Implementation of Intraoperative Ultrasound Localization for Breast-Conserving Surgery in a Large, Integrated Health Care System is Feasible and Effective.

BACKGROUND: Intraoperative ultrasound (IUS) localization for breast cancer is a noninvasive localization technique. In 2015, an IUS program for breast-conserving surgery (BCS) was initiated in a large, integrated health care system. This study evaluated the clinical results of IUS implementation. METHODS: The study identified breast cancer patients with BCS from 1 January to 31 October 2015 and from 1 January to 31 October 2019. Clinicopathologic characteristics were collected, and localization types were categorized. Clinical outcomes were analyzed, including localization use, surgeon adoption of IUS, day-of-surgery intervals, and re-excision rates. Multivariate logistic regression analysis was performed to evaluate predictors of re-excision. RESULTS: The number of BCS procedures increased 23%, from 1815 procedures in 2015 to 2226 procedures in 2019. The IUS rate increased from 4% of lumpectomies (n = 79) in 2015 to 28% of lumpectomies (n = 632) in 2019 (p < 0.001). Surgeons using IUS increased from 6% (5 of 88 surgeons) in 2015 to 70% (42 of 60 surgeons) in 2019. In 2019, 76% of IUS surgeons performed at least 25% of lumpectomies with IUS. The mean time from admission to incision was shorter with IUS or seed localization than with wire localization (202 min with IUS, 201 with seed localization, 262 with wire localization in 2019; p < 0.001). The IUS re-excision rates were lower than for other localization techniques (13.6%, vs 19.6% for seed localization and 24.7% for wire localization in 2019; p = 0.006), and IUS predicted lower re-excision rates in a multivariable model (odds ratio [OR], 0.59). CONCLUSIONS: In a high-volume integrated health system, IUS was adopted for BCS by a majority of surgeons. The use of IUS decreased the time from admission to incision compared with wire localization, and decreased re-excision rates compared with other localization techniques.

Small Cell Lung Carcinoma and Synchronous Rectal Adenocarcinoma and Jejunal Gastrointestinal Stromal Tumor Present in a Patient With History of Laryngeal Squamous Cell Carcinoma.

BACKGROUND: The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. CASE REPORT: We report such a case of a 67-year-old male smoker with a history of laryngeal squamous cell carcinoma. He was incidentally identified through follow up computed tomography to have three masses in the lung, rectum and jejunum, respectively. Biopsies were performed and demonstrated synchronous lung small cell carcinoma (pT1bN0) and rectal adenocarcinoma. The patient underwent fractionated stereotactic radiation (FSRT) to the pulmonary tumor and chemotherapy with cisplatin and etoposide followed by laparoscopic rectum low anterior resection and small bowel segmental resection. Final pathology diagnoses confirmed synchronous microsatellite stable (MMS) moderately differentiated adenocarcinoma of the rectum (pT3N1b) and jejunal gastrointestinal stromal tumor (GIST), spindle cell type (pT2N0). At 8 months follow up postsurgery, the patient was doing well and no tumor recurrences were identified. CONCLUSION: To the best of our knowledge, this is the first documented case of synchronous primary small cell lung carcinoma, rectal adenocarcinoma, and GIST in the English literature. The rarity, diagnosis and treatment challenges of these entities are discussed.

Surgical strategies for synchronous colorectal liver metastases in 156 consecutive patients: classic, combined or reverse strategy?

BACKGROUND: An increasing number of patients with synchronous colorectal liver metastases (CLM) are candidates for resection. The optimal treatment sequence in these patients has not been defined. STUDY DESIGN: Data on 156 consecutive patients with synchronous resectable CLM and intact primary were reviewed. Surgical strategies were defined as combined (combined resection of primary and liver), classic (primary before liver), and reverse (liver before primary) after preoperative chemotherapy. Postoperative morbidity and mortality rates and overall survival were analyzed. RESULTS: One hundred forty-two patients (83%) had resection of all disease. Seventy-two patients underwent classic, 43 combined, and 27 reverse strategies. Median numbers of CLMs per patient were 1 in the combined, 3 in the classic, and 4 in the reverse strategy group (p = 0.01 classic vs reverse; p < 0.001 reverse vs combined). Postoperative mortality rates in the combined, classic, and reverse strategies were 5%, 3%, and 0%, respectively (p = NS), and postoperative cumulative morbidity rates were 47%, 51%, and 31%, respectively (p = NS). Three-year and 5-year overall survival rates were, respectively, 65% and 55% in the combined, 58% and 48% in the classic, and 79% and 39% in the reverse strategy (NS). On multivariate analysis, liver tumor size >3 cm (hazard ratio [HR] 2.72, 95% CI 1.52 to 4.88) and cumulative postoperative morbidity (HR 1.8, 95% CI 1.03 to 3.19) were independently associated with overall survival after surgery. CONCLUSIONS: The classic, combined, or reverse surgical strategies in patients with synchronous presentation of CLM are associated with similar outcomes. The reverse strategy can be considered as an alternative option in patients with advanced CLM and an asymptomatic primary.

ERK/BCL-2 pathway in the resistance of pancreatic cancer to anoikis.

BACKGROUND: Anoikis is a special type of programmed cell death after loss of cell-cell and cell-extracellular matrix interactions. Resistance to anoikis is likely involved in the process of metastasis, specifically during the tumor cell migration through lymph or vascular channels. We have previously shown that BCL-2 confers resistance to other forms of programmed cell death (i.e., apoptosis); furthermore, the extracellular signaling-regulated kinase (ERK) signaling pathway regulates BCL-2 expression. We therefore tested the hypothesis that pancreatic cancer cell lines are resistant to anoikis and this resistance is due to activation of ERK1/2 and subsequent overexpression of BCL-2. MATERIALS AND METHODS: Pancreatic cancer cell lines (MIA-PaCa-2 and BxPC-3) were examined for cell death following loss of adherence to extracellular matrix. Subclones of the MIA-PaCa-2 cell line (either selected in vivo for increased metastatic potential [MIA-LM2] or overexpressing BCL-2 [MIA-BCL2]) were also examined for induction of anoikis following loss of extracellular matrix adherence. Finally, the effect of the ERK inhibitor (PD98059) on BCL-2 expression and induction of anoikis was examined. RESULTS: Under conditions of loss of cell-extracellular matrix interaction, pancreatic cancer cells undergo varying amounts of anoikis. Basal levels of activated ERK and BCL-2 paralleled the sensitivity to induction of anoikis. The highly metastatic cell line, MIA-LM2, was more resistant to anoikis than the parental cell line. Inhibition of ERK down-regulated BCL-2 and was associated with restoration of sensitivity to anoikis. CONCLUSIONS: Activation of a signaling pathway from ERK to overexpression of BCL-2 may confer resistance to anoikis, a critical step in the development of metastasis. Targeting the ERK/BCL-2 pathway may lead to sensitization of pancreatic cancer to anoikis, thereby decreasing the ability of these cells to metastasize.

Fibrin sealant does not decrease seroma output or time to drain removal following inguino-femoral lymph node dissection in melanoma patients: a randomized controlled trial (NCT00506311).

BACKGROUND: This study assessed the impact of closed suction drains and evaluated whether the intraoperative use of a fibrin sealant decreased time to drain removal and wound complications in melanoma patients undergoing inguino-femoral lymph node dissection. METHODS: A pilot study (n = 18) assessed the impact of a closed suction drain following inguino-femoral lymph node dissection. A single-institution, prospective trial was then performed in which patients were randomized to a group that received intraoperative application of a fibrin sealant following inguino-femoral lymph node dissection or to a control group that did not receive sealant. RESULTS: The majority of the patients enrolled felt the drains caused moderate or severe discomfort and difficulties with activities of daily living. Thirty patients were then randomized; the median time to drain removal in the control group (n = 14) was 30 days (range, 13-74) compared to 29 days (range, 11-45) in the fibrin sealant group (n = 16; P = 0.6). Major and minor complications were similar in the two groups. CONCLUSION: Postoperative closed suction drains were associated with major patient inconvenience. Applying a fibrin sealant at the time of inguino-femoral lymph node dissection in melanoma patients did not reduce the time to drain removal or postoperative morbidity. Alternative strategies are needed.

Current diagnosis and management of unusual pancreatic tumors.

BACKGROUND: The finding of a solid or cystic mass in the pancreas is becoming more common secondary to the increasing use of cross-sectional imaging and the improved sensitivity of such studies for the detection of pancreatic abnormalities. Because of the aggressive natural history of pancreatic cancer, this has caused concern that all pancreatic abnormalities may be cancer as well as confusion over proper diagnostic and treatment algorithms. This review provides an overview of the natural history, diagnostic considerations, and treatment recommendations for the less common tumors of the pancreas which can be misinterpreted as pancreatic cancer including: solid pseudopapillary tumors (SPT), acinar cell carcinoma (ACC), lymphoplasmacytic sclerosing pancreatitis (LPSP), primary pancreatic lymphoma (PPL), and metastatic renal cell carcinoma to the pancreas. DATA SOURCES: A Medline search was conducted to identify studies investigating the clinicopathologic features, molecular genetics, pathogenesis, diagnosis, and treatment of SPT, ACC, LPSP, PPL, and pancreatic metastases. CONCLUSIONS: It is often possible to obtain an accurate pretreatment diagnosis for these unusual pancreatic tumors and to successfully differentiate them from the more common pancreatic malignancies.

Parathyroid exploration in the reoperative neck: improved preoperative localization with 4D-computed tomography.

BACKGROUND: Reoperation for hyperparathyroidism (HPT) carries an increased risk for morbidity and failure to cure. Accurate preoperative localization minimizes operative risk but is often difficult to achieve in the reoperative setting. Four-dimensional computed tomography (4D-CT) is an emerging technique that uses functional parathyroid anatomy for precise preoperative localization. We evaluated 4D-CT as a tool for localization of hyperfunctioning parathyroid tissue in the reoperative setting. STUDY DESIGN: A prospective endocrine database was queried to identify 45 patients who underwent reoperative parathyroidectomy after preoperative localization using 4D-CT. The patients were categorized into 1 of 3 groups: group 1 included those who had previous neck surgery for non-HPT conditions; group 2 included those who had undergone a previously unsuccessful neck exploration for HPT; and group 3 included patients with HPT who had a previous neck exploration with resection of at least 1 hypercellular parathyroid. RESULTS: The sensitivity of 4D-CT for localization was 88% compared with 54% for sestamibi imaging. Four-dimensional CT more often correctly localized (p=0.0003) and lateralized (p=0.005) hyperfunctional parathyroid tissue than sestamibi did. Four-dimensional CT successfully localized hyperfunctional parathyroid tissue in 18 (82%) of 22 group 1 patients, 10 (91%) of 11 group 2 patients, and 8 (67%) of 12 group 3 patients. Three patients were lost to followup. At a mean followup of 9.8 months, 39 (93%) of 42 patients were surgically cured and 3 patients (7%; 2 in group 3) had persistent HPT. CONCLUSIONS: Four-dimensional-CT is an ideal tool for preoperative localization of hyperfunctioning parathyroid tissue in the reoperative setting. Localization and successful reoperation are most difficult in patients who have undergone an earlier operation that included resection of at least one hypercellular parathyroid suggesting multigland disease.

Comparison of two methods of future liver remnant volume measurement.

BACKGROUND: In liver transplantation, a minimum graft to patient body weight (BW) ratio is required for graft survival; in liver resection, total liver volume (TLV) calculated from body surface area (BSA) is used to determine the future liver remnant (FLR) volume needed for safe hepatic resection. These two methods of estimating liver volume have not previously been compared. The purpose of this study was to compare FLR volumes standardized to BW versus BSA and to assess their utility in predicting postoperative hepatic dysfunction after hepatic resection. METHODS: Records were reviewed of 68 consecutive noncirrhotic patients who underwent major hepatectomy after portal vein embolization between 1998 and 2006. FLR (cubic centimeter) was measured preoperatively with three-dimensional helical computed tomography; TLV (cubic centimeter) was calculated from the patients' BSA. The relationship between FLR/TLV and FLR/BW (cubic centimeter per kilogram) was examined using linear regression analysis. Receiver operating characteristic (ROC) curve analysis was used to determine FLR/TLV and FLR/BW cutoff values for predicting postoperative hepatic dysfunction (defined as peak bilirubin level>3 mg/dl or prothrombin time>18 s). RESULTS: Regression analysis revealed that the FLR/TLV and FLR/BW ratios were highly correlated (Pearson correlation coefficient, 0.98). The area under the ROC curve was 0.85 for FLR/TLV and 0.84 for FLR/BW (95% confidence interval, 0.71-0.97). Sixteen of the 68 patients developed postoperative hepatic dysfunction. The ROC curve analysis yielded a cutoff FLR/BW value of

BCL-2 functions as an activator of the AKT signaling pathway in pancreatic cancer.

BCL-2 is the prototypic anti-apoptotic protein involved in the regulation of apoptosis. Overexpression of BCL-2 is common in pancreatic cancer and confers resistance to the apoptotic effect of chemo- and radiotherapy. Although these cellular effects of BCL-2 are traditionally related to pathways involving the mitochondrial membrane, we sought to investigate whether BCL-2 is involved in other signaling pathways regulating cell survival and focused on AKT. We examined the effect of overexpression of BCL-2 in the MIA-PaCa-2 human pancreatic cancer cell line on the function and subcellular location of AKT. We observed that the stable subclones of MIA-PaCa-2 overexpressing BCL-2 demonstrated increased activity of AKT as well as IKK (a downstream target of AKT), increasing the transcriptional activity of NF-kappaB. Using immunoprecipitation techniques, we observed co-immunoprecipitation of AKT and BCL-2. Immunocytochemistry demonstrated co-localization of BCL-2 and AKT, which was abrogated by treatment with HA14-1, a small molecule inhibitor of BH-3-mediated protein interaction by BCL-2. Furthermore, treatment with HA14-1 decreased phosphorylation of AKT and increased sensitivity to the apoptotic effect of the chemotherapeutic agent, paclitaxel. These results demonstrate an additional mechanism of regulation of cell survival mediated by BCL-2, namely through AKT activation, in the MIA-PaCa-2 pancreatic cancer cell line. Therefore, directed inhibition of BCL-2 may alter diverse pathways controlling cell survival and overcome the apoptotic resistance that is the hallmark of pancreatic cancer.

Total mesorectal excision and pelvic node dissection for rectal cancer: an appraisal.

Total mesorectal excision has revolutionized the surgical treatment of rectal cancer since its introduction in the 1980s. The rationale, technique, and outcomes of total mesorectal excision in rectal cancer are explored. Lateral pelvic lymph node dissection is used by the Japanese in selected patients and has remained a controversial approach in the management of rectal cancer. The technique, controversies, and outcomes are summarized.

An analysis of cost and clinical outcome in palliation for advanced pancreatic cancer.

BACKGROUND: The optimal palliative method for patients with unresectable pancreatic cancer remains controversial. METHODS: A retrospective chart review evaluated patients who underwent exploration for presumed resectable pancreatic cancer. Cost-based analysis was performed using relative value units (RVUs) that included the initial surgical procedure and any additional procedure required to achieve satisfactory palliation. RESULTS: Of 96 patients (1993--2002), 6% had biliary bypass, 42% had duodenal bypass, 40% had double bypass, and 13% had no procedure with equivalent clinical outcomes. If biliary bypass was not initially performed, there was a significant incidence of biliary complications before definitive endoscopic stenting (P=.01). If duodenal bypass was not initially performed, 11% developed duodenal obstruction (P=.04). Total RVUs was highest for a double bypass and lowest for no initial surgical palliative procedure. CONCLUSIONS: Although surgical bypass procedures at initial exploration provide durable palliation, these procedures are associated with greater costs.

Reduction in BCL-2 levels by 26S proteasome inhibition with bortezomib is associated with induction of apoptosis in small cell lung cancer.

Overexpression of the anti-apoptotic protein BCL-2 is frequently observed in small cell lung cancers (SCLC) and is associated with chemoresistance. We examined the signaling pathways involved in upregulation of BCL-2 in SCLC, and whether inhibition of NF-kappaB using the 26S proteasome inhibitor bortezomib had any effect on BCL-2 levels or apoptosis. Mutation of a NF-kappaB site in the BCL-2 promoter reduced promoter activity to less than 20% of the wild-type promoter. Treatment with bortezomib resulted in decreased transcription of the BCL-2 promoter, decreased BCL-2 levels, and induced apoptosis. These data provide the necessary laboratory background for further investigation of bortezomib in the treatment of SCLC.

Targeting BCL-2 overexpression in various human malignancies through NF-kappaB inhibition by the proteasome inhibitor bortezomib.

BACKGROUND: BCL-2 overexpression occurs in many cancer types and is associated with chemoresistance and radioresistance. The mechanisms responsible for its aberrant expression are thought to be transcriptionally mediated but remain unclear. We examined the cell type-specific mechanism of BCL-2 gene transcription in various solid organ malignancies. METHODS: Regulation of BCL-2 gene transcription was examined in seven different human cancer cell lines including two pancreatic (MIA-PaCa-2, PANC-1), two prostate (LNCaP, PC-3), two lung (Calu-1, A549) and one breast (MCF-7) cancer cell line. Cells were treated with inhibitors of phosphatidylinositol-3 kinase (PI3K), MEK/ERK, and p38MAPK. The effect of mutation of a NF-kappaB site in the BCL-2 promoter was determined, as was the effect of inhibition of NF-kappaB function using a 26S proteasome inhibitor (bortezomib) on both BCL-2 transcription and induction of apoptosis. RESULTS: BCL-2 expression varied both between and within tumor types; four of seven cell lines demonstrated high BCL-2 levels (MIA-PaCa-2, PC-3, Calu-1 and MCF-7). No signaling pathway was uniformly responsible for overexpression of BCL-2; however, mutation of the NF-kappaB site decreased BCL-2 promoter activity in all cell lines. Inhibition of NF-kappaB activity decreased BCL-2 protein levels independently of the signaling pathway involved in transcriptional activation of the BCL-2 gene. CONCLUSIONS: Diverse signaling pathways variably regulate BCL-2 gene expression in a cell type-specific fashion. Therapy to decrease BCL-2 levels in various human cancers would be more broadly applicable if targeted to transcriptional activation rather than signal transduction cascades. Finally, the apoptotic efficacy of proteasome inhibition with bortezomib paralleled the ability to inhibit NF-kappaB activity and decrease BCL-2 levels.

Immediate breast reconstruction after mastectomy increases wound complications: however, initiation of adjuvant chemotherapy is not delayed.

BACKGROUND: Immediate breast reconstruction is being increasingly used after mastectomy, although it may increase the incidence of wound complications. The indications for chemotherapy in breast cancer are expanding and wound complications following mastectomy may delay the initiation of adjuvant chemotherapy. HYPOTHESIS: Immediate breast reconstruction after mastectomy for breast cancer does not lead to an increased incidence of wound complications nor delay the initiation of systemic chemotherapy. DESIGN AND SETTING: Retrospective medical record review at a tertiary care center. PATIENTS: One hundred twenty-eight women treated with a mastectomy for breast cancer over an 8-year period (January 1, 1995, through December 31, 2002). MAIN OUTCOME MEASURES: Surgical site complications (infectious and noninfectious) and time to initiation of postoperative chemotherapy. RESULTS: One hundred forty-eight mastectomy procedures in 128 women with breast cancer were evaluated. We analyzed 4 subgroups according to whether or not immediate breast reconstruction was part of the surgical procedure (76 or 72 procedures, respectively) and whether or not postoperative adjuvant chemotherapy was administered (81 or 47 patients, respectively). There was an increased incidence of wound complications in patients who underwent immediate breast reconstruction compared with those who did not (6/72 [8.3%] vs 17/76 [22.3%]; P = .02). However, these complications did not delay initiation of postoperative chemotherapy. CONCLUSIONS: Although we observed an increased incidence of wound complications when immediate breast reconstruction was combined with mastectomy, there was no delay in the initiation of adjuvant therapy. Immediate breast reconstruction should remain an important treatment option after mastectomy even when postoperative chemotherapy is anticipated.

Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line.

BACKGROUND: Non-small-cell lung cancer (NSCLC) has a poor prognosis. Despite advances in therapy, survival has improved only slightly. The 26S proteasome regulates multiple cellular processes through degradation of ubiquitin-tagged proteins. The proteasome inhibitor, bortezomib (Velcade, formerly PS-341), has been shown to be an active anticancer agent both in vitro and in vivo in multiple tumor types. PURPOSE: To determine the molecular and cellular effects of the proteasome inhibitor in NSCLC as well as to evaluate the effectiveness of sequential treatment with bortezomib and gemcitabine/carboplatin (G/C) chemotherapy both in vitro and in vivo. METHODS: All experiments were performed in the A549 NSCLC cell line. MTT assays were used to evaluate cytotoxicity. Western blotting evaluated protein levels. Measures of apoptosis included FACS analysis, DAPI staining and caspase-3 cleavage. Long-term cell viability was determined using an anchorage-dependent clonogenic assay. Sequential studies were performed in vitro and in vivo. RESULTS: Bortezomib increased p21(waf1/cip1), induced G(2)/M arrest, and triggered a small amount of apoptosis. The apoptotic effect of G/C chemotherapy was eliminated when bortezomib was administered prior to the chemotherapy; however, it was accentuated when the bortezomib was given simultaneously or after the chemotherapy. CONCLUSIONS: Bortezomib improves efficacy in combination with gemcitabine and carboplatin in NSCLC, but sequential effects are important and must be considered when developing therapeutic regimens.

Proteasome inhibition with PS-341 (bortezomib) in lung cancer therapy.

PS-341 (bortezomib) represents a new class of therapeutics that targets the ubiquitin-proteasome pathway. It has broad-spectrum single-agent anticancer activity and can potentiate chemotherapy and radiation in preclinical models. Early phase clinical studies have shown tolerability and activity in multiple myeloma, lymphoma, prostate cancer, and lung cancers. By its mechanism of inhibiting protein degradation, PS-341 targets a wide range of pathways relevant to tumor progression and therapy resistance and can directly modulate expression of cyclins, p27(Kip1), p53, nuclear factor-kappaB, Bcl-2, and Bax. PS-341 is currently in phase I/II clinical development in both non-small cell lung cancer and small cell lung cancer. This article will review the preclinical and clinical experience with PS-341 as it relates to lung cancer.