Andrzej Kurylcio

Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling

Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T-cell activation. Mechanistic investigations indicated that these effects relied upon cross-talk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape. Cancer Res; 76(11); 3156-65. ©2016 AACR.

Application of artificial neural networks for predicting presence of non-sentinel lymph node metastases in breast cancer patients with positive sentinel lymph node biopsies

Introduction The aim of this study was to present a new predictive tool for non-sentinel lymph node (nSLN) metastases. Material and methods One thousand five hundred eighty-three patients with early-stage breast cancer were subjected to sentinel lymph node biopsy (SLNB) between 2004 and 2012. Metastatic SLNs were found in 348 patients – the retrospective group. Selective axillary lymph node dissection (ALND) was performed in 94% of cases. Involvement of the nSLNs was identified in 32.1% of patients following ALND. The correlation between nSLN involvement and selected epidemiological data, primary tumor features and details of the diagnostic and therapeutic management was examined in metastatic SLN group. Multivariate analysis was performed using an artificial neural network to create a new nomogram. The new test was validated using the overall study population consisting of the prospective group (365 patients – SLNB between 01–07.2013). Results Accuracy of the new test was calculated using area under the receiver operating characteristics curve (AUC). We obtained AUC coefficient equal to 0.87 (95% confidence interval: 0.81–0.92). Sensitivity amounted to 69%, specificity to 86%, accuracy – 80% (retrospective group) and 77%, 46%, 66% (validation group), respectively. The Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram the calculated AUC value was 0.71, for Stanford – 0.68, for Tenon – 0.67. Conclusions In the analyzed group only the MSKCC nomogram and the new model showed AUC values exceeding the expected level of 0.70. Our nomogram performs well in prospective validation on patient series. The overall assessment of clinical usefulness of this test will be possible after testing it on different patient populations.

Response to Barranger E, Ihrai T, response to the article by Thill et al.: "The Central-European SentiMag study: Sentinel lymph node biopsy with supermagnetic iron oxide (SPIO) vs. radioisotope". The Breast 2014, 23(2):175-9.

The documented procedure of magnetic SLN detection starts with a transcutaneous measurement to localize the optimal incision site. After incision the detection is completed by a subcutaneous measurement and on the excised SLN. At no time it is necessary to make contact between SLN and probe otherwise the obligatory transcutaneous measurement would be senseless. All these aspects are part of the obligatory product training on the use of the SentiMag.

Frey operation for chronic pancreatitis associated with pancreas divisum: case report and review of the literature

Pancreas divisum (PD) is the most common congenital anomaly of the pancreas, which increases susceptibility to recurrent pancreatitis. Usually, after failure of initial endoscopic therapies, surgical treatment combining pancreatic resection or drainage is used. The Frey procedure is used for chronic pancreatitis, but it has not been reported to be applied in an adult patient with PD-associated pancreatitis. The purpose of the paper was to describe effective treatment of this rare condition by the Frey procedure after failure of interventional endoscopic treatment. A 39-year-old female patient was initially treated for recurrent acute pancreatitis. After endoscopic diagnosis of PD, the minor duodenal papilla was incised and a plastic stent was inserted into the dorsal pancreatic duct. During the following 36 months, the patient was hospitalised several times because of recurrent episodes of pancreatitis. Thereafter, local resection of the pancreatic head combined with lateral pancreaticojejunostomy was performed with no complications. After 54 months of follow-up, the patient demonstrates abnormal glucose metabolism, with a need for enzyme supplementation, and she is free of pain. Local resection of the pancreatic head combined with lateral pancreaticojejunostomy (Frey procedure) offers a favourable outcome after failure of endoscopic papillotomy and duct stenting for pancreatitis associated with PD.

Prognostic value of p27kip1 expression in adenocarcinoma of the pancreatic head region

BACKGROUND p27(kip1) is a tumour suppressor gene, functioning as a cyclin-dependent kinase inhibitor, and an independent prognostic factor in breast, colon, and prostate adenocarcinomas. Conflicting data are reported for adenocarcinoma of the pancreas. The aim of this study was to establish the prognostic value of p27(kip1) expression in adenocarcinoma of the pancreatic head region. PATIENTS AND METHODS The study included 45 patients (male/female ratio 2:1; mean age 59, range 38-82 years) with adenocarcinomas of the pancreatic head region: 24 - pancreatic head, 18 - periampullary and 3 - uncinate process. The patients underwent the Kausch-Whipple pancreatoduodenectomy (n=39), pylorus-preserving pancreatoduodenectomy (n=5), or nearly total pancreatectomy (n=1). Eight patients received adjuvant chemotherapy postoperatively. Follow-up time ranged from 3 to 60 months. Tumours were staged according to the pTNM classification (UICC 1997). Immunohistochemistry was done on paraffin-embedded blocks from tumour sections. Quantitative determination of p27(kip1) expression was based on the proportion of p27(kip1) -positive cells (< 5% = negative). Survival analysis was carried out using the Kaplan-Meier method and Cox regression model. RESULTS Positive p27(kip1) expression was detected in 22 tumours (49%), whereas 23 tumours (51%) were p27(kip1)-negative. There were no significant correlations between p27(kip1) index and stage or lymph node involvement. Median survival time in patients with p27(kip1)-positive tumours was 19 months, whereas in patients with p27(kip1)-negative tumours it was 18 months (p=0.53). A significant relationship was found between p27(kip1)-negative tumours and radical resection (p=0.04). Multivariate survival analysis revealed that the localization of the tumour (pancreatic head/uncinate process vs periampullary) was the only significant and independent prognosticator (p = 0.01, Cox regression model). Resection margins involvement and grade remained nearly significant prognostic factors (p=0.07 and p=0.09, respectively). CONCLUSION We conclude that p27(kip1) has limited overall prognostic utility in resected carcinoma of the pancreatic head region, but its potential role as a marker of residual disease needs to be further assessed.

Intraoperative radiotherapy with low energy photons in recurrent colorectal cancer: a single centre retrospective study

Aim of the study Intraoperative radiotherapy (IORT) may improve outcome of surgical treatment of recurrent colorectal cancer (CRC). The aim of this study is to determine the feasibility, safety and long-term results of surgical treatment of recurrent CRC with orthovolt IORT. Material and methods Fifty-nine consecutive CRC patients with local recurrence (LR), undergoing surgery, were included in the retrospective analysis of prospectively collected data. The modified Wanebo classification was used to stage LR (Tr). Twenty-five (43%) patients received IORT using INTRABEAM® PRS 500. The complications were classified according to the Clavien-Dindo classification. Results There were 32 males and 27 females, with a median age of 63 years. Multi-visceral resections were performed in 37 (63%) patients. Median hospitalization time after surgery with IORT was 7 days. One (1.7%) in-hospital postoperative death was reported. Grade 3/4 postoperative complications were found in 11 (19%) patients. Intraoperative radiotherapy had no effect on the postoperative hospitalization time, morbidity and mortality. Median survival after R0 resection was 32 months. Complete resection (R0), no synchronous liver metastases (M0), and no lateral and posterior pelvic wall involvement, were significant predictors of improved survival. Stage of LR was found to be an independent prognostic factor in the multivariate analysis (p = 0.03); Cox regression model). In patients with LR stage < Tr5, a 3-year overall survival (OS) rate was 52%. Conclusions Combination of surgical resection and orthovolt IORT is a safe and feasible procedure that does not increase the risk of postoperative complications or prolongs the hospital stay. Despite aggressive surgery supported by IORT, the advanced stage of LR is a limiting factor of long-term survival.

Duodenal obstruction due to annular pancreas associated with carcinoma of the duodenum

Annular pancreas, the second most common anomaly of the pancreas, is the development of a ring of pancreatic tissue that surrounds and often embraces the duodenum. It was first described by Tiedelmann in 1818 and named “annular pancreas” by Ecker in 1862 [1]. It is usually present in childhood, with symptoms due to duodenal obstruction. In 50% of cases, clinical manifestations become visible after childhood, with abdominal pain, chronic duodenal obstruction, peptic ulceration, obstructive jaundice, pancreatitis, and pancreatic head mass [2, 3]. Therefore, duodeno-jejunostomy is usually applied to relieve strictures caused by such an annulus. Bypass surgery is the treatment of choice [4]. Primary duodenal carcinoma is rare and represents 0.3% of all gastrointestinal malignancies and 25–35% of malignant tumours of the small intestine [5, 6]. Resectability and the presence of distant metastatic disease are the strongest determinants of outcome for patients with duodenal adenocarcinoma. In cases of cancers of the first and second part of the duodenum, the most common procedure is pancreaticoduodenectomy. Despite advancements in techniques of diagnosis and resection and decreased perioperative mortality and morbidity, 5-year survival varies from 37% [7] to 57% [8]. Malignancy in the setting of annular pancreas is an unusual event, and hence only a few cases associated with pancreatic carcinoma, ampullary carcinoma, and cholangiocarcinoma have been reported [9–13]. Only 1 case of annular pancreas associated with duodenal carcinoma has been reported, but without description of the follow-up [14]. We report a case of duodenal carcinoma in a patient with an annular pancreas treated with radical surgery with complete follow-up data. A 53-year-old lady suffered from nausea, post-prandial fullness, and vomiting, and weight loss. She was diagnosed (endoscopy Figure 1, CT scan of the abdomen Figure 2) to have duodenal obstruction with gastric bezoar. The upper intestinal contrast study findings of annular filling defect in the duodenum, prestenotic dilatation, and reverse peristalsis in the proximal segment were suggestive of annular pancreas. A pathology report of the endoscopic biopsy material taken from the stenotic part of the duodenum revealed suspicion of malignancy, i.e. atypic cells. The patient was scheduled for a laparotomy with intraoperative pathological investigation of the suspected lesion, and if malignancy is proven a pancreaticoduodenectomy is anticipated. During the operation a band of fibrous (probably pancreatic) tissue of hard texture encircling the second part of the duodenum was found (Figure 3). Division of the pancreatic ring was done and the abnormal tissue sent for immediate pathology. Once malignant diagnosis was confirmed, and classical Kausch-Whiple pancreaticoduodenectomy with standard lymphadenectomy was done without perioperative complications. The resection specimen had been routinely fixed in buffered 10% formaldehyde and embedded in paraffin wax (Figure 4). Operative time was 300 min, and blood loss was 420 ml. The postoperative course was uneventful; therefore, the patient was discharged from the hospital on the sixteenth postoperative day. A definitive pathological report confirmed tubular carcinoma (G2) of the duodenum associated with the annular pancreas with no lymph node involvement (pT2N0M0) (Figures 5–8). No adjuvant chemotherapy was administered. The patient was followed-up every 3 months thereafter for the first 3 years. In the first (2008) and second year (2009) of the follow-up, abdominal CT-scan was done without signs of recurrence. After 54 months the patient became heavily jaundiced and cachectic, and was therefore hospitalised. Advanced loco-regional recurrence was found on MR cholangiogram, with no liver metastases. The patient died, and no autopsy was performed. Figure 1 Endoscopic view of the duodenum showing ulceration with duodenal stenosis at the second portion Figure 2 Computed tomography scan image revealing a significant dilatation of the stomach with bezoar and the proximal duodenum Figure 3 Intraoperative view of the annular pancreas encircling the second part of the duodenum Figure 4 Cross-sectional view showing the duodenum surrounded by the pancreas tissue (annular pancreas) Figure 5 Tubular adenocarcinoma of the duodenum. Neoplastic tubules border on normal duodenal glands (four-micron sections of representative blocs of the lesion were stained with haematoxylin and eosin (H + E); 100×) Figure 8 Fragment of the pancreas (annular pancreas), which is not involved in cancerous infiltrate (H + E; 100×) Figure 6 Tubular adenocarcinoma of the duodenum. Neoplastic tubules border on normal duodenal glands (four-micron sections of representative blocs of the lesion were stained with haematoxylin and eosin (H + E); 200×) Figure 7 Neoplastic infiltrate of the muscular coat of the duodenum encompasses both an inner circular layer and an outer longitudinal layer (H + E; 100×) Annular pancreas is a rare congenital abnormality, and in adult patients it presents with clinical features that differ from those seen in newborns [15]. Duodenal obstruction is a rare symptom of annular pancreas in adults. It is necessary to remember about the coexistence of the annular pancreas when patients with pancreatic or periampullary malignancies are complicated with unexpected obstruction of the second portion of the duodenum in proportion to the size [9]. Features in the adult patient include peptic ulceration, duodenal obstruction, acute pancreatitis, and obstructive jaundice. Treatment strategies for annular pancreas with obstructive jaundice remain controversial, but usually pancreaticoduodenectomy is necessary [2]. In adult patients pancreatic head malignancy usually produces jaundice, and more rarely duodenal obstruction. Nearly always the main cause of this clinical picture is pancreatic head carcinoma, but pancreas annulare should be taken into consideration. The duodenal ring should always be verified on pathological examination since it may harbour this rare type of adenocarcinoma. In adult patients with duodenal obstruction due to annular pancreas, consideration of associated or coexisting duodenal malignancy is mandatory. Only radical surgery (pancreaticoduodenectomy) may provide long-term survival in such cases.

Melanoma and other malignant skin cancers in psoriatic patients treated with phototherapy. Role of the p16 protein in psoriasis

Recently, the potential risk of malignant skin cancer development in psoriatic patients has been highlighted. It seems that some pathogenetic factors in psoriasis could predispose to a malignant transformation. So far, the relationship between the therapeutic schemes in psoriasis and possible neoplastic transformation has not been clearly explained. The phototherapy is considered a very effective therapeutic method in psoriasis, however, the pathogenesis of some malignancies is associated with the exposure to UV radiation. One of the defence mechanisms that protect the cells from damaging and mutagenic factors, such as UV radiation, seems to be the p16 protein. Moreover, in recent years, the altered expression of the p16 protein in the diseases not related to malignant transformation, including psoriasis, has been observed. The new hypothesis suggesting a participation of the p16 protein in psoriatic plaque formation has appeared.

Imaging methods for the local lymphatic system of the axilla in early breast cancer in patients qualified for sentinel lymph node biopsy

Breast cancer is the most common malignancy in women in well-developed countries. Despite a constant increase in its incidence, the percentage of patients diagnosed with the disease in the non-invasive stage is also rising. This allows more frequently for the use of breast-preserving surgical techniques, involving the breast and the regional lymphatic system. According to current guidelines of expert panels and research societies, the recommended method of identifying the sentinel lymph node is the use of an isotope marker with a dye (a combined isotope and dye method). Cooperation with a nuclear medicine unit is essential (performing a preoperative lymphoscintigraphic scan to identify the lymphatic drainage basin and sentinel lymph node). In the case of smaller centers treating breast cancer, it can be associated with a number of difficulties, including organizational ones, and also increasing general treatment costs. A possible solution to these problems is to use alternative techniques of visualizing the sentinel lymph node, which do not require a radiotracer. In this paper we discuss the currently available methods of mapping the lymphatic system of the axillary region in patients with early breast cancer. The review is limited to reporting on methods of proven (based on clinical research) high diagnostic value.

Treatment of peritoneal surface neoplasms with intraperitoneal chemotherapy in hyperthermia

Abstract Effective treatment of peritoneal surface neoplasms is possible through the simultaneous use of cytoreductive surgery with intraperitoneal chemotherapy in hyperthermia. It is successfully performed in patients with peritoneal pseudomyxoma, mesothelioma, as well as a limited and resectable peritoneal carcinomatosis in the course of colorectal cancer. It can also be used in patients with gastric or ovarian cancer but also metastatic colorectal cancer or metastases to the ovaries from gastric cancer. Aggressive surgical management of patients with primary or secondary neoplasms of the peritoneal surface was initiated by Sugarbaker’s research group.