95.6%) cases. There was a definite learning curve, and all false-negative sentinel nodes occurred in the first part of the study; sentinel nodes identified in the last 87 procedures were 100% predictive. In 16 of 42 (38.0%) clinically negative/pathologically positive axillae, the sentinel node was the only tumor-involved lymph node identified. The anatomic location of the sentinel node was examined in the 54 most recent procedures; ten cases had only level II nodal metastases that could have been missed by sampling or low (level I) axillary dissection. CONCLUSIONS: This experience indicates that intraoperative lymphatic mapping can accurately identify the sentinel node--i.e., the axillary lymph node most likely to contain breast cancer metastases--in some patients. The technique could enhance staging accuracy and, with further refinements and experience, might alter the role of ALND.     

Lymphatic invasion, tumor size, and age are independent predictors of axillary lymph node metastases in women with T1 breast cancers

OBJECTIVE: To identify characteristics of the primary tumor highly associated with lymph node metastases. SUMMARY BACKGROUND DATA: Recent enthusiasm for limiting axillary lymph node dissection (ALND) in women with breast cancer may increase the likelihood that nodal metastases will be missed. Identification of characteristics of primary tumors predictive of lymph node metastases may prompt a more extensive surgical and pathologic search for metastases in patients with negative sentinel lymph nodes or limited ALND. METHODS: The authors studied 850 consecutive patients who underwent ALND for T1 breast cancer. Age, tumor size, histopathologic diagnosis, tumor differentiation, presence of lymphatic invasion, and estrogen and progesterone receptor results were studied prospectively. Stepwise logistic regression was used to identify variables independently associated with axillary lymph node metastases. RESULTS: Lymphatic invasion, tumor size, and age were independently associated with lymph node metastases. Fifty-one percent of the 181 patients with lymphatic invasion had axillary lymph node metastases, compared with 19% of the 669 patients without lymphatic invasion. Thirty-five percent of the 470 patients with tumors >1 cm had nodal involvement compared with 13% of the 380 patients with smaller cancers. Thirty-seven percent of the 63 women younger than age 40 had lymph node involvement compared with 25% of the 787 women older than age 40. Significant correlations were noted between lymphatic invasion and patient age and between lymphatic invasion and tumor size. The proportion of tumors with lymphatic invasion decreased progressively with increasing age and increased with increasing tumor size. CONCLUSIONS: Axillary lymph node metastases are most significantly related to lymphatic invasion in the primary tumor, followed, in order of significance, by tumor size and patient age. Axillary nodal metastases should be suspected in the presence of lymphatic invasion of large tumors in young patients.     

5-Fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer

Oncolytic herpes viruses are attenuated, replication-competent viruses that selectively infect, replicate within, and lyse cancer cells and are highly efficacious in the treatment of a wide variety of experimental cancers. The current study seeks to define the pharmacologic interactions between chemotherapeutic drugs and the oncolytic herpes viral strain NV1066 in the treatment of pancreatic cancer cell lines. The human pancreatic cancer cell lines Hs 700T, PANC-1, and MIA P_aC_a-2 were treated in vitro with NV1066 at multiplicities of infection (MOI; ratio of the number of viral particles per tumor cell) ranging from 0.01 to 1.0 with or without 5-fluorouracil (5-FU) or gemcitabine. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Viral replication was measured using a standard plaque assay. Six days after combination therapy, 76% of Hs 700T cells were killed compared with 43% with NV1066 infection alone (MOI = 0.1) or 0% with 5-FU alone (2 βmol/L) (P < .01). Isobologram and combination-index analyses confirmed a strongly synergistic pharmacologic interaction between the agents at all viral and drug combinations tested (LD5 to LD95) in the three cell lines. Dose reductions up to 6- and 78-fold may be achieved with combination therapy for NV1066 and 5-FU, respectively, without compromising cell kill. 5-FU increased viral replication up to 19-fold compared with cells treated with virus alone. Similar results were observed by combining gemcitabine and NV1066. We have demonstrated that 5-FU and gemcitabine potentiate oncolytic herpes viral replication and cytotoxicity across a range of clinically achievable doses in the treatment of human pancreatic cancer cell lines. The potential clinical implications of this synergistic interaction include improvements in efficacy, treatment-associated toxicity, tolerability of therapeutic regimens, and quality of life. These data provide the cellular basis for the clinical investigation of combined oncolytic herpes virus therapy and chemotherapy in the treatment of pancreatic cancer. Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 141-18, 2005 (oral presentation). Supported in part by training grant T 32 CA09501 (D.P.E. and K.J.H.), AACR-AstraZeneca Cancer Research and Prevention fellowship (P.S.A), grants RO1 CA 76416 and RO1 CA/DK80982 (Y.F.) from the National Institutes of Health, grant BC024118 from the U.S. Army (Y.F.), grant IMG0402501 from the Susan G. Komen Foundation (Y.F.), and grant 032047 from Flight Attendant Medical Research Institute (Y.F.).     

Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer

OBJECTIVE: To assess the strategy of combining oncolytic herpes simplex virus (HSV) therapy with immunomodulatory therapy as treatment for experimental colon cancer. The oncolytic HSV recombinant NV1023 and the interleukin 12 (IL-12)-secreting oncolytic NV1042 virus were evaluated in vitro and in vivo with respect to antitumor efficacy. SUMMARY BACKGROUND DATA: Genetically engineered, replication-conditional, attenuated HSVs have shown oncolytic activity against a wide variety of solid malignancies. Other strategies for treating cancer have involved immunomodulation and cytokine gene transfer using viral vectors. This study has combined both of these strategies by inserting the murine IL-12 gene into a replication-competent HSV. This approach allows oncolytic therapy to replicate selectively within and lyse tumor cells while providing the host immune system with the cytokine stimulus necessary to recruit and activate inflammatory cells needed to enhance the antitumor effect. METHODS: NV1023 is a multimutant HSV based on the wild-type HSV-1 F strain. NV1042 was created by insertion of the mIL-12 gene into NV1023. Cytotoxicity and viral proliferation of both NV1023 and NV1042 within murine CT26 colorectal cancer cells were first shown. Cells infected with NV1042 were then shown to produce significant levels of IL-12. Using an experimental flank model of colon cancer, mice were treated with both high and low doses of NV1023 or NV1042 and were followed up for both cure and reduction in tumor burden. RESULTS: Both viruses could replicate within and kill CT26 cells in vitro, with 100% cytotoxicity achieved after infection by either virus. Only NV1042 could produce mIL-12. Therapy using high viral doses to treat animals in vivo showed equal efficacy between NV1023 and NV1042, with five of seven cures for each virus. When viral doses were lowered, only the cytokine-producing NV1042 virus could reduce tumor burden and cure animals of their disease. CONCLUSIONS: Both NV1023 and NV1042 have the oncolytic potential to kill colon cancer cells at higher doses. Cytokine production by NV1042 may allow lower doses of viral therapy to be used without losing antitumor efficacy. The combination of oncolytic viral therapy and immunomodulatory strategies should be further investigated as treatment for colon cancer.     

Herpes simplex virus based gene therapy enhances the efficacy of mitomycin C for the treatment of human bladder transitional cell carcinoma

PURPOSE: Oncolytic replication competent herpes simplex virus type-1 (HSV) mutants have the ability to replicate in and kill malignant cells. We have previously reported the ability of replication competent HSV to control bladder cancer growth in an orthotopic murine model. We hypothesized that the combination of a chemotherapeutic agent used for intravesical treatment, namely mitomycin C (MMC) (Bristol-Myers Squibb Oncology, Princeton, New Jersey), and oncolytic HSV would exert a synergistic effect for the treatment of human transitional cell carcinoma. MATERIALS AND METHODS: We used mutant HSV NV1066 (Medigene, San Diego, California), which is deleted for viral genes ICP0 and ICP4, and selectively infects cancer cells, to treat the transitional cell carcinoma lines KU19-19 and SKUB. Cell survival was determined by lactate dehydrogenase assay for each agent as well as for drug-viral combinations from days 1 to 5. The isobologram method and the combination index method of Chou-Talalay were used to assess the synergistic effect. RESULTS: NV1066 enhanced MMC mediated cytotoxicity at all combinations tested for KU19-19 and SKUB. The combination of the 2 agents demonstrated a synergistic effect and allowed dose reduction by 12 and 10.4 times (NV1066), and by 3 and 156 times (MMC) for the treatment of KU19-19 and SKUB, respectively, while achieving an estimated 90% cell kill. CONCLUSIONS: These data provide the cellular basis for the clinical investigation of combined MMC and oncolytic HSV therapy for the treatment of bladder cancer.     

Histologic localization of sentinel lymph node metastases in breast cancer

Data from a recent study support the hypothesis that axillary lymph node metastases frequently localize near the inflow junction of the afferent lymphatic vessel. Our goal was to evaluate the microscopic location of axillary sentinel lymph node metastases in a prospective study of breast cancer patients. A total of 305 axillary sentinel lymph nodes from 213 breast cancer patients undergoing surgery at our institution were evaluated. Preoperative lymphoscintigraphy using technetium-labeled sulfur colloid and intraoperative isosulfan blue dye injection were used for identifying the sentinel lymph node. Intraoperatively, the surgeon placed a suture either at the point of entry of isosulfan blue dye or at the area with the highest radioactive counts, and this area was inked at the grossing bench before processing. Metastases were identified in 55 of the 305 lymph nodes examined. Thirty-four nodes contained metastases in both the inked half and the opposite half. Metastatic tumor was identified in the inked half alone in 18 lymph nodes. Only three nodes contained metastatic tumor in the opposite half with no tumor in the inked half (p <0.001). Similar results were found when nodes tagged at the point of blue dye entry and nodes tagged at the area with the highest radioactive counts were analyzed separately. Our findings suggest that metastatic tumor has a higher probability of being present in the region of the inflow junction of the afferent lymphatic vessel. This information may be useful in determining the optimal method for evaluating axillary sentinel lymph node specimens from breast cancer patients.     

Lymphatic tumor burden negatively impacts the ability to detect the sentinel lymph node in breast cancer

Sentinel lymph node (SLN) biopsy is the preferred method of nodal breast cancer staging. Techniques of SLN biopsy rely on transport of interstitial molecules through mammary lymphatics. Lymphatic flow may be disrupted by tumor emboli. Increased lymphatic tumor burden may be responsible for failure to identify the sentinel lymph node in patients with breast cancer. A prospective database of 110 patients who had SLN biopsy between January 2001 and December 2002 was analyzed. The number of metastatic axillary lymph nodes was used as a measure of lymphatic tumor burden. SLN was found in 94 per cent of cases. It was not found in seven patients; five of them had extensive axillary metastases (71%) compared to 23 per cent when SLN was found (P = 0.001). The average number of metastatic lymph nodes was larger when SLN was not found compared to when SLN was found (12.8 vs. 3.9, respectively, P = 0.002). Increasing numbers of metastatic nodes correlated with decreasing success in SLN biopsy (P = 0.075). The incidence of axillary metastases is higher in patients in whom the sentinel node is not found. High lymphatic tumor burden may have a causative role in SLN biopsy technical failure. Axillary dissection should be performed if SLN is not found, regardless of the tumor size or histology.     

Virally directed fluorescent imaging improves diagnostic sensitivity in the detection of minimal residual disease after potentially curative cytoreductive surgery

Completeness of cytoreduction is an independent prognostic factor after cure-intended surgery for peritoneal carcinomatosis. NV1066, a genetically engineered herpes simplex virus carrying the transgene for green fluorescent protein, selectively infects cancer cells. We sought to determine the feasibility of virally directed fluorescent imaging in the intraoperative detection of minimal residual disease after cytoreductive surgery. NV1066 infected human gastric cancer cells, OCUM-2MD3, and mesothelioma JMN cells at all doses. The infected cells expressed green fluorescent protein and were killed. OCUM-2MD3, and mesothelioma JMN cells at all doses. Peritoneal carcinomatosis was established in mice by injection of OCUM cells into the peritoneal cavity. Forty-eight hours after intraperitoneal injection of NV1066, two experienced surgeons resected all visible disease and identified mice free of disease. Eight of 13 mice thought to be free of disease were found to have residual disease as identified by green fluorescence (mean number of observations: 5; range: 1–9). Residual disease was most frequently observed in the retroperitoneum, pelvis, peritoneal surface, and liver. Specificity of NV1066 infection to tumor nodules was confirmed by immunohistochemistry and by polymerase chain reaction for viral gene. Virally directed fluorescent imaging, a novel molecular imaging technology, can be used for real-time visualization of minimal residual disease after cytoreductive surgery and can improve the completeness of cure-intended resection. Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 14–18, 2005 (oral presentation) Supported in part by AstraZeneca Cancer Research and Prevention fellowship (P.S.A), training grant T 32 CA09501 (D.P.E and K.J.H.), grants RO1 CA 76416 and RO1 CA/DK80982 (Y.F.) from the National Institutes of Health, grant BC024118 from the U.S. Army (Y.F.), grant IMG0402501 from the Susan G. Komen Foundation (Y.F. and P.S.A), and grant 032047 from the Flight Attendant Medical Research Institute (Y.F. and P.S.A).     

Clinicopathologic analysis of sentinel lymph node mapping in early breast cancer

Axillary nodal status is the most significant prognosticator for predicting survival and guiding adjuvant therapy in breast cancer patients. Sentinel lymph node biopsy (SLNB) represents a minimally invasive procedure with low morbidity for staging axillary nodal status. In this article we review and report our experiences in patients with early breast cancer who underwent SLNB at the Revlon/UCLA Breast Center. Between September 1998 and May 2000, a total 83 SLNBs were performed in 81 patients with proven breast cancer and negative axillary examination who elected to have SLNB as the first step of nodal staging. Two patients had bilateral breast cancer. SLNB was localized by using both 99Tc sulfur colloid (83 cases) and isosulfan blue dye (75 cases). Data of these patients were prospectively collected and analyzed. The clinical and pathologic characteristics of women with positive and negative sentinel lymph nodes (SLNs) were compared to identify features predictive of SLN metastasis. Of the 83 cases, the SLN was successfully localized in 82 (98.8%). Sixty-three percent of patients had SLNs found in level I only, 18.3% in both level I and II, and 4.9% in level II alone. The vast majority (84.3%) of these cases had T1 breast cancer with an average size of 1.55 cm for the entire series. Twenty-three patients (28%) had positive SLNs, with an average of 1.5 positive SLNs per patient. Fifteen had metastases detected by hematoxylin and eosin staining and 8 had micrometastases detected by immunohistochemistry (IHC) using anticytokeratin antibodies. Ten of the former group agreed to and 2 of the latter group opted for full axillary lymph node dissection (ALND). An average of 17.5 lymph nodes were removed from each ALND procedure. Additional metastases or micrometastases were found in seven patients (in a total of 28 lymph nodes). Three patients with completely negative SLNs experienced additional axillary lymph node removal due to their election of free flap reconstruction. None had metastases detected in these lymph nodes. The absence of estrogen and progesterone receptors (ER/PR) by IHC (p = 0.036) and the presence of lymphatic/vascular invasion (LVI) (p = 0.002) predicted positive SLNs in patients with early breast cancer in a univariate analysis; in a multivariate analysis only LVI was predictive (p = 0.0125). Histologic type, nuclear grade, tumor differentiation, HER-2/neu and p53 status, S-phase fraction, and DNA ploidy did not predict SLN status. Immediate postoperative complications were uncommon and delayed complications completely absent. Because of the high detection rate, accurate staging, and minimal morbidity, SLNB should be offered as a choice to women with small breast cancers and clinically negative nodes. Because positive LVI and negative ER/PR status are highly predictive of pathologically positive SLNs in small breast cancers, women whose cancers meet these criteria should be advised preoperatively about their risk of having a positive SLN and may benefit from intraoperative assessment (frozen section and/or touch preparation) of their SLNs.     

Lymph-node dissection in breast cancer

Background: Along with the ongoing modifications in treatment of primary breast cancer, the purpose and extent of lymph-node dissection has changed. The following is an overview of the current knowledge and practice of lymph-node dissection in breast cancer, with special regard to expected developments in the near future. Axillary dissection is described as a ten-step procedure, including dissection of level-I and -II and Rotter’s nodes, without level-III nodes, providing at least ten lymph nodes for accurate staging information. Discussion: Axillary dissection still offers the most efficient local control in node-positive patients, whereas, in primarily node-negative patients, irradiation seems to be equally effective. In general, lymph-node dissection does not alter overall survival but there is no doubt that surgical therapy still contributes to cure in early-breast-cancer patients and seems to be curative for certain patients with stage-I carcinoma. The lymph node status of the axilla is crucial for the indication of adjuvant therapy in early invasive breast cancer, but an increasing number of clinical node-negative patients could be managed with information based on features of the primary tumor, regardless of the nodal status. The most promising new concept for the selection of node-positive patients, while avoiding unnecessary morbidity of axillary dissection in early-breast-cancer patients, is the sentinel-node concept. The principle is based on the identification of the first ”sentinel” lymph node reached by lymphatic flow. Thus, only proven node-positive patients undergo axillary dissection. Local failure of internal mammary lymph nodes is rarely recognized; however, internal mammary lymph nodes seem to have an underestimated prognostic significance in about 10–20% of axillary node-negative patients. This may lead to the withholding of systemic therapy for patients with early breast cancer. Nevertheless, there is no indication for a routine parasternal dissection today. The sentinel-node concept may also support the selection of diagnostic internal lymph-node biopsy and subsequent adjuvant therapy in cases with no axillary lymph-node metastases but with internal lymph-node metastases. Received: 25 September 1998 Accepted: 17 October 1998     

Detection of cancer cells in the axillary drainage using RT-PCR after operations for breast cancer

The object of this study was to examine whether MUC-1 can be detected in the axillary lymphatic drainage of patients who have undergone conservative surgery for breast cancer and to assess the correlations between the presence of MUC-1 and prognostic factors in breast cancer. Sixty-eight women with invasive ductal carcinoma of the breast underwent wide local excision and axillary lymph node dissection. Axillary drains were inserted in all these cases, and the presence of MUC-1 and beta-actin was evaluated by RT-PCR in the lymphatic fluid collected after the operation. Prognostic factors included tumour size and grade, vascular and lymphatic invasion, clearance margins of the resected specimens and status of the axillary lymph nodes. RT-PCR assays for MUC-1 in the axillary fluid were positive in 17 patients (25%). The presence of MUC-1 was associated with increased tumour size and showed a positive correlation with axillary lymph node metastases and incomplete resection of the tumour. RT-PCR can disclose cancer cells in the axillary fluid after conservative surgery for breast cancer. The presence of MUC-1 in the axillary drainage may be associated with poor prognostic features, and its detection may have implications for therapy as it suggests that re-excision should be considered.     

Axillary dissection after unsuccessful sentinel lymphadenectomy for breast cancer.

Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) has been demonstrated to provide sensitive axillary staging for breast cancer. LM/SL has a steep learning curve, and factors associated with unsuccessful LM/SL are not well known. Two hundred sixty patients with breast carcinoma and clinically negative axillae underwent injection of about 5 cm3 of isosulfan blue dye (Lymphazurin, US Surgical Corp, Norwalk, CT) into breast tissue surrounding a cancer or biopsy site. After 5 minutes of breast compression, blue-stained lymph nodes were sought. In 47 patients, no blue nodes were detected; a standard axillary dissection was performed. All 47 patients were women with a mean age of 56 years (range, 34-80). Ductal carcinoma was most common (91.5%). Mean tumor size was 1.99 cm. Axillary dissection yielded a mean of 15.8 lymph nodes (range, 6-35). Sixteen patients (34%) had positive lymph nodes (mean, 7.6; median, 6; range, 1-24). Factors associated with LM/SL difficulty include surgeon inexperience, medial hemisphere primary location, extensive axillary metastases, and extranodal invasion. Inability to identify a sentinel node in a clinically negative axilla is a risk factor for extensive axillary tumor burden. Axillary dissection should be performed for patients with unsuccessful LM/SL, particularly those with lateral hemisphere primaries.     

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??Objective:To study the high risk factors of intramammary lymphatic metastasis in breast cancer patients received extended radical mastectomy. Methods:The clinical data of 1679 breast cancer patients received extended radical mastectomy between 1956 and 2003 in the Cancer Hospital of Fudan University was analyzed retrospectively.Four individual variables, such as patient age, tumor size, tumor site and axillary nodes metastasis status,were selected to investigate high risk factors of the intramammary lymphatic metastasis in different conditions. Results:Tumor size was not a independent predictor of intramammary lymphatic metastasis. Axillary node status was an important predictor of intramammary lymphatic metastasis.Tumor site and age had different effects on intramammary lymphatic metastasis in different conditions.The incidence of intramammary lymphatic metastasis is 4.4%,18.8%,28.1%,41.5% for patients with negative axillary nodes,1 to 3 positive axillary nodes,4-6 positive axillary nodes,7 or more positive axillary nodes,respectively. Conclusion:Four or more positive axillary nodes, internal tumor and positive axillary nodes,young patients with tumor greater than 5.0cm were high risk factors of intramammary lymphatic metastasis.     

Selective Extirpation of Tattooed Lymph Node in Combination with Sentinel Lymph Node Biopsy in the Management of Node-Positive Breast Cancer Patients after Neoadjuvant Systemic Therapy

IntroductionAxillary dissection has little diagnostic and therapeutic benefit in node-positive breast cancer patients in whom axillary disease has been completely eradicated after neoadjuvant chemotherapy (ypN0). We sought to assess the efficacy of an algorithm used for the identification of the ypN0 patient consisting of intraoperative evaluation of sentinel and tattooed (initially positive) lymph nodes.MethodsIncluded were T1 and T2 breast cancer patients with 1–3 positive axillary lymph nodes marked with carbon who were referred for neoadjuvant chemotherapy followed by a surgery. Axillary dissection was performed only in the patients with residual axillary disease after neoadjuvant chemotherapy on ultrasound or with metastases described in the sentinel or tattooed lymph nodes either intraoperatively or in the final histology.ResultsOut of 62 initially included node-positive patients, 15 (24%) were spared axillary dissection. The detection rate of tattooed lymph nodes after neoadjuvant chemotherapy was 81%. The ypN0 patients were identified with 91% sensitivity and 38% specificity using ultrasound and intraoperative assessment of both sentinel and tattooed lymph node according to the final histology.Discussion/ConclusionLymph node marking with carbon dye is a useful and cost-effective method, which can be successfully implemented in order to reduce the number of patients undergoing axillary dissection. Low specificity of the presented algorithm was caused mostly by the overestimation of residual axillary disease on ultrasound.     

Routine preoperative lymphoscintigraphy is not necessary prior to sentinel node biopsy for breast cancer.

BACKGROUND: This prospective study was performed to ascertain the added benefit of lymphoscintigraphy to a standard method of intraoperative lymphatic mapping and sentinel node biopsy for breast cancer. METHODS: Patients with invasive breast cancer were injected with 99mTc sulfur colloid prior to sentinel node biopsy; preoperative lymphoscintigraphy was then performed in half of the patient population. RESULTS: Sentinel node identification was possible in 45 of 50 patients (90%). All 14 patients (31%) with axillary nodal metastases had at least one histologically positive sentinel node (0% false negative rate). Lymphoscintigraphy revealed sentinel nodes in 17 of the 24 patients (70.8%) imaged. All 17 of these patients had one or more axillary sentinel nodes identified using intraoperative lymphatic mapping. In addition, 5 of 7 patients with a negative preoperative lymphoscintogram had an axillary sentinel lymph node(s) identified intraoperatively. None of the tumors showed drainage to the internal mammary lymph node chain by lymphoscintigraphy despite the fact that there were 5 patients with inner quadrant tumors. There was no significant advantage with respect to sentinel lymph node localization (91.7% versus 88.5%, P = not significant) or false negative rate (0%, both groups, P = not significant) in the group undergoing preoperative lymphoscintigraphy when compared with the patients in whom lymphoscintigraphy was not performed. CONCLUSIONS: Preoperative lymphoscintigraphy adds little additional information to intraoperative lymphatic mapping, and its routine use is not justified.     

Effective treatment of pancreatic tumors with two multimutated herpes simplex oncolytic viruses

Pancreatic cancer is an aggressive, rapidly fatal disease against which current nonsurgical therapy has minimal impact. This study evaluates the efficacy of two novel, replication-competent, multimutated herpes viruses (G207 and NV1020) in an experimental model of pancreatic cancer. Four human pancreatic carcinoma cell lines were exposed to G207 or NV1020, and cell survival and viral progeny production were determined. Flank tumors in athymic mice were subjected to single or multiple injections of 1 X 10⁷ G207 or NV1020, and tumor volume was evaluated over time. For all of the cell lines, G207 and NV1020 produced infection, viral replication, and cell lysis (P <0.05). NV1020 resulted in a higher production of viral progeny compared to G207. The efficacy of viral tumor cell kill was greatest in those cells with the shortest in vitro doubling time. For flank tumors derived from hs766t, single or multiple injections of both viruses were equally effective and significantly reduced flank tumor burden (P <0.05). Complete hs766t flank tumor eradication was achieved in 25% (5 of 20) of animals treated with G207 and 40% (8 of 20) of animals treated with NV1020. In vivo efficacy correlated with in vivo tumor doubling time. There were no adverse effects related to viral administration observed in any animal. NV1020 and G2O7 effectively infect and kill human pancreatic cancer cells in vitro and in vivo. Given the lack of effective nonoperative treatments for pancreatic cancer, oncolytic herpes viruses should be considered for clinical evaluation. Presented in part at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 21–24, 2000.     

Touch imprint cytological analysis of sentinel lymph nodes for detecting axillary metastases in patients with breast cancer.

BACKGROUND: Sentinel lymph node biopsy is a procedure that examines the first tumour-draining lymph node. Touch imprint cytology may provide a quick method for intraoperative screening of sentinel lymph nodes for the presence of metastases. METHODS: Touch imprint cytological analysis of sentinel lymph nodes was compared prospectively with the findings obtained on routine paraffin sections. Touch imprint slides from 55 patients with breast cancer were prepared during operation from multiple sections of sentinel lymph nodes, stained with haematoxylin and eosin. A cytopathologist blinded to the histological results interpreted the smears. RESULTS: The concordance between touch imprint and paraffin sections of sentinel lymph nodes was 98 per cent (54 of 55). When touch imprint analysis of sentinel lymph nodes was compared with paraffin sectioning of all lymph nodes from the axillary node dissection, the concordance was 95 per cent (52 of 55). The sensitivity and specificity of sentinel lymph node touch imprints in detecting metastases were 82 and 100 per cent respectively. The positive and negative predictive values were 100 and 93 per cent respectively. CONCLUSION: Touch imprint cytology is potentially useful for the intraoperative evaluation of sentinel lymph nodes in patients with breast cancer.