A Randomized Single-Blinded Study Comparing Preoperative with Post-Mastectomy PECS Block for Post-operative Pain Management in Bilateral Mastectomy with Immediate Reconstruction.

BACKGROUND: Ultrasound-guided pectoralis muscle blocks (PECS I/II) are well established for postoperative pain control after mastectomy with reconstruction. However, optimal timing is unclear. We conducted a randomized controlled single-blinded single-institution trial comparing outcomes of block performed pre-incision versus post-mastectomy. METHOD: Patients with breast cancer undergoing bilateral mastectomy with immediate expander/implant reconstruction were randomized to receive ultrasound-guided PECS I/II either pre-incision (PreM, n = 17) or post-mastectomy and before reconstruction (PostM, n = 17). The primary outcome was the average pain score using the Numerical Rating Score during post-anesthesia care unit (PACU) and inpatient stay, with the study powered to detect a difference in mean pain score of 2. Secondary outcomes included mean pain scores on postoperative day (POD) 2, 3, 7, 14, 90, and 180; pain catastrophizing scores; narcotic requirements; PACU/inpatient length of stay; block procedure time; and complications. RESULT: No significant differences between the two groups were noted in average pain score during PACU (p = 0.57) and 24-h inpatient stay (p = 0.33), in the 2 weeks after surgery at rest (p = 0.90) or during movement (p = 0.30), or at POD 90 and 180 at rest (p = 0.42) or during movement (p = 0.31). Median duration of block procedure (PreM 7 min versus PostM 6 min, p = 0.21) did not differ. Median PACU and inpatient length of stay were the same in each group. Inpatient narcotic requirements were similar, as were length of stay and post-surgical complication rates. CONCLUSION: Intraoperative ultrasound-guided PECS I/II block administered by surgeons following mastectomy had similar outcomes to preoperative blocks. TRIAL REGISTRATION: This trial is registered with Clinical Research Information Service (NCT03653988).

The role of Tcfap2c in tumorigenesis and cancer growth in an activated Neu model of mammary carcinogenesis.

TFAP2C/AP-2γ influences development of the mammary gland and regulates patterns of gene expression in luminal and HER2-amplified breast cancer. The roles of TFAP2C in mammary gland tumorigenesis and in pathways critical to cancer progression remain poorly understood. To gain greater insight into oncogenic mechanisms regulated by TFAP2C, we examined mammary tumorigenesis in MMTV-Neu transgenic female mice with or without conditional knockout (KO) of Tcfap2c, the mouse homolog of TFAP2C. Loss of Tcfap2c increased the latency of tumorigenesis and tumors that formed demonstrated reduced proliferative index and increased apoptosis. In addition, tumors formed in Tcfap2c KO animals had a significant reduction in Egfr levels without a change in the expression of the Neu oncogene. The MMneu-flAP2C cell line was established from tumor tissue derived from MMTV-Neu/Tcfap2c(L/L) control animals and parallel cell lines with and without expression of Tcfap2c were created by transduction with adenovirus-empty and adenovirus-Cre, respectively. KO of Tcfap2c in vitro reduced activated phosphorylated-Erk, decreased cell viability, repressed tumor growth and was associated with attenuation of Egfr expression. Chromatin immunoprecipitation and direct sequencing and expression analysis confirmed that Egfr was a Tcfap2c target gene in murine, as well as human, mammary carcinoma cells. Furthermore, decreased viability of mammary cancer cells was directly related to Egfr functional blockade. We conclude that TFAP2C regulates tumorigenesis, cell growth and survival in HER2-amplified breast cancer through transcriptional regulation of EGFR. The findings have important implications for targeting the EGFR pathway in breast cancer.

TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis.

Molecular subtypes of breast cancer are characterized by distinct patterns of gene expression that are predictive of outcome and response to therapy. The luminal breast cancer subtypes are defined by the expression of estrogen receptor-alpha (ERα)-associated genes, many of which are directly responsive to the transcription factor activator protein 2C (TFAP2C). TFAP2C participates in a gene regulatory network controlling cell growth and differentiation during ectodermal development and regulating ESR1/ERα and other luminal cell-associated genes in breast cancer. TFAP2C has been established as a prognostic factor in human breast cancer, however, its role in the establishment and maintenance of the luminal cell phenotype during carcinogenesis and mammary gland development have remained elusive. Herein, we demonstrate a critical role for TFAP2C in maintaining the luminal phenotype in human breast cancer and in influencing the luminal cell phenotype during normal mammary development. Knockdown of TFAP2C in luminal breast carcinoma cells induced epithelial-mesenchymal transition with morphological and phenotypic changes characterized by a loss of luminal-associated gene expression and a concomitant gain of basal-associated gene expression. Conditional knockout of the mouse homolog of TFAP2C, Tcfap2c, in mouse mammary epithelium driven by MMTV-Cre promoted aberrant growth of the mammary tree leading to a reduction in the CD24(hi)/CD49f(mid) luminal cell population and concomitant gain of the CD24(mid)/CD49f(hi) basal cell population at maturity. Our results establish TFAP2C as a key transcriptional regulator for maintaining the luminal phenotype in human breast carcinoma. Furthermore, Tcfap2c influences development of the luminal cell type during mammary development. The data suggest that TFAP2C has an important role in regulated luminal-specific genes and may be a viable therapeutic target in breast cancer.

Adult-onset nesidioblastosis causing hypoglycemia: an important clinical entity and continuing treatment dilemma.

HYPOTHESIS: Nesidioblastosis is an important cause of adult hyperinsulinemic hypoglycemia, and control of this disorder can often be obtained with a 70% distal pancreatectomy. DESIGN: The records of all adult patients operated on for hypoglycemia between 1974 and 1999 were reviewed retrospectively. Patients with the pathologic diagnosis of nesidioblastosis were contacted for follow-up (1.5-21 years) and are presented. Patients' results were compared with those of 36 other individuals with this disorder who were previously reported in the literature. SETTING: The University of Chicago Medical Center (Chicago, Ill), a tertiary care facility. PATIENTS: A consecutive sample of all patients operated on for hypoglycemia. INTERVENTIONS: Seventy percent distal pancreatectomy for all patients with nesidioblastosis, and maintenance therapy with verapamil hydrochloride for 2 patients. MAIN OUTCOME MEASURES: Achievement of normoglycemia with and without medication, development of insulin-dependent diabetes mellitus, pancreatic exocrine insufficiency, and need for reoperation. RESULTS: Of 32 adult patients who underwent surgical exploration for hyperinsulinemic hypoglycemia at our institution, 27 (84%) were found to have 1 or more insulinomas, and 5 (16%) were diagnosed with nesidioblastosis. Each patient with nesidioblastosis underwent a 70% distal pancreatectomy. Follow-up duration for the 5 patients ranged from 1.5 to 21 years, with 3 patients (60%) asymptomatic and taking no medications, and 2 patients (40%) experiencing some recurrences of hypoglycemia. The 2 patients with recurrences are now successfully treated with a calcium channel blocker, an approach, to our knowledge, never before reported for adult-onset nesidioblastosis. CONCLUSIONS: Nesidioblastosis is an uncommon but clinically important cause of hypoglycemia in the adult population, and must always be considered in a patient with a presumptive preoperative diagnosis of insulinoma. This study indicates that a 70% distal pancreatectomy is often successful in controlling hypoglycemia, and rarely results in diabetes mellitus. However, the optimal treatment of this disorder remains to be determined.

Should internal mammary nodes be sampled in the sentinel lymph node era?

BACKGROUND: Controversy exists regarding internal mammary lymph nodes (IMNs) in the staging and treatment of breast cancer. Sentinel lymph node identification with radiocolloid can map drainage to IMNs and directed biopsy can be performed with minimal morbidity. Furthermore, recent studies suggest that IMN drainage of breast tumors may be underestimated. To gain further insight into the prognostic value of IMNs, we reviewed the outcome of patients in whom the IMN status was routinely assessed. METHODS: A retrospective review of 286 patients with breast cancer who underwent IMN dissection between 1956 and 1987 was conducted. RESULTS: Median follow-up is 186 months, age was 52 years (range, 21-85 years), tumor size was 2.5 cm, and number of IMNs removed was 5 (range, 1-22); 44% received chemotherapy, 16% endocrine therapy, and 5% radiotherapy. Presence of IMN metastases correlated with primary tumor size (P < .0001) and number of positive axillary nodes (P < .0001) but did not correlate with primary tumor location or age. Overall, the 20-year disease-free survival is significantly worse for the 25% of patients with IMN metastases (P < .0001). In patients with positive axillary nodes and tumors smaller than 2 cm, there was a significantly worse survival (P < .0001) in the patients with IMN metastases. This difference in survival was not seen in women with tumors larger than 2 cm. CONCLUSIONS: Patients with IMN metastases, regardless of axillary node status, have a highly significant decrease in 20-year disease-free survival. Treatment strategies based on knowledge of sentinel IMN status may lead to improvement in survival, especially for patients with small tumors. At present, sentinel IMN biopsies should be performed in a clinical trial setting.

Oncogene profile of papillary thyroid carcinoma.

BACKGROUND: Our purpose was to study the expression of multiple oncogenes in papillary thyroid cancer for possible interactions and prognostic significance. METHODS: Twenty papillary thyroid carcinomas were studied for expression/mutation of 3 oncogenes: ras, ret/PTC, and erbB-2/neu. H, N, and K ras codons were examined by polymerase chain reaction (PCR), single-stranded conformation polymorphism, and sequencing. The thyroid oncogene ret/PTC was identified by reverse transcription (RT)-PCR. Gene amplification of erbB-2/neu was analyzed by differential PCR. The transmembrane domain of erbB-2/neu was sequenced for activating mutations. Quantitation of erbB-2/neu mRNA was evaluated by competitive RT-PCR, and protein expression was determined by immunohistochemistry. RESULTS: Among 20 tumors, 3 had insular/anaplastic dedifferentiation, 13 were intrathyroidal, and 7 were metastatic to cervical lymph nodes (6) or lung (1). An H-ras 13 mutation was found in 1 metastatic tumor and an N-ras 61 mutation in 1 intrathyroidal tumor. ret/PTC was identified in 3 intrathyroidal and 5 metastatic tumors. No erbB-2/neu DNA amplification or mutations were identified, although 4 tumors had elevated erbB-2/neu mRNA levels. Three of 20 patients had abnormalities detected in multiple oncogenes; 2 had elevated erbB-2/neu mRNA and ret/PTC rearrangements, and 1 of these had pulmonary metastasis. An intrathyroidal papillary cancer had an N61 ras mutation and a ret/PTC gene rearrangement. CONCLUSIONS: ret/PTC rearrangements are present in 40% of papillary thyroid carcinomas and may play a role in metastatic behavior. In contrast, ras mutations are rare (10%). erbB-2/neu gene amplification and activating mutations are not detected, although elevated mRNA levels were found in 20% of papillary carcinomas. The lack of correlation among the 3 oncogenes in 17 of 20 (85%) papillary thyroid carcinomas suggests that they were not cumulative factors in the pathogenesis of these tumors.

Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.

We report two familial adenomatous polyposis (FAP) kindreds with thyroid cancer, harboring two apparently novel germlineAPC mutations. The clinical phenotype in the first kindred was typical of classical adenomatous polyposis, whereas the second kindred exhibited an attenuated adenomatous polyposis phenotype. There was a female predominance with a mean age of 34 years (range, 23-49) at cancer diagnosis. Multiple sections of four thyroid tumors from three FAP patients were analyzed in detail. Histological examination of thyroid tumors showed a range of morphological features. Some tumors exhibited typical papillary architecture and were associated with multifocal carcinoma; in others, there were unusual areas of cribriform morphology, and spindle-cell components with whorled architecture. Immunoreactivity for thyroglobulin and high molecular weight keratins was strong. Somatic APC mutation analysis revealed an insertion of a novel long interspersed nuclear element-1-like sequence in one tumor sample, suggesting disruption of APC. In three FAP patients, ret/PTC-1 and ret/PTC-3 were expressed in thyroid cancers. No positivity was observed for ret/ PTC-2. p53 immunohistochemistry was positive in only one section of a recurrent thyroid tumor sample. Our data suggest that genetic alterations in FAP-associated thyroid cancer involve loss of function of APC along with the gain of function of ret/PTC, while alterations of p53 do not appear to be an early event in thyroid tumorigenesis.

Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia.

Rearrangements involving the RET protooncogene have been implicated in the development of papillary thyroid carcinoma (PC). Transgenic mice, expressing thyroid-targeted RET/PTC-1, develop PC; but the clinical significance of this oncogene remains uncertain. We examined the expression of RET/PTC-1, -2, and -3 in human thyroid microcarcinomas and clinically evident PC to determine its role in early stage vs. developed PC and to examine the diversity of RET/PTC in multifocal disease. RNA was extracted from paraffin-embedded microcarcinomas and clinically evident PCs; the results obtained from paraffin-embedded tissue were confirmed on RNA from corresponding snap-frozen tissue of clinically evident PCs. RT and PCR was performed using primers for RET/PTC-1, -2, and -3; PGK-1 (the housekeeping gene) analysis was used to ensure integrity of the RNA and efficiency of the RT reaction. PCR products were resolved by gel electrophoresis, and Southern hybridization was performed with RET/PTC-1, -2, and -3 probes. A polyclonal antibody to the carboxyterminus of RET was used for immunohistochemistry on paraffin sections. Thirty-nine occult papillary thyroid microcarcinomas from 21 patients were analyzed. Of the 30 tumors (77%) positive for RET/PTC rearrangements, 12 were positive for RET/PTC-1, 3 for RET/ PTC-2, 6 for RET/PTC-3, and 9 for multiple RET/PTC oncogenes. In clinically evident tumors, 47% had RET/PTC rearrangements. Immunohistochemistry demonstrated close correlation with RT-PCR-derived findings. RET/PTC expression is highly prevalent in microcarcinoma and occurs more frequently than in clinically evident PC (P < 0.005). Multifocal disease, identified in 17 of the 21 patients, exhibited identical RET/PTC rearrangements within multiple tumors in only 2 patients; the other 15 patients had diverse rearrangements in individual tumors. Our results indicate that RET/PTC oncogene rearrangements may play a role in early-stage papillary thyroid carcinogenesis, but they seem to be less important in determining progression to clinically-evident disease. In multifocal disease, the diversity of RET/PTC profiles, in the majority of cases, suggests that individual tumors arise independently in a background of genetic or environmental susceptibility.

Cytoplasmic staining of erbB-2 but not mRNA levels correlates with differentiation in human thyroid neoplasia.

OBJECTIVE: Amplification and overexpression of the erbB-2 proto-oncogene in human carcinomas may have prognostic significance. Its role in thyroid carcinoma is controversial. We investigated human thyroid tumours for erbB-2 gene amplification, activating mutations in the transmembrane domain, quantitative mRNA expression and protein expression. MATERIALS AND METHODS: DNA and mRNA were extracted from 47 morphologically characterized, frozen thyroid tumours including 10 nodular hyperplasias, 3 follicular carcinomas and 34 papillary carcinomas (4 with tall-cell features, 2 with insular and 2 with anaplastic de-differentiation). DNA amplification was analysed by differential PCR. The transmembrane domain of erbB-2 was sequenced in all tumours for activating mutations in position 659. Levels of mRNA expression were determined by competitive mRNA RT-PCR. Immunohistochemistry (IHC) for erbB-2 protein expression in corresponding paraffin-embedded samples was evaluated. RESULTS: Our results showed no DNA amplification of erbB-2. Sequencing of the transmembrane domain of erbB-2 revealed no activating mutations. The level of mRNA expression was variable, 11 papillary carcinomas showing statistically significant elevated mRNA levels compared with corresponding normal thyroid tissue; however, this did not correlate with other indicators of poor prognosis. In contrast to elevated mRNA levels in tumours, the level of protein staining correlated with degree of differentiation, normal and hyperplastic tissue being strongly positive and poorly differentiated tumours negative. CONCLUSION: There are no mutations or amplifications of the erbB-2 gene in human thyroid tumours. Elevated erbB-2 mRNA expression in some thyroid tumours is not associated with clinical features of poor prognosis; however, the significance of the elevated mRNA levels is unclear, as it did not result in protein overexpression. Instead, cytoplasmic erbB-2 protein detection by IHC correlates with differentiation of human thyroid tumours and may be a feature of good prognosis.

ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential?

The ret/PTC oncogene is unique to papillary thyroid cancer. Three forms of this oncogene, formed by translocation of three different genes to the tyrosine kinase domain of the ret protooncogene, result in constitutive kinase activation. Correlation with clinical outcome is controversial; ret/PTC-1 has been suggested to predict aggressive behavior. There is no morphological description of ret/PTC-positive tumors. We analyzed 60 thyroid carcinomas for ret/PTC expression to determine correlation with clinical history, disease stage, or tumor morphology. Ribonucleic acid extracted from frozen tissue was reverse transcribed; PCR was performed to amplify ret/PTC-1, 2, and -3. The TPC-1 cell line was the positive control for ret/PTC-1. All tumors were characterized morphologically. Clinical data were collected. The 57 papillary and 3 follicular carcinomas were resected from 44 female patients and 15 males. The average age at diagnosis was 46.2 yr (range. 24-83 yr). Three patients had a history of neck irradiation. At diagnosis, 11 patients had extrathyroidal tumor extension, 20 had lymph node metastases, and 1 had lung metastasis. Thirteen patients had tall cell papillary carcinomas; 3 tumors had focal insular or anaplastic dedifferentiation. The average follow-up was 13.4 months, during which 4 patients had recurrent disease. No deaths occurred. One papillary carcinoma (1.7%) was positive for ret/PTC-1, none was positive for ret/PTC-2, and 2(3.4%) were positive for ret/PTC-3. Although all 3 patients who had tumors containing ret/PTC rearrangements were under the age of 45 yr (range, 26-44 yr) and had small tumors (< 1.2 cm), 2 of these 3 patients presented with lymph node metastases, and the third had lymphatic invasion. ret/PTC oncogene expression did not correlate with radiation history. In summary, ret/PTC oncogene rearrangements were found in 3 of 60 (5%) thyroid carcinomas and were not present in tumors with aggressive morphological features. However, we found ret/PTC rearrangements in young patients (< 45 yr of age) with small thyroid carcinomas showing a predisposition for lymphatic involvement, suggesting a possible role in the development of this subgroup of tumors.

Prospective evaluation of selective venous sampling for parathyroid hormone concentration in patients undergoing reoperations for primary hyperparathyroidism.

BACKGROUND: The utility of standard radiologic imaging studies in guiding reoperative parathyroid surgery for primary hyperparathyroidism is widely known and accepted. The additional information gained by selective venous sampling in that patient population has not been well defined. We report the results of our experience with this method. METHODS: Between 1982 and 1992, 223 consecutive patients underwent reoperations for persistent or recurrent primary hyperparathyroidism after a prospectively determined series of imaging studies. Patients underwent noninvasive testing consisting of ultrasonography, computed tomography, technetium thallium scanning, and magnetic resonance imaging. Patients with negative, equivocal, or discordant results on the noninvasive studies proceeded to angiography. If angiography was negative, selective venous sampling was performed. RESULTS: Eighty-six patients (39%) with negative or equivocal noninvasive test and angiogram results underwent selective venous sampling. Seventy-six patients (88%) had a significant gradient in levels of parathyroid hormone from veins draining the left side of the neck (n = 25), the right side of the neck (n = 33), both sides of the neck (n = 7), and the thymus (n = 11). Correlation of these findings with operative findings revealed a sensitivity of 88% and a specificity of 86%. In the subgroup of patients who underwent venous sampling and had completely negative results of standard radiologic studies (35 of 86; 40%), 28 patients (80%) had venous gradients and seven patients (20%) had no gradient. Of those 28 patients in whom the venous sampling gradients were the only positive localization study, the venous samplings were helpful in 23 patients (true positive gradients), and the operative success rate was 93%. In the seven patients with no positive preoperative localizing studies including venous sampling, there were two operative failures (operative success, 71%). CONCLUSIONS: Our results show that selective venous sampling is a highly sensitive and specific method to regionally localize abnormal parathyroid glands not imaged by standard noninvasive and invasive radiologic techniques. Venous sampling is the study of choice in guiding reoperative procedures for occult abnormal parathyroid glands that are undetected despite the use of all available imaging studies.

A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas.

OBJECTIVE: This study determined, prospectively, whether duodenotomy (DX) should be routinely performed in explorations for patients with Zollinger-Ellison syndrome (ZES). SUMMARY BACKGROUND DATA: Duodenal gastrinomas are now being found with increasing frequency in patients with Zollinger-Ellison syndrome. The surgical approach used to detect these tumors is controversial. Some recommend intraoperative endoscopy with transillumination (IOE) at surgery, while others recommend routine DX. METHODS: Beginning in 1989, the authors prospectively compared the ability of palpation, intraoperative ultrasound (IOUS), IOE, and DX (in that sequence) to detect gastrinomas in 35 consecutive patients with ZES. Each patient also underwent preoperative localization studies. RESULTS: Thirty-three of 35 patients (94%) had tumor detected and excised; duodenal gastrinomas were excised in 27 patients (77%). The average size of the duodenal tumors was 0.8 cm, significantly smaller (p < 0.005) than the pancreatic and lymph node tumors in this series. Standard palpation after a Kocher maneuver identified 19 of the 31 duodenal tumors (61%) in the 27 patients. IOUS revealed only eight duodenal tumors (26%) and no new lesions. IOE identified 20 duodenal gastrinomas (64%) and 6 new lesions. DX identified 31 duodenal tumors (100%) and 5 additional tumors. The morbidity rate was 17%. One patient had a duodenal fistula after operation (2.8%) and subsequently recovered. No patient died. CONCLUSIONS: These results demonstrate that the duodenum is the most common location for gastrinoma in patients with ZES (77%) and that DX to detect and remove duodenal gastrinomas should be routinely performed in all explorations for patients with ZES.