P. Perri

Treatment of peritoneal carcinomatosis with intent to cure.

Low‐grade malignant tumors arise in the abdomen, do not infiltrate, and “redistribute” on the peritoneum with no extraregional spreading. In these cases, aggressive surgery combined with localized chemotherapy may provide cure.

Prognostic factors and oncologic outcome in 146 patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: Italian multicenter study S.I.T.I.L.O.

AIM The present study was specifically designed to assess the major clinical and pathological variables of patients with colorectal peritoneal carcinomatosis in order to investigate whether currently used criteria appropriately select candidates for peritonectomy procedures (cytoreductive surgery) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). PATIENTS AND METHODS Preoperative, operative and follow-up data on 146 consecutive patients presenting with peritoneal carcinomatosis of colorectal origin and treated by surgical cytoreduction combined with HIPEC in 5 Italian Hospital and University Centers were prospectively entered in a common database. Univariate and multivariate analyses were used to assess the prognostic value of clinical and pathologic factors. RESULTS Over a minimum 24-month follow-up, the overall morbidity rate was 27.4% (mortality rate: 2.7%) and was directly related to the extent of surgery. Peritoneal cancer index (PCI), unfavorable peritoneal sites, synchronous or previously resected liver metastasis and the completeness of cytoreduction, all emerged as independent prognostic factors correlated with survival. CONCLUSIONS Until research provides more effective criteria for selecting patients based upon the biomolecular features of carcinomatosis, patients should be selected according to the existing independent prognostic variables.

Serum tissue polypeptide specific antigen (TPS): a complementary tumor marker to CA 15-3 in the management of breast cancer

The efficacy of CEA and CA15-3 tumor markers in monitoring breast cancer was evaluated in 1365 patients with either benign (n=534) or malignant (n=831) breast diseases. Thirty-nine breast cancer patients were monitored before and after neoadjuvant chemotherapy. Three hundred forty-nine patients were monitored during post-surgical follow-up for either a minimum of 5 years or until time of recurrence. Twenty-one patients with metastases were also monitored during chemotherapy. Elevated CA 15-3 and TPS levels were found in 28.6% and 30.0% of patients. CA 15-3 and TPS sensitivities rose to 71.9% and 66.3% in metastatic patients, respectively. The addition of TPS to CA 15-3 increased the sensitivity up to 44.4% in the overall population, and to 87.6% in patients with metastases. During post-surgical follow-up CA 15-3 was elevated in 65.7% and TPS in 61.3% of patients with recurrence. The combination of TPS and CA 15-3 increased the overall sensitivity by 12.7%. Longitudinal monitoring of metastatic patients undergoing chemotherapy demonstrated that, when positive, both CA 15-3 and TPS paralleled response to treatment. TPS monitoring may provide additional value when used in combination with CA15-3 during post-surgical follow-up of breast cancer patients.

A multicenter prospective phase II randomized trial of epirubicin/vinorelbine versus pegylated liposomal doxorubicin/vinorelbine as first-line treatment in advanced breast cancer. A GOIM study

BackgroundTo evaluate activity and tolerability of two anthracycline-containing regimens as first-line treatment for anthracycline-naïve relapsed breast cancer patients.MethodsPatients with relapsed breast cancer not previously treated with adjuvant anthracyclines were randomly assigned to epirubicin/vinorelbine (arm A: EPI/VNB, EPI 90 mg/m2 on day 1, VNB 25 mg/m2 on days 1,5 plus G-CSF subcutaneously on days 7-12, with cycles repeated every 21 days), or to pegylated liposomal doxorubicin/VNB (arm B: PLD/VNB, PLD 40 mg/m2 on day 1, VNB 30 mg/m2 on days 1, 15, with cycles repeated every 4 weeks). Primary objective was to evaluate the efficacy of the two regimens in terms of response rate, secondarily toxicity, progression free survival and overall survival.ResultsOne hundred and four patients have been enrolled (arm A 54, arm B 50): characteristics were well balanced between the 2 arms. Responses were as follows: arm A, 3 (5.6%) CR, 20 (37%) PR, (ORR 42.6%, 95%CI 29.3%-55.9%); arm B, 8 (16%) CR, 18 (36%) PR, (ORR 52%, 95%CI 38.2%-65.8%). Median progression free survival was 10.7 months in arm A (95% CI, 8.7-12.6), and 8.8 months in arm B (95% CI, 7.1-10.5). Median overall survival was 34.6 months in arm A (95%CI, 19.5-49.8) and 24.8 months in arm B (95%CI, 15.7-33.9). As toxicity concerns, both treatment regimens were well tolerated; myelosuppression was the dose-limiting toxicity, with G3-4 neutropenia occurring in 18.5% and 22% of the patients of arm A and B, respectively. No relevant differences in main toxic effects have been observed between the two arms, except for alopecia, more common in arm A, and cutaneous toxicity, observed only in arm B. No clinical congestive heart failures have been observed, one case of tachyarrhythmia was reported after the last EPI/VNB cycle, and two reversible ≥ 20% LVEF decreases have been observed in arm A.ConclusionsBoth anthracycline- containing regimens evaluated in the present study seem to be active and with a satisfactory tolerability in anthracycline-naïve relapsed breast cancer patients.

Liposomal doxorubicin in the perfusional treatment of advanced soft tissue limb sarcoma.

Summary Liposome-containing doxorubicin has been employed in the treatment of advanced soft tissue limb sarcoma during hyperthermic perfusion. A phase I-II study was carried out starting with a standard dose of 10 mg//L of limb volume, the dosage was escalated with 2 mg for each triplet of patients. The maximum tolerable (MTD) dose was established as the amount able to cause a grade IV limb reaction at least in two out of three patients, the temperature level remained unchanged (41.5°C). The grade of limb reaction ranged between I-II (mild edema and erythema). Only in two patients treated with 18 mg/L of limb volume was a grade IV limb reaction observed, therefore MTD at a temperature of 41.5°C is 16 mg. A good tumor response was observed in 29% of the patients, partial response in 71%. The tumor shrinkage after perfusion permitted conservative surgery in 91% of the cases.

Clinical Practice of Hyperthermic Extremity Perfusion In Combination with Radiotherapy and Chemotherapy

The technique of norm thermic antiblastic perfusion was first introduced into clinical practice by Krementz in 1957 (KREMENTZ et al. 1958). This method permits temporary isolation of the tumor- bearing limb from the systemic circulation by means of an extracorporeal circuit. In this manner, high dosages of antineoplastic drugs (5-10 times greater than those administered systemically) can be administered into a restricted area, with high drug concentrations being achieved in the tumor and surrounding tissues.

Tumor Regression Grade After Neoadjuvant Chemoradiation and Surgery for Low Rectal Cancer Evaluated by Multiple Correspondence Analysis: Ten Years as Minimum Follow-up

Background: The role of Mandards tumor regression grade (TRG) classification is still controversial in defining the prognostic role of patients who have undergone neoadjuvant chemoradiation (CRT) and total mesorectal excision. The present study evaluated multiple correspondence analysis (MCA) as a tool to better cluster variables, including TRG, for a homogeneous prognosis. Patients and Methods: A total of 174 patients with a minimum follow‐up period of 10 years were stratified into 2 groups: group A (TRG 1–3) and group B (TRG 4–5) using Mandards classification. Overall survival and disease‐free survival were analyzed using univariate and multivariate analysis. Subsequently, MCA was used to analyze TRG plus the other prognostic variables. Results: The overall response to CRT was 55.7%, including 13.2% with a pathologic complete response. TRG group A correlated strictly with pN status (P = .0001) and had better overall and disease‐free survival than group B (85.1% and 75.6% vs. 71.1% and 67.3%; P = .06 and P = .04, respectively). The TRG 3 subset (about one third of our series) showed prognostically heterogeneous behavior. In addition to multivariate analysis, MCA separated TRG 1 and TRG 2 versus TRG 4 and TRG 5 well and also allocated TRG 3 patients close to the unfavorable prognostic variables. Conclusion: TRG classification should be used in all pathologic reports after neoadjuvant CRT and radical surgery to enrich the prognostic profile of patients with an intermediate risk of relapse and to identify patients eligible for more conservative treatment. Thus, MCA could provide added value. Micro‐Abstract: The tumor regression grade (TRG) role was investigated by multiple correspondence analysis (MCA) in 174 low rectal cancer patients undergone neoadjuvant chemoradiation and radical surgery, with a minimum follow‐up of 10 years. The TRG 1 and 2 showed better survival than TRG 4 and 5 subgroups. MCA allocated TRG 3 together with other prognostic variables better than multivariate analysis.

An unusual case of metaplastic breast carcinoma following neoadjuvant chemotherapy.

To the Editor: Metaplastic breast carcinomas (MBCs) are a rare and heterogeneous group of breast carcinomas. MBCs often display extensive metàplasis, a Greek word that was introduced by Virchow to describe a transformation, in which a cell type changes into another cell type. Accordingly, squamous, spindle cell, and/or mesenchymal differentiation are frequently found in parts or all of the carcinomatous epithelium of an MBC. Although the results of recent genetic studies support a monoclonal origin of the heterogeneous components of a metaplastic tumor, the mechanisms that underlie metàplasis are unknown. Here, we report a case of MBC following neoadjuvant chemotherapy (NAC). The patient was a 65-year-old woman who presented with a palpable mass in the upper lateral quadrant of her right breast. The results of the clinical, ultrasound, and mammographic examinations showed the presence of a dense tumor (4 cm ¥ 3 cm ¥ 3 cm) in the upper outer quadrant of her right breast with no involvement of the axillary nodes. After fineneedle aspiration cytology and core needle biopsy of the breast tumor, the woman was diagnosed as having an invasive ductal, not otherwise specified (NOS), carcinoma (Fig. 1a). When the tumor was immunohistochemically stained for biomarkers, the cells were estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER-2) positive, and progesterone receptor (PR) negative. Neoadjuvant chemotherapy that comprised herceptin, epidoxorubicin, and taxol was then started for two months. At the end of the treatment period, the entire tumor and the axillary lymph nodes were removed by radical mastectomy and axillary lymph node dissection. The postoperative pathological stage for this patient was T2 N0 M0, IIA. After surgery, the patient did not receive any additional chemotherapy or radiation therapy, and was disease-free, 17 months after surgery. Gross examination of the surgically-resected tumor showed a firm and whitish lesion which measured 3 cm ¥ 2 cm ¥ 1.5 cm. Microscopically, the neoplasm was predominantly composed of nodular areas whose peripheries were lined by poorly differentiated basaloid or spindle-shaped carcinomatous cells, and in which progressive squamous epithelial differentiation toward the center was present (Fig. 1b). The squamous component was well-differentiated, and keratinization with prominent pearl formation was evident. Some of the intraductal lesions were cystic with keratinized debris in a large central lumen. Focal tubular gland formation was present. Ductal-squamous transition (Fig. 1c) and cells with a clear cytoplasm and without any obvious signs of keratinization were seen in the nodule’s central region. Mitoses were scanty. The nodules showed both pushing non-infiltrative borders, as well as stromal invasion. An invasive component with very discernible squamous differentiation was also seen (Fig. 1d). Prominent desmoplasia was present in the peritumoral stroma, and lymphocytes were scattered in the stroma at the tumor edge. No vascular or neural invasion of the tumor was observed, and the neoplasm did not involve the overlying skin. Cytoplasmic vacuolization was seen in some of the residual normal ducts. Immunohistochemically, the neoplastic cells of the excised tumor were positive for high molecular weight cytokeratins (CKs) 5/6 (Fig. 2a) and 14, the broad-spectrum CK, MNF 116, tumor protein p63 (Fig. 2b), epithelial membrane antigen, and epidermal growth factor receptor (EGFR). Positive reactivity for CK7 was restricted to the neoplastic tubular structures, and negative reactivity for CK7 was observed in the poorly differentiated cells, the most mature keratinized cells, and the keratin pearls. The stromal myofibroblastic cells that surrounded the neoplastic areas were positive for vimentin and smooth muscle actin. Focal vimentin positivity was also observed throughout the excised tumor. Also, the neoplastic cells were ER negative, PR negative, and HER-2 negative, and had a high Ki-67 proliferation rate. We made a final pathological diagnosis as an invasive and intraductal metaplastic adenosquamous carcinoma whose surgical margins were free of neoplastic involvement. Each of the 30 resected lymph nodes from the right axilla was negative for the cancer. Metaplastic breast carcinomas can be classified into subtypes according to their phenotypic appearance. The clinical features and radiological appearance of MBCs are not different from those of infiltrating ductal NOS carcinoma. According to reports, the median size of an MBC is larger than that of ordinary carcinoma of the breast, and metastases to the axillary nodes are relatively uncommon. However, some authors have commented that the advanced stage and lymph node involvement are associated with a behavior which is more aggressive than that of ordinary invasive ductal carcinoma of the breast. Although there are literature reports that most ductal carcinomas display different tissue responses after NAC, features of metàplasis have not yet been reported for an excised tumor after chemotherapy. The only post-treatment histological change that we observed in the excised tumor was cytoplasmic vacuolization in rare normal ducts. Pathology International 2012; 62: 72–74 doi:10.1111/j.1440-1827.2011.02750.x

0092 A prospective clinical study for molecular intra-operative detection of lymph node metastasis in breast cancer patients by “one step nucleic acid amplification (OSNA)” in comparison with intensive histological investigation

609 Background: The aims of the study were 1) to assess the accuracy of a new intra-operative molecular diagnostic tool named OSNA, based on the measurement of cytokeratin 19 (CK19) mRNA, in the detection of axillary sentinel lymph node (SLN) metastases in patients with breast carcinoma 2) to determine the concordance of OSNA analysis with multilevel haematoxylin and eosin (H&E) and immunohistochemical (IHC) examination. METHODS A prospective series of 247 consecutive SLNs from 187 breast cancer patients was evaluated. The OSNA assay (Sysmex, Kobe - Japan) follows a short sample preparation step and subsequent rapid amplification of CK19 mRNA based on reverse transcription loop-mediated isothermal amplification. Each SLN was immediately divided into four slices. Two alternate slices were used for the intra-operative OSNA assay. The remaining two slices were investigated by six-level histopathology with 100 μm skip ribbons using routine H&E and CK19 IHC staining. The results of histology and OSNA were then compared. RESULTS Pts characteristics: infiltrating ductal/infiltrating lobular/mucinous/medullar/DCIS: 130/10/1/1/25. OSNA and histo-pathological methods identified 54 SLNs positive and 185 negative cases (2/3 contained isolated tumour cells). We found 8 discordant cases, 2 OSNA negative with micrometastasis found by IHC/H&E analysis, 5 OSNA positive for micrometastases but IHC/H&E negative and 1 case macrometastatic at OSNA, while negative at IHC/H&E analysis. The overall concordance of OSNA with histopathology was 96.7% with a specificity of 96.8% and sensitivity of 96.4%. These discordances could be due to sampling bias such that a micrometastasis was confined to the slices used for OSNA or the slices used for histology. CONCLUSIONS The current study suggests that the performance provided by OSNA assay is comparable to intensive histopathological work-up even when using only half a lymph node. The method could be applied as a rapid and reliable intra-operative diagnostic tool thus preventing breast cancer patients from a diagnostic delay or second surgery due to a postoperatively diagnosed positive SLN. No significant financial relationships to disclose.

Abstract P1-01-09: Molecular Detection of Sentinel Lymph Node Metastases in Breast Cancer Patients: Correlation between Cytokeratin 19 mRNA Copy Number Detected by One Step Nucleic Acid Amplification (OSNA) and Risk of Metastases in Axillary Lymph Nodes

Background: The accuracy of the OSNA assay for metastases detection in sentinel lymph nodes (SLNs) has recently been validated in our Institute and adopted as an intra-operative test for breast cancer (BC) patient management. The aims of this study in a series of early BC patients, were: 1) to correlate the copy numbers of cytokeratin 19 (CK19) mRNA with the size of nodal metastases and with the risk of additional disease in non-sentinel lymph nodes (NSLNs); 2) to investigate the relationship between SLN status with OSNA method, and conventional bio-pathological factors taking into account the molecular BC classification: luminal A, luminal B, HER2 subtype, and triple-negative; 3) to identify a subgroup of patients with positive SLN with higher risk of NSLNs metastatic involvement. Material and Methods: 750 SLNs from 580 patients were clinically processed using both OSNA assay and post-operative histology. The results of these two methods were then compared. The correlation between the size of metastases and the copy numbers of CK19 mRNA was calculated using the Spearman correlation coefficient. Complementary axillary lymph node dissection (ALND) was performed concurrently in case of OSNA assay positivity and the probability of having a positive lymph node axillary dissection was calculated by the unconditional logistic regression model. This series of BC patients were divided into four main subtypes taking in account the BC classification based on the immunohistochemistry phenotypic patterns. Results: OSNA positivity was reported in 24.6% of the patients for a sensitivity of 94.2%. Considering the 145 patients with SLN positivity the size of metastatic foci was significantly correlated to the copy numbers of CK19 mRNA. The complex relationships among the bio-pathological variables analyzed by multiple correspondence analysis (MCA) showed that the metastatic involvement of NSLNs is associated with SLNs with a high copy numbers of CK19 mRNA and HER2 subtype tumors. OSNA specificity (95%) and negative predictive value (98.4%) clearly demonstrated its reliability to guide ALND decision. Conclusions: Our results showed that OSNA is an excellent method for the detection of metastases in SLN and its adoption in our clinical practice has determined a significant improvement in the diagnosis of metastatic BC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-09.