Copy Number Variations (CNVs) Account for 10.8% of Pathogenic Variants in Patients Referred for Hereditary Cancer Testing.

BACKGROUND/AIM: Germline copy number variation (CNV) is a type of genetic variant that predisposes significantly to inherited cancers. Today, next-generation sequencing (NGS) technologies have contributed to multi gene panel analysis in clinical practice. MATERIALS AND METHODS: A total of 2,163 patients were screened for cancer susceptibility, using a solution-based capture method. A panel of 52 genes was used for targeted NGS. The capture-based approach enables computational analysis of CNVs from NGS data. We studied the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and of the non-commercial tool panelcn.MOPS. Additionally, we tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA). RESULTS: Pathogenic/likely pathogenic variants (P/LP) were identified in 464 samples (21.5%). CNV accounts for 10.8% (50/464) of pathogenic variants, referring to deletion/duplication of one or more exons of a gene. In patients with breast and ovarian cancer, CNVs accounted for 10.2% and 6.8% of pathogenic variants, respectively. In colorectal cancer patients, CNV accounted for 28.6% of pathogenic/likely pathogenic variants. CONCLUSION: In silico CNV detection tools provide a viable and cost-effective method to identify CNVs from NGS experiments. CNVs constitute a substantial percentage of P/LP variants, since they represent up to one of every ten P/LP findings identified by NGS multigene analysis; therefore, their evaluation is highly recommended to improve the diagnostic yield of hereditary cancer analysis.

Surgery with hyperthermic intraperitoneal chemotherapy after response to induction chemotherapy in patients with peritoneal metastasis of gastric cancer.

BACKGROUND: Gastric cancer (GC) with peritoneal metastases (PM) has a dismal prognosis and to date only a few management options have been reported. Of those, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) after induction bidirectional intraperitoneal and systemic chemotherapy (BIPSC) appear as a promising treatment option for these patients. Outcome data including safety and efficacy of CRS with radical Gastrectomy and HIPEC after response to combination of laparoscopic HIPEC (LHIPEC) with BIPSC as an induction therapy in patients with PM of GC was evaluated in this retrospective observational study. METHODS: Diagnostic Laparoscopy was performed in 53 patients with PM of GC who admitted to the Center for Treatment of Peritoneal Surface Malignancies, Istanbul, between 2013 and 2016. Peritoneal cancer index (PCI), ascites status and cytology were determined. The patients underwent LHIPEC and then, BIPSC induction chemotherapy using intraperitoneal docetaxel (30 mg/m2) and cisplatin (30 mg/m2) and intravenous Docetaxel/Cisplatin/5-Fluorouracil (DCF) for 3 cycles. In selected patients, CRS with radical gastrectomy and HIPEC were performed after the response to induction therapy. BIPSC was continued for 3 more cycles with a dose reduction in an adjuvant setting. RESULTS: All LHIPEC procedures were uneventful with Grade 1-2 side effects (11/53, 20,8%). As a response to induction chemotherapy PCI was reduced from 19.6±8 (range, 6-39) to 13.6±9.8 (range, 1-39) (P<0.001). Ascites was detected in 55% (29 out of 53) and cytology was positive in 51% (27 out of 53) of the patients before induction chemotherapy. Ascites was completely abolished and all cytology became negative. Then, 34 of 53 (64.15%) patients underwent CRS with radical gastrectomy and HIPEC. CC0/1 resection was achieved in 22 (64.70%) of patients (P<0.05). The median survival time was 18.9±13.4 (95% CI: 15.2-22.6 months. Combined surgery and HIPEC related mortality occurred in 1 out of 34 patients (2.9%) due to developed diffuse intravascular coagulation at postoperative day 2. Grade 2 operative complications included biliary fistula in one, and duodenal stump leakage in two patients (8.7%). All of the fistula closed with conservative management. The median survival time was 18.9±13.4 months and the median progression-free survival time was 15.6±12.9 with 1-, 2-, and 5-year survival rates of 82.4%, 59% and 17.6% in patients with PM of GC. Multivariate analysis identified high peritoneal cancer index (P=0.000) and complete resection (P<0.05) as independent predictors for better progression-free and overall survival. CONCLUSIONS: The best outcomes can be expected with optimal cytoreduction and limited peritoneal dissemination in response to induction chemotherapy. Knowledgeable selection of patients with PM of GC is essential to perform surgery with HIPEC safely with acceptable mortality and morbidity.

Clinical Utility of Functional RNA Analysis for the Reclassification of Splicing Gene Variants in Hereditary Cancer.

BACKGROUND: Classification of splicing variants (SVs) in genes associated with hereditary cancer is often challenging. The aim of this study was to investigate the occurrence of SVs in hereditary cancer genes and the clinical utility of RNA analysis. MATERIAL AND METHODS: 1518 individuals were tested for cancer predisposition, using a Next Generation Sequencing (NGS) panel of 36 genes. Splicing variant analysis was performed using RT-PCR and Sanger Sequencing. RESULTS: In total, 34 different SVs were identified, 53% of which were classified as pathogenic or likely pathogenic. The remaining 16 variants were initially classified as Variant of Uncertain Significance (VUS). RNA analysis was performed for 3 novel variants. CONCLUSION: The RNA analysis assisted in the reclassification of 20% of splicing variants from VUS to pathogenic. RNA analysis is essential in the case of uncharacterized splicing variants, for proper classification and personalized management of these patients.

Primary Retroperitoneal Müllerian Adenocarcinoma: Report of Two Cases Treated With Radical Surgery.

BACKGROUND: Primary retroperitoneal Müllerian adenocarcinoma (PRMA) is a very rare type of primary retroperitoneal tumour. CASE 1: A 45-year-old woman presented with left lower extremity swelling and pain. Imaging revealed that the tumour had invaded the left common iliac vein and artery, internal and external iliac arteries, sciatic and obturator nerves, and pelvic wall. CASE 2: A 37-year-old was admitted with pelvic pain. Imaging showed the tumor at the left iliac bifurcation infiltrating the internal iliac artery and left sciatic, obturator, and femoral nerves. Both of these patients were treated with radical surgery that achieved no visible tumour at the end of the operation. CONCLUSION: There is no guideline for the diagnosis and management of this entity due to its rarity. These cases should be managed at highly specialized centres with expertise in radical surgery.

Dealing with the gray zones in the management of gastric cancer: The consensus statement of the Istanbul Group.

The geographical location and differences in tumor biology significantly change the management of gastric cancer. The prevalence of gastric cancer ranks fifth and sixth among men and women, respectively, in Turkey. The international guidelines from the Eastern and Western countries fail to manage a considerable amount of inconclusive issues in the management of gastric cancer. The uncertainties lead to significant heterogeneities in clinical practice, lack of homogeneous data collection, and subsequently, diverse outcomes. The physicians who are professionally involved in the management of gastric cancer at two institutions in Istanbul, Turkey, organized a consensus meeting to address current problems and plan feasible, logical, measurable, and collective solutions in their clinical practice for this challenging disease. The evidence-based data and current guidelines were reviewed. The gray zones in the management of gastric cancer were determined in the first session of this consensus meeting. The second session was constructed to discuss, vote, and ratify the ultimate decisions. The identification of the T stage, the esophagogastric area, imaging algorithm for proper staging and follow-up, timing and patient selection for neoadjuvant treatment, and management of advanced and metastatic disease have been accepted as the major issues in the management of gastric cancer. The recommendations are presented with the percentage of supporting votes in the results section with related data.

Management of sentinel node re-mapping in patients who have second or recurrent breast cancer and had previous axillary procedures.

BACKGROUND: In patients with recurrent or second primary ipsilateral breast cancer, axillary staging is the key factor in locoregional control and a strong prognostic characteristic. The efficient evaluation of lymphatic drainage of re-sentinel lymph node biopsies (re-SLNBs) has remained a challenge in the management of ipsilateral primary or recurrent breast cancer patients who are clinically lymph node negative. This study explores whether a SLNB for patients with primary or recurrent breast cancer is possible after previous axillary surgery. It evaluates potential reasons for mapping failure that might be associated with patients in this group. METHODS: Between March 2006 and November 2013, 458 patients were subjected to a breast SLNB. A lymphoscintigraphy procedure was performed on 330 patients for sentinel lymph node (SLN) mapping on the day of surgery. Seven patients with either a second primary cancer in the same breast or recurrent breast cancer were described. Two of these seven patients had axillary lymph node dissection (ALND) during previous treatments and five had SLNB. A dual mapping method was used for all patients. Preoperative lymphoscintigraphy was performed four hours before surgery. RESULTS: SLNs were successfully remapped in six of seven (85.7%) patients, of whom five (71.43%) had previously undergone SLNB and two (28.57%) previous ALND. Localizations of SLNs were ipsilateral axillary in three patients, ipsilateral internal mammary in one patient, and contralateral axillary in two patients. An altered distribution of lymph nodes was discovered in both patients with previous ALND. In one of the two patients, metastases were found in an aberrant lymph drainage basin at the location of a non-ipsilateral axillary node (contralateral axillary SLN). The second previously ALND patient had an internal mammary SLN. In one patient, mapping was unsuccessful and the SLN was not identified. CONCLUSIONS: Altered lymphatic drainage incidence increases following breast-conserving surgery for an initial breast cancer, and the location of SLNs becomes unpredictable at the time of a second primary or recurrent ipsilateral breast cancer. This leads to the necessity of using a radionuclide (lymphoscintigraphy) for a successful re-mapping procedure. A re-SLNB is precise and beneficial even though there are few patients. A lymphoscintigraphy can identify SLNs at their new unpredicted location.

Actinomycotic hepatic abscess.

Actinomycotic hepatic abscess was diagnosed in a 46-year-old male driver from Ukraine presenting with the symptoms of malaise, loss of appetite, upper right quadrant pain, weight loss, and night sweats which had been present for last 2 months. Computed tomography (CT) of the abdomen revealed a hypodense mass in the left liver lobe which was suspected as hepatocellular carcinoma. Histopathological examination of the CT guided biopsy specimen yielded a diagnosis of actinomycotic abscess of the liver. Treatment with intravenous penicillin for 6 weeks followed by a course of oral penicillin for 14 weeks resulted in complete cure as evidenced by clinical improvement and radiological disappearance of the lesion.

Angiogenesis as a target for cancer therapy.

Antiangiogenic drugs are unique for having highly specific targets while carrying the potential to be effective against a wide variety of tumors. Moreover, some of the major limitations of cytotoxic therapies likely will be avoided by this entirely new class of anticancer weapons. After the realization of the potential advantages of antiangiogenic therapy, the field of angiogenesis research is growing exponentially. Still, there is much to learn about the machinery that tumors use to recruit new blood vessels, and the results of the clinical trials will show the best way to apply that knowledge for cancer therapy.