Biological subtype, treatment response and outcomes in inflammatory breast cancer using data from the National Cancer Database.

BACKGROUND: Although inflammatory breast cancer (IBC) is postulated to be a distinct biological entity, practice guidelines and previous data suggest that treatment and outcomes are influenced by standard approximated biological subtype. The aim of this study was validation in a large recent National Cancer Database (NCDB) patient cohort. METHODS: Patients with non-metastatic IBC treated in 2010-2015 with neoadjuvant systemic therapy and surgery were identified from the NCDB. Approximated biological subtypes were categorized as oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), ER-/HER2- and HER2+. Total pathological complete response (pCR) was defined as ypT0/ypTis, ypN0. χ2 tests were used to compare pCR rates, and Kaplan-Meier curves and Cox proportional hazards regression to analyse overall survival. RESULTS: Among 4068 patients with IBC (median age 56 years), the approximated biological subtype was ER+/HER2- in 1575 (38·7 per cent), HER2+ in 1323 (32·5 per cent) and ER-/HER2- in 1170 (28·8 per cent). A total of 3351 patients (84·0 per cent) were cN+ at presentation, with no differences across subtypes. Total pCR rates varied significantly by subtype: ER+/HER2- (6·2 per cent), HER2+ (38·8 per cent), ER-/HER2- (19·1 per cent) (P < 0·001), as did breast pCR rates (10·4, 44·5 and 25·2 per cent respectively) and nodal pCR rates (16·9, 56·9 and 33·1 per cent). The 5-year overall survival rate varied significantly across subtypes (ER+/HER2- 64·9 per cent, HER2+ 74·0 per cent, ER-/HER2- 44·0 per cent; P < 0·001) and by pCR within subtypes (all P < 0·001). In multivariable analysis, ER-/HER2- subtype (hazard ratio 2·89 versus HER2+ as reference; P < 0·001) and absence of total pCR (hazard ratio 3·23; P < 0·001) predicted worse survival. CONCLUSION: Both treatment response and survival in patients with IBC varied with approximated biological subtype, as among other invasive breast cancers. These data support continued tailoring of systemic treatment to approximated biological subtype and highlight the recent improved outcomes in patients with HER2+ disease.

ANTECEDENTES: En tanto que el cáncer inflamatorio de mama (inflammatory breast cancer, IBC) se ha postulado como una entidad biológica distinta, las guías de práctica clínica y datos previos sugieren que el tratamiento y los resultados están influenciados por aproximación al subtipo biológico estándar. El objetivo de este estudio fue la validación en una cohorte reciente de pacientes incluidas en una extensa Base de Datos Nacional de Cáncer (National Cancer Database, NCDB). MÉTODOS: A partir de la NCDB, se identificaron las pacientes con IBC no metastásico tratadas en con neoadyuvancia sistémica y cirugía durante el periodo 2010-2015. El subtipo biológico aproximado se categorizó como ER+/HER2-, ER-/HER2- y HER2+. La respuesta patológica completa total (pathologic complete response, pCR) se definió como ypT0/ypTis, ypN0. Se utilizaron pruebas de ji al cuadrado para comparar las tasas de pCR y las curvas de Kaplan-Meier y la regresión de riesgos proporcionales de Cox para analizar la supervivencia global (overall survival, OS). RESULTADOS: En las 4.068 pacientes con IBC (mediana de edad 56 años), el subtipo biológico aproximado fue ER+/HER2- en 1.575 (39%), HER2+ en 1.323 (33%) y ER-/HER2- en 1.170 (29%). Un total de 3.351 pacientes (84%) eran cN+ en el momento de la presentación, sin diferencias entre los subtipos. Las tasas totales de pCR variaron significativamente en función del subtipo: ER+/HER2- (6%), HER2+ (39%), ER-/HER2- (19%), P < 0,001, así como las tasas de pCR de la mama (10%, 45%, 25%) y las tasas de pCR de los ganglios linfáticos (17%, 57%, 33%). La OS a los 5 años varió significativamente según los subtipos (ER+/HER2- 65%, HER2+ 74%, ER-/HER2- 44%, P < 0,001) y según la pCR en cada uno de los subtipo (en cada uno P < 0,01). En el análisis multivariable, el subtipo ER-/HER2- (cociente de riesgos instantáneos, hazard ratio, HR 2,9, P < 0,001 versus HER2+) y la ausencia de pCR total (HR 3,2, P < 0,001) predijeron una peor supervivencia. CONCLUSIÓN: Tanto la respuesta al tratamiento del IBC y como la supervivencia variaron en función del subtipo biológico aproximado, tal como sucede en otros cánceres de mama invasivos. Estos datos apoyan la importancia de continuar ajustando el tratamiento sistémico al subtipo biológico aproximado y resaltan la mejoría reciente de los resultados en las pacientes HER2+.

Management of regional lymph nodes in the elderly melanoma patient: patient selection, accuracy and prognostic implications.

BACKGROUND: Among older melanoma patients, lymphatic mapping failure, lower rates of SLN positivity and poor prognosis are reported reasons for omission of sentinel lymph node biopsy (SLNB). We investigated reasons for non-compliance with guidelines, sensitivity and prognostic significance of SLNB and completion lymphadenectomy (CLND) for elderly melanoma patients. METHODS: Retrospective review of patients ≥65 years with ≥1 mm thick melanoma treated at a single Institution. Wilcoxon, chi-square and Fisher's exact tests were used for analysis as appropriate. Univariable and multivariable Cox regressions were used to analyze time-to-event variables. RESULTS: 72 of 358 patients (20%) did not undergo SLNB. Reasons for omission included selective neck dissection in 26 (7%), patient refusal in 11 (3%), physician recommendation in 15 (4%) and significant comorbidities in 8 (2%). Of the 286 patients undergoing SLNB, only 5 (1.7%) had lymphatic mapping failures. 76 patients (26.6%) were SLN-positive. The sensitivity of SLNB was 90.5%, the negative predictive value was 96.3% and the false negative rate was 3.8%. Sixty-seven (88%) SLN-positive patients underwent CLND and 10 (15%) had positive non-SLNs. Reasons for omission of CLND included patient refusal in 3 (4%), surgeon recommendation in 5 (7%) and postoperative complication in 1 (1%). SLN and non-SLN status were independently associated with disease-free survival. SLN status was independently associated with melanoma-specific survival. CONCLUSIONS: SLNB was successful in 98.7% of elderly patients with high sensitivity and a low false negative rate. Only 2% of our elderly patients appeared too frail for SLNB. Age alone should not be a contraindication to SLNB and CLND for melanoma.

Correlating sonography, mammography, and pathology in the assessment of breast cancer size.

BACKGROUND: With the increasing use of neoadjuvant and minimally invasive therapy, the accuracy of preoperative determination of breast tumor size becomes important. Therefore, we undertook this study to compare mammography and ultrasonography (US). METHODS: A total of 180 invasive breast cancer patients were prospectively examined by mammography and US; 146 eligible patients had tumors visualized by both modalities. RESULTS: In 69% of cases, US was better than or equivalent to mammography in determining tumor size. Both underestimated tumor size; mean (median) underestimation was 3.8 +/- 0.7 mm (1.7 mm) by US and 3.5 +/- 0.9 mm (2 mm) by mammogram. Maximal tumor dimension was accurate within 5 mm in 65% of cases by mammography and 75% of cases by US. For mammographically determined size (versus pathologic size) correlation, r, was 0.4 and for US it was 0.63 and improved for only T1 and T2 tumors. CONCLUSIONS: These data suggest that US is more accurate than mammography in assessing breast cancer size.

Predicting the biologic behavior of ductal carcinoma in situ: an analysis of molecular markers.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast encompasses a heterogeneous group of noninvasive cancers that now represents 19% of new breast cancer cases. Optimal treatment remains controversial. We undertook this study to characterize the relationship between angiogenic markers and the biologic behavior of various DCIS phenotypes. METHODS: We performed histopathologic review and immunohistochemistry for p53, vascular endothelial growth factor (VEGF), and factor VIII-related antigen on 103 specimens of pure DCIS. RESULTS: VEGF expression was seen in 89 tumors (86%) and correlated with microvessel density (MVD). Among VEGF-negative tumors, mean MVD (number of microvessels per square millimeter) was 48 +/- 19, versus 117 +/- 7 for tumors expressing VEGF (P =.001). Strong p53 expression was observed in 28 tumors (27%) and was associated with comedo histology, high tumor grade, necrosis, high MVD, and ipsilateral tumor recurrence (all P < or =.03). Among 8 patients with ipsilateral recurrence, 5 (63%) had tumors with strong p53 expression, whereas only 24% of patients without recurrence had tumors with strong p53 expression (P =.03). Although 7 of 8 patients with ipsilateral recurrence had tumors with VEGF and high MVD, neither parameter achieved statistical significance. CONCLUSIONS: These data suggest that molecular alterations may help predict the biologic aggressiveness of DCIS. Mutant p53 expression predisposes the patient toward ipsilateral recurrence, perhaps by promoting angiogenesis. Further investigation may identify clinically useful markers and novel treatment strategies.

Laparoscopic ultrasound enhances diagnostic laparoscopy in the staging of intra-abdominal neoplasms.

Routine laparoscopy and laparoscopic ultrasound (LUS) for staging intra-abdominal malignancies remains controversial. Thus, we undertook a prospective study to assess the value of preoperative laparoscopy with LUS for patients with intra-abdominal tumors judged resectable by preoperative studies. Laparoscopy was successfully performed in 76 of 77 patients, and 60 underwent LUS. Of 33 patients with presumed pancreatic cancer, laparoscopic findings changed the operative management of 11 patients, and LUS altered the management of an additional 6 patients. Laparotomy was avoided in 9 patients (27%). Among 14 patients with hepatobiliary tumors, laparotomy was avoided in 9 patients in whom laparoscopy and/or LUS revealed either benign or advanced disease. Operative management was altered in 4 of 18 patients with gastric or esophageal cancer by laparoscopic findings. LUS did not add to the management of these patients. Of 12 patients with presumed intra-abdominal lymphoma, 9 were diagnosed with lymphoma and 3 with benign disease, without laparotomy in all but 1 case. Laparoscopy and LUS are valuable tools for evaluating the resectability of pancreatic and hepatobiliary tumors. Laparoscopy, and to a lesser degree LUS, greatly facilitates diagnosing patients with intra-abdominal lymphomas and spares an occasional patient with esophagogastric carcinoma from undergoing laparotomy.

Molecular prognostic markers in intermediate-thickness cutaneous malignant melanoma.

BACKGROUND: The limitations of morphologic criteria alone in determining the prognosis for a patient with a particular intermediate-thickness primary melanoma have prompted efforts to identify other markers. METHODS: In this study, the authors analyzed expression of p53, beta1 integrin, and beta3 integrin in primary tumors from 111 patients with intermediate-thickness malignant melanoma. RESULTS: Eighty-nine (80%) had detectable p53 protein, 58 (52%) expressed beta1 integrin, and 71 (64%) expressed beta3 integrin. Patients with beta3 positive melanomas were more likely to die of their disease (32 of 71 patients, 45%) than those with beta3 negative tumors (3 of 40 patients, 8%) (P < 0.0001). The number of involved lymph nodes, Clark's level, beta1 integrin expression, thickness, and mitotic rate also had prognostic significance. beta3 integrin was associated with subsequent lung metastases and beta1 integrin with lymph node involvement. CONCLUSIONS: Integrin expression, along with histopathologic criteria, is a prognostic marker for intermediate-thickness malignant melanoma and may indicate the site of subsequent metastasis. These observations may have clinical utility and suggest areas for future investigation.

Postlaparoscopic small bowel obstruction. Rethinking its management.

BACKGROUND: Patients with early postoperative small bowel obstruction (SBO) are usually managed nonoperatively with nasogastric suction, intravenous fluids, and observation. The majority of early postoperative SBO resolve without an operation. METHODS: We performed a retrospective review of patients who had been diagnosed with postlaparoscopic SBO at three Chicago area teaching hospitals. RESULTS: The patients were initially managed nonoperatively for up to 7 days. However, all of them subsequently required an operation. In every case, the postlaparoscopic SBO was caused by the small bowel being incarcerated in a peritoneal defect created either by trocar placement or peritoneal incision for herniorrhaphy. CONCLUSION: In contradistinction to the approach used for early SBO after laparotomy, prompt operative intervention for postlaparoscopic SBO is recommended.

Plasma c-erbB-2 levels in breast cancer patients: prognostic significance in predicting response to chemotherapy.

PURPOSE: To determine the significance of plasma c-erbB-2 levels to assess the extent of disease spread and to predict the response to chemotherapy in node-positive breast cancer patients. METHODS: We determined plasma levels of c-erbB-2 in 79 stages II and III breast cancer patients who received cyclophosphamide, methotrexate, and flourouracil (CMF)/cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP) chemotherapy. All patients had a minimum follow-up of greater than 60 months or until disease recurrence. Plasma samples were obtained before and after chemotherapy. Plasma c-erbB-2 levels were quantified by enzyme-linked immunoassay. c-erbB-2 levels were analyzed in relation to the patients' axillary lymph node status, menopausal status, disease status, disease-free survival (DFS), and steroid receptor status of tumor. RESULTS: Plasma c-erbB-2 levels varied widely in breast cancer patients. In general, when all patients were included in the analyses, plasma c-erbB-2 levels before chemotherapy correlated significantly with the number of positive axillary lymph nodes and with postchemotherapy c-erbB-2 levels. No association was observed between pre- or postchemotherapy c-erbB-2 levels and other variables (patients' age at diagnosis, receptor status of the tumor, or disease status). The prognostic significance of different factors (ie, nodal status [one to three v > three positive nodes], menopausal status [pre- v postmenopausal women], estrogen receptor [ER] status [ER+ v ER-], and pre- and postchemotherapy c-erbB-2 levels) in predicting DFS was determined in all study patients. Among the variables examined, nodal status was the strongest predictor of DFS in these patients. The second most significant prognostic marker was postchemotherapy c-erbB-2 level. Prechemotherapy c-erbB-2 levels showed prognostic significance for DFS in a subset of breast cancer patients (ie, patients with > three positive nodes). Patients with greater than three positive lymph nodes and those with greater than 100 fmol/mL of plasma c-erbB-2 levels before therapy had significantly shorter DFS than did those patients with 100 fmol/mL or less c-erbB-2 levels. CONCLUSION: In breast cancer patients, determination of c-erbB-2 levels before therapy is an important biomarker to assess the extent of disease spread in the lymph nodes. Postchemotherapy c-erbB-2 levels are also a prognostic indicator for DFS in patients who receive chemotherapy. Finally, in a subgroup of patients with greater than three positive nodes, prechemotherapy c-erbB-2 levels are a prognostic marker for response of patients to standard chemotherapy.

A prospective analysis of office-based breast ultrasound.

OBJECTIVE: To determine the usefulness of office-based breast ultrasound. DESIGN: Prospective, nonrandomized study. SETTING: Academic-affiliated community teaching hospital. PATIENTS: Among 653 consecutive patients seen in our office during a 30-month period, we performed 660 ultrasound examinations. The presenting complaint included a palpable mass in 53%, abnormal mammogram in 39%, and nipple discharge or retraction in 3%. INTERVENTION: Ultrasound examination was performed using a handheld 7.5-MHz linear array transducer. Findings and pertinent clinicopathologic data were recorded prospectively in our Breast Ultrasound Registry. MAIN OUTCOME MEASURE: Contribution of breast ultrasound to diagnosis and treatment. RESULTS: The sonogram was normal in 201 cases (30%), showed duct ectasia in 20 cases (3%), a simple cyst or seroma in 101 cases (15%), and a focal complex or solid abnormality in 338 cases (51%). Among the last group, 114 (97%) of 118 lesions thought to be benign on ultrasonography proved to be benign, whereas 13 (12%) of 111 indeterminate and 72 (75%) of 96 sonographically suspicious lesions proved to be cancer (including 13 cases with normal mammograms). Ultrasonographic features of malignancy included an anteroposterior-to-lateral dimension ratio of 1 or greater, heterogeneous hypoechoicity, irregular shadowing, and fuzzy and/or jagged margins. Ultrasound-guided needle biopsy accurately diagnosed 46 benign nonpalpable lesions and 20 malignant nonpalpable lesions. CONCLUSIONS: These data suggest that ultrasonography is a useful adjunct to clinical and mammographic evaluation of breast disease. Breast ultrasound identifies cysts, aids in differentiating benign from malignant lesions, and facilitates office needle biopsy of nonpalpable abnormalities, permitting timely and cost-effective patient care.

Mutant p53 expression: a marker of diminished survival in well-differentiated soft tissue sarcoma.

The aim of this study was to assess the translational value of the quantitative assay of mutant p53 protein expression as both a prognostic indicator and a tool to determine appropriate therapy in a group of relatively innocuous and morphologically similar soft tissue sarcomas (STSs). Using a quantitative ELISA, we analyzed mutant p53 protein expression in 47 well-differentiated (grade I) STSs from patients treated in our Department of Surgical Oncology. Sixteen of 47 tumors expressed up to 42.6 ng mutant p53 protein/mg total protein. After a mean follow-up of 112 months, 63% of the patients with mutant p53+ tumors but only 16% of the patients with mutant p53- tumors had died (P < 0.01). Mutant p53 expression of >/=4.5 ng predicted even greater reduction in survival. These data show that mutant p53 expression identifies biologically aggressive grade I STSs. This molecular marker should have translational value as a tool to select those patients likely to benefit from aggressive multimodal therapy and intense surveillance.

Beta 1 integrin expression: a marker of lymphatic metastases in cutaneous malignant melanoma.

BACKGROUND: Experimental evidence suggests that integrins are key regulators of the development of melanoma metastases, influencing both the likelihood and site of metastases. Whereas effective treatment of cutaneous melanoma remains surgical, elective lymph node dissection (ELND) is controversial. The present study was designed to investigate the relationship between integrin expression by a given primary melanoma and occult regional lymph node metastases. MATERIALS AND METHODS: We studied beta 1 integrin expression, by quantitative immunohistochemistry using an image analyzer, in the primary melanomas of 90 ELND patients. RESULTS: beta 1 integrin was expressed in > or = 10% of the primary tumor in 92% of cases eith lymph node involvement versus 9% of node negative cases (p < 0.001). CONCLUSIONS: Our data demonstrate that quantitative immunohistochemistry for beta 1 integrin expression in primary melanomas can identify patients likely to have occult lymph node metastases. This suggests that beta 1 integrins play a role in the lymphatic dissemination of cutaneous melanoma.

Beta3 integrin expression in melanoma predicts subsequent metastasis.

Previous studies have suggested that differential expression and/or activation of integrins facilitates metastatic progression in murine and human melanoma. While recent data show that the integrin alphavbeta3 is involved in tumor angiogenesis and that tumor growth may be abrogated by alphavbeta3 inhibitors in vitro, the clinical significance of beta3 integrin expression in human malignant melanoma is not known. To assess the prognostic value of beta3 integrin expression, we examined primary cutaneous melanomas from 160 patients followed for a mean of 98 months or until death. We quantified the percentage of tumor area stained with beta3 integrin Ab CD-61 using an image analyzer. beta3 integrin expression was detected in 107/160 primary melanomas (69%). beta3-integrin-positive (beta3+) tumors were thicker (mean 2.98 +/- 0.3 mm) than beta3-integrin-negative (beta3-) melanomas (mean 1.64 +/- 0.2 mm) (P = 0.002). Patients with beta3+ melanomas were more likely to relapse (57/107, 53%) and to die from disease (45/107, 42%) than those with beta3- tumors (6/53, 11%; and 4/53, 8%, respectively) (P < 0.001). Overall survival was greater for beta3- than for beta3+ patients (mean 102 +/- 9 vs 69 +/- 6 months) (P = 0.001). These data show that beta3 integrin expression in primary cutaneous melanoma predicts subsequent metastatic progression. Further study of beta3 integrins in the development of melanoma metastases may yield new therapeutic strategies, as well as prognostic information, for the treatment of this cancer.

Beta 1 integrin expression in malignant melanoma predicts occult lymph node metastases.

BACKGROUND: Elective lymph node dissection for malignant melanoma is still controversial. Experimental studies suggest that differential expression, activation, or both of beta1 integrins facilitate melanoma metastases. However, the clinical significance of beta1 integrin expression in human melanoma is unclear. METHODS: We examined primary cutaneous melanomas from 76 patients undergoing elective lymph mode dissection. We quantified the percentage of tumor area stained by beta1 integrin antibody with an image analyzer. RESULTS: beta1 integrin was expressed in all 23 primary tumors from patients with pathologically positive lymph nodes (LNs) but in only 14 (26%) of 53 cases with pathologically negative nodes (p < 0.001). No patients with beta1 integrin-negative tumors had LN involvement, whereas 23 (62%) of 37 patients with beta1 integrin-positive tumors had LN metastases (p < 0.001). Furthermore, 21 (91%) of 23 cases with LN metastases but only 4 (8%) of 53 cases without had beta1 integrin staining of 10% or more of tumor area (p < 0.001). CONCLUSIONS: Our study is the first to show a correlation between expression of a molecular marker in the primary cutaneous melanoma and likelihood of regional LN metastases. beta1 immunostaining of 10% or more of tumor area reliably predicts patients most likely to harbor occult LN metastases and likely to benefit from ELND.

Acral lentiginous melanoma.

OBJECTIVE: To analyze whether the histologic subtype acral lentiginous melanoma confers independent prognostic significance. DESIGN: Case series retrospective review. SETTING: Academic surgical practice. PATIENTS OR OTHER PARTICIPANTS: Fifty-six patients with histologically confirmed acral lentiginous melanoma identified from patients with malignant melanoma consecutively treated by the faculty of the Department of Surgical Oncology at the University of Illinois at Chicago. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Lymph node metastases, disease-free survival, and overall concurrent or subsequent survival. RESULTS: The average age of our patients with acral lentiginous melanoma was 61.1 years. Thirty-four (61%) were white, and the remaining 22 (39%) were African-American, Hispanic, or Asian. Thirty (54%) were male and 26 (46%) were female. The primary tumor occurred on the lower extremity in 46 (82%) of the cases and on the upper extremity in the remaining 10 (18%). Twenty-four primary tumors (43%) were greater than 4.00 mm thick. Analyzed by means of a logistic regression model, the rate of lymph node metastases did not significantly differ among patients with acral lentiginous melanoma, superficial spreading melanoma, and nodular malignant melanoma. Furthermore, when corrected for tumor thickness, disease-free and overall survival were the same for the three histologic groups. Multifactorial analysis identified only thickness as a prognostic variable for disease-free survival and overall survival. CONCLUSIONS: Despite the greater age, diverse ethnic background, and distinctive tumor characteristics of our patients with acral lentiginous melanoma, this histologic subtype does not, in itself, affect the outcome of these patients.

Postoperative T-tube tract choledochoscopy.

One hundred twenty-six patients underwent postoperative fiberoptic T-tube tract choledochoscopy for the management of retained biliary calculi as demonstrated by T-tube cholangiography. Extraction was successful in 94% of patients with retained stones. Thirty-nine patients had more than 1 stone, 20 patients had heptic duct stones, and 14 patients had large stones requiring electrohydraulic lithotripsy or laser fragmentation. Stone removal was not possible in six patients, secondary to either slippage of the T-tube with obliteration of the tract, inability to remove the stones with available instruments, a tortuous tract, or choledochoscope malfunction. Minor complications, most commonly transient fever, occurred in 12 patients. No serious complications or deaths occurred. The advantages of T-tube tract choledochoscopy include direct visualization of the biliary tree, avoidance of radiation exposure, and easy access to hepatic duct stones. This is the preferred method for treating retained biliary calculi in patients with a T-tube in situ.