"WATCH AND WAIT" STRATEGY IN RECTAL CANCER PATIENTS WITH A COMPLETE CLINICAL RESPONSE AFTER NEOADJUVANT CHEMORADIATION THERAPY: A SINGLE-CENTER EXPERIENCE.

BACKGROUND: The non-operative management of rectal adenocarcinoma (RA) after neoadjuvant chemoradiation therapy (nCRT) has gained increasing attention. The "Watch and Wait" ("W&W") strategy allows one to avoid surgery-related reduction in the quality of life due to permanent pelvic organ dysfunction or irreversible stoma. Still, the oncological safety of this strategy is under evaluation. AIM: To share a single-center experience of the "W&W" strategy. MATERIALS AND METHODS: The retrospective analysis of 125 patients who received nCRT in 2016-2021 was performed. Patients who met the European Society for Medical Oncology (ESMO, 2017) criteria of clinical complete response (cCR) and received non-operative management were analyzed. RESULTS: Ten patients (8%) were re-staged after nCRT as cCR and followed the "W&W" strategy. Patients' characteristics: 7 female, 3 male; mean age 67.3 years. Tumor characteristics: pre-treatment N+ was present in 7 cases; G1 adenocarcinoma in a majority of cases; mean tumor distance from the anal verge - 5.85 cm; mean tumor circumference - 71%; mean tumor length - 3.87 cm. The mean follow-up time was 30 months. Local regrowth or/and distant metastases developed in 3 cases. The 2-year disease-free survival was 70%. CONCLUSIONS: Most of the patients following the "W&W" strategy have benefited. However, to reduce the number of relapses, it is necessary to perform a more careful selection of patients.

A novel frequent BRCA1 recurrent variant c.5117G > A (p.Gly1206Glu) identified after 20 years of BRCA1/2 research in the Baltic region: cohort study and literature review.

BACKGROUND: Several recent studies in the Baltic region have found extended spectrum of pathogenic variants (PV) of the BRCA1/2 genes. The aim of current study is to analyze the spectrum of the BRCA1/2 PV in population of Latvia and to compare common PV between populations of the Baltic region. METHODS: We present a cohort of 9543 unrelated individuals including ones with cancer and unaffected individuals from population of Latvia, who were tested for three most common BRCA1 founder PV. In second line testing, 164 founder negative high-risk individuals were tested for PV of the BRCA1/2 using next generation sequencing (NGS). Local spectrum of the BRCA1/2 PV was compared with the Baltic region by performing a literature review. RESULTS: Founder PV c.5266dupC, c.4035delA or c.181 T > G was detected in 369/9543 (3.9%) cases. Other BRCA1/2 PV were found in 44/164 (26.8%) of NGS cases. Four recurrent BRCA1 variants c.5117G > A (p.Gly1706Glu), c.4675G > A (p.Glu1559Lys), c.5503C > T (p.Arg1835*) and c.1961delA (p.Lys654fs) were detected in 18/44 (41.0%), 5/44 (11.4%), 2/44 (4.5%) and 2/44 (4.5%) cases respectively. Additionally, 11 BRCA1 PV and six BRCA2 PV were each found in single family. CONCLUSIONS: By combining three studies by our group of the same cohort in Latvia, frequency of the BRCA1/2 PV for unselected breast and ovarian cancer cases is 241/5060 (4.8%) and 162/1067 (15.2%) respectively. The frequency of three "historical" founder PV is up to 87.0% (369/424). Other non-founder PV contribute to at least 13.0% (55/424) and this proportion probably will rise by increasing numbers of the BRCA1/2 sequencing. In relative numbers, c.5117G > A is currently the third most frequent PV of the BRCA1 in population of Latvia, overcoming previously known third most common founder variant c.181 T > G. In addition to three BRCA1 founder PV, a total of five recurrent BRCA1 and two recurrent BRCA2 PV have been reported in population of Latvia so far. Many of the BRCA1/2 PV reported in Latvia are shared among other populations of the Baltic region.

Omadacycline for Acute Bacterial Skin and Skin-Structure Infections.

BACKGROUND: Acute bacterial skin and skin-structure infections are associated with substantial morbidity and health care costs. Omadacycline, an aminomethylcycline antibiotic that can be administered once daily either orally or intravenously, is active against pathogens that commonly cause such infections, including antibiotic-resistant strains. METHODS: In this double-blind trial, we randomly assigned adults with acute bacterial skin and skin-structure infections (in a 1:1 ratio) to receive omadacycline (100 mg given intravenously every 12 hours for two doses, then 100 mg given intravenously every 24 hours) or linezolid (600 mg given intravenously every 12 hours). A transition to oral omadacycline (300 mg every 24 hours) or oral linezolid (600 mg every 12 hours) was allowed after 3 days; the total treatment duration was 7 to 14 days. The primary end point was an early clinical response at 48 to 72 hours, defined as survival with a reduction in lesion size of at least 20% without rescue antibacterial therapy. A secondary end point was an investigator-assessed clinical response at the post-treatment evaluation 7 to 14 days after the last dose, with clinical response defined as survival with resolution or improvement in signs or symptoms of infection to the extent that further antibacterial therapy was unnecessary. For both end points, the noninferiority margin was 10 percentage points. RESULTS: In the modified intention-to-treat population, omadacycline (316 patients) was noninferior to linezolid (311 patients) with respect to early clinical response (rate of response, 84.8% and 85.5%, respectively; difference, -0.7 percentage points; 95% confidence interval [CI], -6.3 to 4.9). Omadacycline also was noninferior to linezolid with respect to investigator-assessed clinical response at the post-treatment evaluation in the modified intention-to-treat population (rate of response, 86.1% and 83.6%, respectively; difference, 2.5 percentage points; 95% CI, -3.2 to 8.2) and in the clinical per-protocol population (96.3% and 93.5%, respectively; difference, 2.8 percentage points; 95% CI, -1.0 to 6.9). In both groups, the efficacy of the trial drug was similar for methicillin-susceptible and methicillin-resistant Staphylococcus aureus infections. Adverse events were reported in 48.3% of the patients in the omadacycline group and in 45.7% of those in the linezolid group; the most frequent adverse events in both groups were gastrointestinal (in 18.0% and 15.8% of the patients in the respective groups). CONCLUSIONS: Omadacycline was noninferior to linezolid for the treatment of acute bacterial skin and skin-structure infections and had a similar safety profile. (Funded by Paratek Pharmaceuticals; OASIS-1 ClinicalTrials.gov number, NCT02378480 .).

High frequency of pathogenic non-founder germline mutations in BRCA1 and BRCA2 in families with breast and ovarian cancer in a founder population.

BACKGROUND: Pathogenic BRCA1 founder mutations (c.4035delA, c.5266dupC) contribute to 3.77% of all consecutive primary breast cancers and 9.9% of all consecutive primary ovarian cancers. Identifying germline pathogenic gene variants in patients with primary breast and ovarian cancer could significantly impact the medical management of patients. The aim of the study was to evaluate the rate of pathogenic mutations in the 26 breast and ovarian cancer susceptibility genes in patients who meet the criteria for BRCA1/2 testing and to compare the accuracy of different selection criteria for second-line testing in a founder population. METHODS: Fifteen female probands and 1 male proband that met National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing were included in the study and underwent 26-gene panel testing. Fourteen probands had breast cancer, one proband had ovarian cancer, and one proband had both breast and ovarian cancer. In a 26-gene panel, the following breast and/or ovarian cancer susceptibility genes were included: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. All patients previously tested negative for BRCA1 founder mutations. RESULTS: In 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in BRCA1, and one proband carried pathogenic mutations in BRCA2. In patients, a variant of uncertain significance was found in BRCA2, RAD50, MRE11A and CDH1. The Manchester scoring system showed a high accuracy (87.5%), high sensitivity (85.7%) and high specificity (88.9%) for the prediction of pathogenic non-founder BRCA1/2 mutations. CONCLUSION: A relatively high incidence of pathogenic non-founder BRCA1/2 mutations was observed in a founder population. The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.

Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a Phase 3, double-blind, randomized study.

BACKGROUND: Delafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms. OBJECTIVES: To establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials. PATIENTS AND METHODS: A Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300 mg or vancomycin 15 mg/kg plus aztreonam 2 g each administered twice daily intravenously for 5-14 days. Non-inferiority was evaluated by objective response (≥20% erythema reduction) at 48-72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71. RESULTS: In the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, -2.6%; 95% CI, -8.78% to 3.57%). Investigator-assessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/aztreonam group, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%). CONCLUSIONS: Delafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48-72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections.

Impact of KRAS variant rs61764370 on breast cancer morbidity.

UNLABELLED: Low-penetrance gene variants and their combinations are topical study objects in breast cancer pathogenesis. Single nucleotide polymorphism rs61764370, localized in 3՛ UTR of KRAS gene, plays an important role in the development and progression of several cancers. The aim of our study was to determine the KRAS variant impact on breast cancer morbidity. PATIENTS AND METHODS: 2214 patients diagnosed with breast cancer and 861 healthy controls were screened for KRAS variant by RFLP method. Available clinical data were collected and processed using statistical analysis methods. Results of present study suggest the KRAS variant impact on breast cancer development risk in premenopausal women, but it has no effect on breast cancer prognosis. We did not observe any KRAS variant effect on breast cancer patient 10-year disease-specific survival rates.

Survival rates of familial and sporadic prostate cancer patients.

AIM: To compare cancer-specific survival rates for familial and sporadic prostate cancer patients. MATERIALS AND METHODS: Gleason score and age at diagnosis of familial group and sporadic group were compared by χ(2) and t-test. Cancer-specific survival rates were analyzed by the Kaplan - Meier method and compared by log-rank test. Statistically significant level was set at p < 0.05. RESULTS: Among 1175 prostate cancer patients, familial group consisted of 215 (18.3%) patients, the sporadic group consisted of 960 (81.7%) patients. The familial group patient's mean age at diagnosis (58.9 years old, 95% confidence interval (CI) 57.8-60.1) was significantly younger than that of sporadic group patients (67.2 years old, 95% CI 66.7-67.6) (p < 0.0001). Comparing Gleason score between familial group and sporadic group revealed no statistically significant difference. The analysis showed that 92% (95% CI 0.88-0.97) of familial group patients had a 10-year cancer-specific survival rates, which was a significantly better outcome than that of sporadic group with 69% (95% CI 0.60-0.78) 10-year cancer-specific survival rates (p = 0.0237). CONCLUSION: The study data demonstrate statistically significant difference between familial group and sporadic group concerning age and cancer-specific survival rates, but not Gleason score.

The CHEK2 del5395 is a founder mutation without direct effects for cancer risk in the latvian population.

Our objective was to determine: 1) whether the checkpoint kinase 2 (CHEK2) del5395 (g.27417113-27422508 del, NC_000022.11) is a founder mutation in the Latvian population, 2) if there is an association between CHEK2 del5395 mutation and cancer risk, and 3) and whether the CHEK2 del5395 mutation impacts cancer predisposition in Chernobyl disaster liquidators (the civil and military personnel who were called upon to deal with consequences of the 1986 nuclear disaster) as well as geriatric populations. We recruited 438 breast cancer patients, 568 colorectal cancer patients, 399 ovarian cancer patients, 419 prostate cancer patients, 526 healthy blood donors, 480 Chernobyl disaster liquidators and 444 geriatric cancer-free participants. DNA samples were isolated from blood samples and subjected to multiplex polymerase chain reaction (PCR). The truncation of del5395 was estimated by fragment size of the multiplex PCR.All groups were compared to the healthy blood donors using Fisher's exact test. All p values were two-sided and the odds ratios (OR) calculated by two-by-two table. In cancer groups, the del5395 mutation was most frequently observed in the ovarian cancer group (1.00%, OR = 1.32). In control groups, the del5395 mutation was most frequent (0.76%) in the healthy donors, which exceeded its frequency in the Chernobyl liquidators group and the geriatric group by 0.01 and 0.08%, respectively. For all groups, the OR appeared to be >1 only in ovarian cancer patients. However, OR rates showed no statistical significance in either cancer or control groups, with the p value fluctuating within the range of 0.39-1.00. The CHEK2 gene del5395 is a founder mutation in the Latvian population, which, however, does not have a direct impact on genetic predisposition toward colorectal, breast, ovarian and prostate cancer.

Von hippel-lindau syndrome: diagnosis and management of hemangioblastoma and pheochromocytoma.

Introduction. Von Hippel-Lindau (VHL) syndrome is a pathological condition that causes various clinical symptoms and is difficult to diagnose. The most common pathological lesions are hemangioblastomas of the central nervous system, retinal angiomas, renal clear cell carcinomas, and pheochromocytomas. Case Report. A 23-year-old female had a syncope episode in 2008. Magnetic resonance imaging (MRI) revealed a right temporal hemangioblastoma, which was treated surgically. Genetic screening identified a VHL gene mutation, and computed tomography (CT) revealed a left adrenal mass. Since it was unclear whether the mass was a pheochromocytoma, or another benign or malignant tumors, laparoscopic adrenalectomy was performed. A month after surgery, the patient complained of general fatigue, poor concentration, loss of appetite, and insomnia. After careful clinical investigation, the patient was referred to a psychiatrist due to suspected depression, which was confirmed. Conclusions. VHL genetic screening should be performed in cases of hemangioblastoma. In VHL syndrome cases, pheochromocytoma cannot always be diagnosed by biochemical catecholamine analyses; therefore, CT or MRI scanning of the abdomen must be performed. Due to the long treatment period, some patients may develop episodes of depression, which can simulate VHL syndrome.

Novel germline MLH1 and MSH2 mutations in Latvian Lynch syndrome families.

BACKGROUND/AIMS: Hereditary non-polyposis colorectal cancer or Lynch syndrome is an autosomal dominantly inherited disease with high penetrance, mostly due to mutations in the MLH1 and MSH2 genes. The aim of this study is to investigate the mutation spectrum of the MLH1 and MSH2 genes. METHODOLOGY: High risk colorectal cancer families were selected from overall 1053 consecutive patients. Screening of germline mutations in the MLH1 and MSH2 was performed by direct sequencing and multiplex ligation-dependent probe amplification. RESULTS: Ten patients fulfilled the Amsterdam I/II criteria and Bethesda guidelines of the Lynch syndrome. Three novel mutations were identified in MLH1 and MSH2 genes, as well as two known mutations in the MLH1 gene. Large rearrangements in the MLH1 gene were found in two patients. CONCLUSIONS: The mutations in the MLH1 and MSH2 genes in Latvian high-risk families are highly heterogeneous. Combination of direct sequencing and MLPA is the most appropriate molecular method of detecting hereditary nonpolyposis colorectal cancer patients and family members at risk.

Overview of tigecycline efficacy and safety in the treatment of complicated skin and skin structure infections - a European perspective.

In a randomized, double-blind, multicenter, multinational, controlled trial, 546 patients with complicated skin and skin structure infections received tigecycline 100 mg/day (a 100-mg initial dose and then 50 mg intravenously twice daily) or the combination of vancomycin 2 g/day (1 g intravenously twice daily) and aztreonam 4 g/day (2 g intravenously twice daily) for up to 14 days. Three hundred eighty-five (385) were from Europe. The primary endpoint was the clinical response in the clinical modified intent-to-treat (c-mITT) and clinically evaluable populations at the test-of-cure visit 12 to 92 days after the last dose. The microbiologic response at the test-of-cure visit was also assessed. Safety was assessed by physical examination, laboratory results and adverse event reporting. Of the patients enrolled in Europe, 376 patients were included in the c-mITT population (tigecycline group, n = 189; vancomycin/aztreonam group, n = 187), and 326 were clinically evaluable (tigecycline group, n = 167; vancomycin/aztreonam group, n = 159). The clinical responses in the tigecycline and the vancomycin/aztreonam groups in the clinically evaluable population were 89.8% versus 95.0%. Microbiologic eradication (documented or presumed) occurred in 84.8% of the European patients receiving tigecycline and 93.2% of the European patients receiving vancomycin/aztreonam. The number of European patients reporting adverse events was similar in the two groups, with increased nausea and vomiting rates in the tigecycline group and an increased incidence of rash and increases in alanine aminotransferase and aspartate aminotransferase levels in the vancomycin/aztreonam group. Current data support findings from the overall results in the Phase 3 study and suggest that tigecycline is safe and effective for the treatment of complicated skin and skin structure infections.

A comparison of quality of life and postoperative results from combined PPH and conventional haemorrhoidectomy in different cases of haemorrhoidal disease.

OBJECTIVE: To compare the early postoperative results and late patient-related postoperative results by a Short-Form 36 quality of life survey after conventional haemorrhoidectomy and PPH procedure with additional surgical intervention in noncomplicated, complicated and delayed cases of the disease. METHOD: The comparison was made between comparable patient groups after conventional haemorrhoidectomy (n = 168) and after PPH with additional surgical intervention (n = 142). The early and late postoperative results and quality of life analysis according to SF-36 questionnaire were compared. RESULTS: The length of procedure was significantly shorter after the PPH procedure (37.4 vs 49.4 min). The amount of postoperative nonopiate analgesics was similar, but consumption of opiates was more in the conventional group. The rate of early postoperative complications was similar. In the PPH group significant improvement in all quality of life parameters was ascertained 6 months after operation, but 6 weeks after surgery several parameters in this group were lower. In the conventional group improvement was ascertained only for several parameters. The significant improvement of quality of life after PPH operations was ascertained especially at a mean period of 6 weeks. CONCLUSION: The PPH procedure performed in complex cases of the disease and combined with other surgical intervention because of the anorectal comorbidity assures better early postoperative results and better postoperative quality of life in a 6-month follow up in comparison with conventional haemorrhoidectomy. The continuation of quality of life studies with a longer follow up is required concerning Longo operation.

[Severe acute pancreatitis: role for laparoscopic surgery]. / Die Rolle der laparoskopischen Chirurgie bei schwerer akuter Pankreatitis.

UNLABELLED: Minimally invasive surgery is a new and promising treatment modality in the management of patients with severe acute pancreatitis (SAP). Aim of our study was the evaluation of our first experiences with laparoscopic surgery in the management of patients with SAP. METHODS: A total of 65 patients complied with Atlanta recommendations for SAP and were included into this retrospective study. Indications for laparoscopic surgery were SAP presented with intraabdominal or retroperitoneal exudates and detected by ultrasound (US) and/or contrast enhanced computer tomography (CT) scan, and the presence of acute calculous cholecystitis when 3 to 5 days of conservative treatment did not show clinical improvement and surgical treatment was considered. Patients with improvement after initial therapy received conservative therapy only. Bacteriological cultures were done for abdominal exudates and necrotic tissue obtained during surgery. RESULTS: Totally, 39 patients were operated and 26 were treated conservatively only. Laparoscopic surgery was started in 31 patients and completed in 26 patients. The overall conversion rate was 16.1 %. Laparoscopic drainage of the intraabdominal exudate was done in 26 patients including drainage of the lesser sac in five of them. Laparoscopic cholecystectomy in 25 cases and laparoscopically assisted jejunostomy in 6 cases were performed as a part of the procedure. Conventional surgery was the primary procedure in 8 patients. Peripancreatic abscess formation was observed in one case one month after laparoscopic procedure and was cured with conventional surgical drainage. Bile leakage from the cystic stump was successfully treated with endoscopic papillotomy in one case. All patients survived after laparoscopic procedures. Overall complication rate was 7.7 % and mortality reached 3.1 %. CONCLUSIONS: Laparoscopic drainage of the abdominal cavity, drainage of the lesser sac and revision of the retroperitoneal compartment can be safely carried out as an alternative to the conventional surgical approach. Laparoscopic cholecystectomy and/or jejunostomy may be additionally performed if indicated.

[Prognostic factors in curative resection of stomach carcinoma. A uni- and multivariate analysis]. / Prognostische Faktoren beim kurativ resezierten Magenkarzinom. Eine uni- und multivariate Analyse.

The TNM system, including tumor infiltration (T category), lymph node infiltration (N category) and metastasis (M category), is a well-established system of prognostic factors. To evaluate the prognostic importance of patient characteristics and tumor parameters 5 clinical and 13 pathological factors were analyzed. Data on 200 consecutive patients with histologically verified stomach cancer were prospectively recorded using a standardized form. In the subgroup with curative resection (R0, n = 108) a uni- and multivariate analysis was performed with respect to 5-year survival. In the univariate analysis statistical significance was demonstrated for the following factors: tumor size, tumor localization, T category, N category, number of infiltrated lymph nodes infiltrated, lymph node compartments, tumor stage, lymph node ratio: infiltrated/inspected. Multivariate analysis, taking into consideration the interaction between prognostic factors, revealed only two factors as statistically significant: number of infiltrated lymph nodes and tumor size. Our results and those in the literature indicate that the infiltration of lymph nodes is the most relevant prognostic factor. In addition to the TNM system the number of infiltrated lymph nodes seems to be of prognostic importance.