Microwave coagulation for liver metastases.

BACKGROUND: Liver metastases (i.e. secondary hepatic malignancies) are significantly more common than primary liver cancer. Long-term survival after radical surgical treatment is approximately 50%. For people in whom resection for cure is not feasible, other treatments must be considered. One treatment option is microwave coagulation utilising electromagnetic waves. It involves placing an electrode into a lesion under ultrasound or computed tomography guidance. OBJECTIVES: To evaluate the beneficial and harmful effects of microwave coagulation versus no intervention, other ablation methods, or systemic treatments in people with liver metastases regardless of the location of the primary tumour. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest date of search was 14 April 2023. SELECTION CRITERIA: Randomised clinical trials assessing beneficial or harmful effects of microwave coagulation and its comparators in people with liver metastases, irrespective of the location of the primary tumour. We included trials no matter the outcomes reported. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodological procedures. Our primary outcomes were: all-cause mortality at the last follow-up and time to mortality; health-related quality of life (HRQoL); and any adverse events or complications. Our secondary outcomes were: cancer mortality; disease-free survival; failure to clear liver metastases; recurrence of liver metastases; time to progression of liver metastases; and tumour response measures. We used risk ratios (RR) and hazard ratios (HR) with 95% confidence intervals (CI) to present the results. Two review authors independently extracted data and assessed the risk of bias using the Cochrane RoB 1 tool. We used GRADE methodology to assess the certainty of the evidence. MAIN RESULTS: Three randomised clinical trials fulfilled the inclusion criteria. The control interventions differed in the three trials; therefore, meta-analyses were not possible. The trials were at high risk of bias. The certainty of evidence of the assessed outcomes in the three comparisons was very low. Data on our prespecified outcomes were either missing or not reported. Microwave coagulation plus conventional transarterial chemoembolisation (TACE) versus conventional TACE alone One trial, conducted in China, randomised 50 participants (mean age 60 years, 76% males) with liver metastases from various primary sites. Authors reported that the follow-up period was at least one month. The trial reported adverse events or complications in the experimental group only and for tumour response measures. There were no dropouts in the trial. The trial did not report on any other outcomes. Microwave ablation versus conventional surgery One trial, conducted in Japan, randomised 40 participants (mean age 61 years, 53% males) with multiple liver metastases of colorectal cancer. Ten participants were excluded after randomisation (six from the experimental and four from the control group); thus, the trial analyses included 30 participants. Follow-up was three years. The reported number of deaths from all causes was 9/14 included participants in the microwave group versus 12/16 included participants in the conventional surgery group. The mean overall survival was 27 months in the microwave ablation and 25 months in the conventional surgery group. The three-year overall survival was 14% with microwave ablation and 23% with conventional surgery, resulting in an HR of 0.91 (95% CI 0.39 to 2.15). The reported frequency of adverse events or complications was comparable between the two groups, except for the required blood transfusion, which was more common in the conventional surgery group. There was no intervention-related mortality. Disease-free survival was 11.3 months in the microwave ablationgroup and 13.3 months in the conventional surgery group. The trial did not report on HRQoL. Microwave ablation versus radiofrequency ablation One trial, conducted in Germany, randomised 50 participants (mean age 62.8 years, 46% males) who were followed for 24 months. Two-year mortality showed an RR of 0.62 (95% CI 0.26 to 1.47). The trial reported that, by two years, 76.9% of participants in the microwave ablationgroup and 62.5% of participants in the radiofrequency ablation group survived (HR 0.63, 95% CI 0.23 to 1.73). The trial reported no deaths or major complications during the procedures in either group. There were two minor complications only in the radiofrequency ablation group (RR 0.19, 95% CI 0.01 to 3.67). The trial reported technical efficacy in 100% of procedures in both groups. Distant recurrence was reported for 10 participants in the microwave ablation group and nine participants in the radiofrequency ablation group (RR 1.03, 95% CI 0.50 to 2.08). No participant in the microwave ablation group demonstrated local progression at 12 months, while that occurred in two participants in the radiofrequency ablation group (RR 0.19, 95% CI 0.01 to 3.67). The trial did not report on HRQoL. One trial reported partial support by Medicor (MMS Medicor Medical Supplies GmbH, Kerpen, Germany) for statistical analysis. The remaining two trials did not provide information on funding. We identified four ongoing trials. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effect of microwave ablation in addition to conventional TACE compared with conventional TACE alone on adverse events or complications. We do not know if microwave ablation compared with conventional surgery may have little to no effect on all-cause mortality. We do not know the effect of microwave ablation compared with radiofrequency ablation on all-cause mortality and adverse events or complications either. Data on all-cause mortality and time to mortality, HRQoL, adverse events or complications, cancer mortality, disease-free survival, failure to clear liver metastases, recurrence of liver metastases, time to progression of liver metastases, and tumour response measures were either insufficient or were lacking. In light of the current inconclusive evidence and the substantial gaps in data, the pursuit of additional good-quality, large randomised clinical trials is not only justified but also essential to elucidate the efficacy and comparative benefits of microwave ablation in relation to various interventions for liver metastases. The current version of the review, in comparison to the previous one, incorporates two new trials in two additional microwave ablation comparisons: 1. in addition to conventional TACE versus conventional TACE alone and 2. versus radiofrequency ablation.

Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk.

BACKGROUND: Screening mammography can detect breast cancer at an early stage. Supporters of adding ultrasonography to the screening regimen consider it a safe and inexpensive approach to reduce false-negative rates during screening. However, those opposed to it argue that performing supplemental ultrasonography will also increase the rate of false-positive findings and can lead to unnecessary biopsies and treatments. OBJECTIVES: To assess the comparative effectiveness and safety of mammography in combination with breast ultrasonography versus mammography alone for breast cancer screening for women at average risk of breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov up until 3 May 2021. SELECTION CRITERIA: For efficacy and harms, we considered randomised controlled trials (RCTs) and controlled non-randomised studies enrolling at least 500 women at average risk for breast cancer between the ages of 40 and 75. We also included studies where 80% of the population met our age and breast cancer risk inclusion criteria. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and full texts, assessed risk of bias, and applied the GRADE approach. We calculated the risk ratio (RR) with 95% confidence intervals (CI) based on available event rates. We conducted a random-effects meta-analysis. MAIN RESULTS: We included eight studies: one RCT, two prospective cohort studies, and five retrospective cohort studies, enrolling 209,207 women with a follow-up duration from one to three years. The proportion of women with dense breasts ranged from 48% to 100%. Five studies used digital mammography; one study used breast tomosynthesis; and two studies used automated breast ultrasonography (ABUS) in addition to mammography screening. One study used digital mammography alone or in combination with breast tomosynthesis and ABUS or handheld ultrasonography. Six of the eight studies evaluated the rate of cancer cases detected after one screening round, whilst two studies screened women once, twice, or more. None of the studies assessed whether mammography screening in combination with ultrasonography led to lower mortality from breast cancer or all-cause mortality. High certainty evidence from one trial showed that screening with a combination of mammography and ultrasonography detects more breast cancer than mammography alone. The J-START (Japan Strategic Anti-cancer Randomised Trial), enrolling 72,717 asymptomatic women, had a low risk of bias and found that two additional breast cancers per 1000 women were detected over two years with one additional ultrasonography than with mammography alone (5 versus 3 per 1000; RR 1.54, 95% CI 1.22 to 1.94). Low certainty evidence showed that the percentage of invasive tumours was similar, with no statistically significant difference between the two groups (69.6% (128 of 184) versus 73.5% (86 of 117); RR 0.95, 95% CI 0.82 to 1.09). However, positive lymph node status was detected less frequently in women with invasive cancer who underwent mammography screening in combination with ultrasonography than in women who underwent mammography alone (18% (23 of 128) versus 34% (29 of 86); RR 0.53, 95% CI 0.33 to 0.86; moderate certainty evidence). Further, interval carcinomas occurred less frequently in the group screened by mammography and ultrasonography compared with mammography alone (5 versus 10 in 10,000 women; RR 0.50, 95% CI 0.29 to 0.89; 72,717 participants; high certainty evidence). False-negative results were less common when ultrasonography was used in addition to mammography than with mammography alone: 9% (18 of 202) versus 23% (35 of 152; RR 0.39, 95% CI 0.23 to 0.66; moderate certainty evidence). However, the number of false-positive results and necessary biopsies were higher in the group with additional ultrasonography screening. Amongst 1000 women who do not have cancer, 37 more received a false-positive result when they participated in screening with a combination of mammography and ultrasonography than with mammography alone (RR 1.43, 95% CI 1.37 to 1.50; high certainty evidence). Compared to mammography alone, for every 1000 women participating in screening with a combination of mammography and ultrasonography, 27 more women will have a biopsy (RR 2.49, 95% CI 2.28 to 2.72; high certainty evidence). Results from cohort studies with methodological limitations confirmed these findings. A secondary analysis of the J-START provided results from 19,213 women with dense and non-dense breasts. In women with dense breasts, the combination of mammography and ultrasonography detected three more cancer cases (0 fewer to 7 more) per 1000 women screened than mammography alone (RR 1.65, 95% CI 1.0 to 2.72; 11,390 participants; high certainty evidence). A meta-analysis of three cohort studies with data from 50,327 women with dense breasts supported this finding, showing that mammography and ultrasonography combined led to statistically significantly more diagnosed cancer cases compared to mammography alone (RR 1.78, 95% CI 1.23 to 2.56; 50,327 participants; moderate certainty evidence). For women with non-dense breasts, the secondary analysis of the J-START study demonstrated that more cancer cases were detected when adding ultrasound to mammography screening compared to mammography alone (RR 1.93, 95% CI 1.01 to 3.68; 7823 participants; moderate certainty evidence), whilst two cohort studies with data from 40,636 women found no statistically significant difference between the two screening methods (RR 1.13, 95% CI 0.85 to 1.49; low certainty evidence). AUTHORS' CONCLUSIONS: Based on one study in women at average risk of breast cancer, ultrasonography in addition to mammography leads to more screening-detected breast cancer cases. For women with dense breasts, cohort studies more in line with real-life clinical practice confirmed this finding, whilst cohort studies for women with non-dense breasts showed no statistically significant difference between the two screening interventions. However, the number of false-positive results and biopsy rates were higher in women receiving additional ultrasonography for breast cancer screening. None of the included studies analysed whether the higher number of screen-detected cancers in the intervention group resulted in a lower mortality rate compared to mammography alone. Randomised controlled trials or prospective cohort studies with a longer observation period are needed to assess the effects of the two screening interventions on morbidity and mortality.

Electrocoagulation for liver metastases.

BACKGROUND: Primary liver tumours and liver metastases from colorectal carcinoma are two of the most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the people with metastatic liver disease will die from metastatic complications. Electrocoagulation by diathermy is a method used to destroy tumour tissue, using a high-frequency electric current generating high temperatures, applied locally with an electrode (needle, blade, or ball). The objective of this method is to destroy the tumour completely, if possible, in a single session. With the time, electrocoagulation by diathermy has been replaced by other techniques, but the evidence is unclear. OBJECTIVES: To assess the beneficial and harmful effects of electrocoagulation by diathermy, administered alone or with another intervention, versus no intervention, other ablation methods, or systemic treatments in people with liver metastases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, CINAHL, ClinicalTrials.gov, ICTRP, and FDA to October 2020. SELECTION CRITERIA: We considered all randomised trials that assessed beneficial and harmful effects of electrocoagulation by diathermy, administered alone or with another intervention, versus comparators, in people with liver metastases, regardless of the location of the primary tumour. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed risk of bias of the included trial using predefined risk of bias domains, and presented the review results incorporating the certainty of the evidence using GRADE. MAIN RESULTS: We included one randomised clinical trial with 306 participants (175 males; 131 females) who had undergone resection of the sigmoid colon, and who had five or more visible and palpable hepatic metastases. The diagnosis was confirmed by histological assessment (biopsy) and by carcinoembryonic antigen (CEA) level. The trial was conducted in Iraq. The age of participants ranged between 38 and 79 years. The participants were randomised to four different study groups. The liver metastases were biopsied and treated (only once) in three of the groups: 75 received electrocoagulation by diathermy alone, 76 received electrocoagulation plus allopurinol, 78 received electrocoagulation plus dimethyl sulphoxide. In the fourth intervention group, 77 participants functioning as controls received a vehicle solution of allopurinol 5 mL 4 x a day by mouth; the metastases were left untouched. The status of the liver and lungs was followed by ultrasound investigations, without the use of a contrast agent. Participants were followed for five years. The analyses are based on per-protocol data only analysing 223 participants. We judged the trial to be at high risk of bias. After excluding 'nonevaluable patients', the groups seemed comparable for baseline characteristics. Mortality due to disease spread at five-year follow-up was 98% in the electrocoagulation group (57/58 evaluable people); 87% in the electrocoagulation plus allopurinol group (46/53 evaluable people); 86% in the electrocoagulation plus dimethyl sulphoxide group (49/57 evaluable people); and 100% in the control group (55/55 evaluable people). We observed no difference in mortality between the electrocoagulation alone group versus the control group (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.94 to 1.03; 113 participants; very low-certainty evidence). We observed lower mortality in the electrocoagulation combined with allopurinol or dimethyl sulphoxide group versus the control group (RR 0.87, 95% CI 0.80 to 0.95; 165 participants; low-certainty evidence). We are very uncertain regarding post-operative deaths between the electrocoagulation alone group versus the control group (RR 1.03, 95% CI 0.07 to 16.12; 152 participants; very low-certainty evidence) and between the electrocoagulation combined with allopurinol or dimethyl sulphoxide groups versus the control group (RR 1.00, 95% CI 0.09 to 10.86; 231 participants; very low-certainty evidence). The trial authors did not report data on number of participants with other adverse events and complications, recurrence of liver metastases, time to progression of liver metastases, tumour response measures, and health-related quality of life. Data on failure to clear liver metastases were not provided for the control group. There was no information on funding or conflict of interest. We identified no ongoing trials. AUTHORS' CONCLUSIONS: The evidence on the beneficial and harmful effects of electrocoagulation alone or in combination with allopurinol or dimethyl sulphoxide in people with liver metastases is insufficient, as it is based on one randomised clinical trial at low to very low certainty. It is very uncertain if there is a difference in all-cause mortality and post-operative mortality between electrocoagulation alone versus control. It is also uncertain if electrocoagulation in combination with allopurinol or dimethyl sulphoxide may result in a slight reduction of all-cause mortality in comparison with a vehicle solution of allopurinol (control). It is very uncertain if there is a difference in post-operative mortality between the electrocoagulation combined with allopurinol or dimethyl sulphoxide group versus control. Data on other adverse events and complications, failure to clear liver metastases or recurrence of liver metastases, time to progression of liver metastases, tumour response measures, and health-related quality of life were most lacking or insufficiently reported for analysis. Electrocoagulation by diathermy is no longer used in the described way, and this may explain the lack of further trials.

Transarterial (chemo)embolisation versus no intervention or placebo for liver metastases.

BACKGROUND: The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma or other extrahepatic primary cancers. Liver metastases are significantly more common than primary liver cancer, and long-term survival rate after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of people; therefore, other treatments have to be considered. One possible option is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Transarterial chemoembolisation (TACE) of the hepatic artery can be achieved by administering a chemotherapeutic drug followed by vascular occlusive agents, and can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected. This can also be performed without chemotherapy, which is called bland transarterial embolisation (TAE). OBJECTIVES: To assess the beneficial and harmful effects of TAE or TACE compared with no intervention or placebo in people with liver metastases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and four more databases (December 2019). We also searched two trials registers and the US Food and Drug Administration database (September 2019). SELECTION CRITERIA: Randomised clinical trials assessing beneficial and harmful effects of TAE or TACE compared with no intervention or placebo for liver metastases. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodological procedures. We extracted information on participant characteristics, interventions, study outcomes, study design, and trial methods. Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of evidence with GRADE. We resolved disagreements by discussion. MAIN RESULTS: We included one randomised clinical trial with 61 participants (43 male and 18 female) with colorectal cancer with liver metastases: 22 received transarterial embolisation (TAE; hepatic artery embolisation), 19 received transarterial chemoembolisation (TACE; 5-fluorouracil hepatic artery infusion chemotherapy with degradable microspheres), and 20 received 'no active therapeutic intervention' as a control. Most tumours were synchronous, unresectable metastases involving up to 75% of the liver. Participants were followed for a minimum of seven months. The trial was at high risk of bias. Very-low-certainty evidence found inconclusive results for mortality at 44 months between the TAE and TACE versus no intervention groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.06; 61 participants). Local recurrence was reported in 10 participants without any details about the group allocation. Very-low-certainty evidence found little or no difference in mortality between the TAE and no intervention groups (RR 0.91, 95% CI 0.75 to 1.10; 42 participants). Median survival was 7 months from trial entry (range 2 to 44 months) in the TAE group and 7.9 months (range 1 to 26 months) in the control group, and 8.7 months after diagnosis (range 2 to 49 months) in the TAE group and 9.6 months (range 1 to 27 months) in the control group. The trial authors reported the differences were not statistically significant. There were no reported side effects in the control group. In the TAE group, 18 participants experienced short-term symptoms of 'post-embolisation syndrome', which were relieved with symptomatic treatment; one participant also had a local puncture site haematoma. Very-low-certainty evidence found little or no difference in mortality between the TACE and no intervention groups (RR 0.83, 95% CI 0.65 to 1.07; 39 participants). Median survival in the TACE group was 10.7 months (range 3 to 38 months) from trial entry, and 13.0 months (range 3 to 38 months) after diagnosis. The trial authors reported that differences between groups were not statistically significant. All participants experienced short-term nausea, with or without vomiting, immediately after treatment; one participant developed a wound infection, and one developed deep vein thrombosis. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Cancer Research Campaign, a non-profit organisation, provided a grant for the trial; Pharmacia Ltd. delivered the Port-a-Cath arterial delivery systems and degradable starch microspheres. We identified one ongoing trial comparing TACE plus chemotherapy versus chemotherapy alone in people with unresectable colorectal liver metastases who failed with first-line chemotherapy (NCT03783559). AUTHORS' CONCLUSIONS: Based on one, small randomised trial at high risk of bias, the evidence is very uncertain about the effect of TAE or TACE versus no active therapeutic intervention on mortality for people with liver metastases as the true effect may be substantially different. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Short-term, minor adverse events were recorded in the intervention groups only. Large trials, following current standards of conduct and reporting, are required to explore the benefits and harms of TAE or TACE compared with no intervention or placebo in people with resectable and unresectable liver metastasis.

Percutaneous ethanol injection for liver metastases.

BACKGROUND: The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma or other extrahepatic primary cancers. Liver metastases are significantly more common than primary liver cancer, and the reported long-term survival rate after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of patients; therefore, other treatments have to be considered. One of these is percutaneous ethanol injection (PEI), which causes dehydration and necrosis of tumour cells, accompanied by small-vessel thrombosis, leading to tumour ischaemia and destruction of the tumour. OBJECTIVES: To assess the beneficial and harmful effects of percutaneous ethanol injection (PEI) compared with no intervention, other ablation methods, or systemic treatments in people with liver metastases. SEARCH METHODS: We searched the following databases up to 10 September 2019: the Cochrane Hepato-Biliary Group Controlled Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE Ovid; Embase Ovid; Science Citation Index Expanded; Conference Proceedings Citation Index - Science; Latin American Caribbean Health Sciences Literature (LILACS); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched clinical trials registers such as ClinicalTrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the US Food and Drug Administration (FDA) (17 September 2019). SELECTION CRITERIA: Randomised clinical trials assessing beneficial and harmful effects of percutaneous ethanol injection and its comparators (no intervention, other ablation methods, systemic treatments) for liver metastases. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures as outlined by Cochrane. We extracted information on participant characteristics, interventions, study outcomes, study design, and trial methods. Two review authors performed data extraction and assessed risk of bias independently. We assessed the certainty of evidence by using GRADE. We resolved disagreements by discussion. MAIN RESULTS: We identified only one randomised clinical trial comparing percutaneous intratumour ethanol injection (PEI) in addition to transcatheter arterial chemoembolisation (TACE) versus TACE alone. The trial was conducted in China and included 48 trial participants with liver metastases: 25 received PEI plus TACE, and 23 received TACE alone. The trial included 37 male and 11 female participants. Mean participant age was 49.3 years. Sites of primary tumours included colon (27 cases), stomach (12 cases), pancreas (3 cases), lung (3 cases), breast (2 cases), and ovary (1 case). Seven participants had a single tumour, 15 had two tumours, and 26 had three or more tumours in the liver. The bulk diameter of the tumour on average was 3.9 cm, ranging from 1.2 cm to 7.6 cm. Participants were followed for 10 months to 43 months. The trial reported survival data after one, two, and three years. In the PEI + TACE group, 92%, 80%, and 64% of participants survived after one year, two years, and three years; in the TACE alone group, these percentages were 78.3%, 65.2%, and 47.8%, respectively. Upon conversion of these data to mortality rates, the calculated risk ratio (RR) for mortality at last follow-up when PEI plus TACE was compared with TACE alone was 0.69 (95% confidence interval (CI) 0.36 to 1.33; very low-certainty evidence) after three years of follow-up. Local recurrence was 16% in the PEI plus TACE group and 39.1% in the TACE group, resulting in an RR of 0.41 (95% CI 0.15 to 1.15; very low-certainty evidence). Forty-five out of a total of 68 tumours (66.2%) shrunk by at least 25% in the PEI plus TACE group versus 31 out of a total of 64 tumours (48.4%) in the TACE group. Trial authors reported some adverse events but provided very few details. We did not find data on time to mortality, failure to clear liver metastases, recurrence of liver metastases, health-related quality of life, or time to progression of liver metastases. The single included trial did not provide information on funding nor on conflict of interest. AUTHORS' CONCLUSIONS: Evidence for the effectiveness of PEI plus TACE versus TACE in people with liver metastases is of very low certainty and is based on one small randomised clinical trial at high risk of bias. Currently, it cannot be determined whether adding PEI to TACE makes a difference in comparison to using TACE alone. Evidence for benefits or harms of PEI compared with no intervention, other ablation methods, or systemic treatments is lacking.

Comparison of mutation profile between primary phyllodes tumors of the breast and their paired local recurrences.

Phyllodes tumor of the breast (PTB) is a rare neoplasm and accounts for 0.2-2.0% of breast cancer in women. Histopathological diagnosis of the tumor is difficult, and histological features do not always predict the course of the disease and the risk of progression. Pathogenesis and molecular biological characteristics as well as PTB prognostic factors are unknown. In search for genetic factors affecting PTB progression, 10 patients were analyzed for whom material from the primary tumor and local recurrence was available. DNA isolated from paraffin blocks was sequenced using the next-generation sequencing method (NGS). In 4 pairs, consisting of primary tumor and local recurrence, probably pathogenic/pathogenic variants were detected, and in three pairs they were observed in the CDKN2A gene, while other variants were found in PTEN and TP53 genes. NGS results indicate that the above-mentioned variants are hereditary, which suggests that the CDKN2A gene might be involved in cancerogenesis of PTB. Additionally, the selected pathogenic variant of EGFR gene was exclusively detected in one recuurent tumor, which might suggest the involvement of this gene in the mechanism of progression. In order to determine if this variant is associated with progression, the frequency of this mutation should be examined in larger group of malignant and borderline tumors.

Usefulness of scoring systems in outcome prediction for older cancer patients undergoing abdominal surgery.

BACKGROUND: Several postoperative outcome scoring systems have been developed and validated, combining both pre- and intraoperative factors. Among others are the Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM), the Estimation of Physiologic Ability and Stress (E-PASS) and the Surgical Apgar Score combined with the American Society of Anesthesiologists physical status classification (SASA). The aim of this study was to compare the above scoring systems in the prediction of 30-day postoperative outcome in older patients with cancer undergoing abdominal surgery. METHODS: Consecutive patients ≥70 years were prospectively enrolled. Pre- and intraoperative variables were used to calculate the scores, the ROC and perform logistic regression analysis. RESULTS: The study sample comprised 201 patients with a median age of 77 (range 70-93) years. The most common surgical procedure was for colorectal (75%), followed by gastric (10.4%) pancreas (7.0%), gall bladder (3.5%), small bowel (2.5%), and other (1.5%) types of cancer. All scores were independent predictors of 30-day postoperative mortality. In case of 30-day morbidity only SASA turned to be significant. The ROC curves were highly valid and area under the curve showed fair to good discriminatory ability (0.60-0.77) for 30-day postoperative mortality and fair (AUC 0.6) in case of SASA for the 30-day postoperative. CONCLUSION: The SASA, E-PASS, and P-POSSUM were confirmed to be predictive of 30-day postoperative mortality in older patients undergoing abdominal elective cancer surgery. Only SASA demonstrated as independent factor predicting postoperative 30-day major morbidity.

Cryotherapy for liver metastases.

BACKGROUND: The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma. Liver metastases are significantly more common than primary liver cancer and long-term survival rates reported for patients after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of patients. Cryotherapy is performed with the use of an image-guided cryoprobe which delivers liquid nitrogen or argon gas to the tumour tissue. The subsequent process of freezing is associated with formation of ice crystals, which directly damage exposed tissue, including cancer cells. OBJECTIVES: To assess the beneficial and harmful effects of cryotherapy compared with no intervention, other ablation methods, or systemic treatments in people with liver metastases. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, and six other databases up to June 2018. SELECTION CRITERIA: Randomised clinical trials assessing beneficial and harmful effects of cryotherapy and its comparators for liver metastases, irrespective of the location of the primary tumour. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We extracted information on participant characteristics, interventions, study outcomes, and data on the outcomes important for our review, as well as information on the design and methodology of the trials. Two review authors independently assessed risk of bias in each study. One review author performed data extraction and a second review author checked entries. MAIN RESULTS: We found no randomised clinical trials comparing cryotherapy versus no intervention or versus systemic treatments; however, we identified one randomised clinical trial comparing cryotherapy with conventional surgery. The trial was conducted in Ukraine. The trial included 123 participants with solitary, or multiple unilobar or bilobar liver metastases; 63 participants received cryotherapy and 60 received conventional surgery. There were 36 women and 87 men. The primary sites for the metastases were colon and rectum (66.6%), stomach (7.3%), breast (6.5%), skin (4.9%), ovaries (4.1%), uterus (3.3%), kidney (3.3%), intestines (1.6%), pancreas (1.6%), and unknown (0.8%). The trial was not reported sufficiently enough to assess the risk of bias of the randomisation process, allocation concealment, or presence of blinding. It was also not possible to assess incomplete outcome data and selective outcome reporting bias. The certainty of evidence was low because of risk of bias and imprecision.The participants were followed for up to 10 years (minimum five months). The trial reported that the mortality at 10 years was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group. The calculated by us relative risk (RR) with 95% Confidence Interval (CI) was: RR 0.88, 95% CI 0.77 to 1.02. We judged the evidence as low-certainty evidence. Regarding adverse events and complications, separately and in total, our calculation showed no evidence of a difference in recurrence of the malignancy in the liver: 86% (54/63) of the participants in the cryotherapy group and 95% (57/60) of the participants in the conventional surgery group developed a new malignancy (RR 0.90, 95% CI 0.80 to 1.01; low-certainty evidence). The frequency of reported complications was similar between the cryotherapy group and the conventional surgery group, except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the conventional surgery group. However, the authors did not report whether there was any evidence of a difference. There were no intervention-related mortality or bile leakages.We identified no evidence for health-related quality of life, cancer mortality, or time to progression of liver metastases. The study reported tumour response in terms of the carcinoembryonic antigen level in 69% of participants, and reported results in the form of a graph for 30% of participants. The carcinoembryonic antigen level was lower in the cryotherapy group, and decreased to normal values faster in comparison with the control group (P < 0.05). FUNDING: the trial did not provide information on funding. AUTHORS' CONCLUSIONS: The evidence for the effectiveness of cryotherapy versus conventional surgery in people with liver metastases is of low certainty. We are uncertain about our estimate and cannot determine whether cryotherapy compared with conventional surgery is beneficial or harmful. We found no evidence for the benefits or harms of cryotherapy compared with no intervention, or versus systemic treatments.

Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis.

BACKGROUND: Pediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials. METHODS AND FINDINGS: Our protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015. We included pediatric cancer Phase I studies, defined as "small sample size, non­randomized, dose escalation studies that defined the recommended dose for subsequent study of a new drug in each schedule tested." We measured risk using grade 3, 4, and 5 (fatal) drug-related adverse events (AEs) and benefit using objective response rates. When possible, data were meta-analyzed. We identified 170 studies meeting our eligibility criteria, accounting for 4,604 patients. The pooled overall objective response rate was 10.29% (95% CI 8.33% to 12.25%), and was lower in solid tumors, 3.17% (95% CI 2.62% to 3.72%), compared with hematological malignancies, 27.90% (95% CI 20.53% to 35.27%); p < 0.001. The overall fatal (grade 5) AE rate was 2.09% (95% CI 1.45% to 2.72%). Across the 4,604 evaluated patients, there were 4,675 grade 3 and 4 drug-related AEs, with an average grade 3/4 AE rate per person equal to 1.32. Our study had the following limitations: trials included in our review were heterogeneous (to minimize heterogeneity, we separated types of therapy and cancer types), and we relied on published data only and encountered challenges with the quality of reporting. CONCLUSIONS: Our meta-analysis suggests that, on the whole, AE and response rates in pediatric Phase I trials are similar to those in adult Phase I trials. Our findings provide an empirical basis for the refinement and review of pediatric Phase I trials, and for communication about their risk and benefit.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer.

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

Bilateral synchronous breast cancer developed as metachronous malignancy after therapy of other primaries.

OBJECTIVES: Cancer morbidity rates have been increasing steadily. A longer lifespan and easier access to modern diagnostic and therapeutic methods are the main reasons for the growing number of cancer survivors. Additionally, some types of oncological treatment, such as radiotherapy or immunosuppression, may also increase the risk of secondary tumors. These factors have resulted in an increased incidence of primary multiple cancers. Multiple primary cancers are generally under-stood as either synchronous, in which the cancers occur at the same time, or metachronous, in which the cancers follow in sequence (for instance, more than 2 months apart).The results published in other studies show that between 2% and 15.8% of all cancer patients have more primary multiple cancers. Within this group with multiple primary cancers, some have bilateral breast cancer, and our study focuses on patients from this group. MATERIAL AND METHODS: Our study describes 10 patients who were treated for bilateral synchronous breast cancer at the Cracow Branch of the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology during the years 1992-2014 and who developed another primary tumor after their treatment bilateral synchronous breast cancer. RESULTS: In our discussion we present detailed data on the incidence of metachronous cancers in the 10 patients, including breast cancer, following the treatment of their other primary tumors. CONCLUSION: The 10 cases of our study, and clinical experiences and publications in general show how important it is for patients to continue medical follow-up after treatment of primary tumors, not only to detect recurrences as early as pos-sible, but also to diagnose any other malignancies occurring in other sites, including secondary, treatment-related tumors.

Radiotherapy alone as a method of treatment for sinonasal mucosal melanoma: A report based on six cases and a review of current opinion.

OBJECTIVES: Radiotherapy in patients with sinonasal mucosal melanoma (SNMM) was given as alternative treatment to surgery in cases with advanced, inoperable tumors or those not eligible for surgery. We presented the outcomes for patients with SNMM treated with radiotherapy alone. MATERIAL AND METHODS: The retrospective review of 6 consecutive SNMM (nasal cavity - 4 pts. and paranasal sinus - 2 pts.) patients (3 males and 3 females at mean age 64 years) treated between 2008 and 2016 was presented. The stage of disease was: T3 (1 pt.), T4a (3 pts.), T4b (2 pts.); with N0 and M0 in all patients. All patients underwent definitive primary photon radiotherapy (IMRT) alone; dose 66-72 Gy was delivered in 22-24 fractions given in 5 fractions (3 Gy) a week. RESULTS: The complete remission was observed in all our patients but only one patient survived 5 years without disease. Five patients died due to multiple distant metastases; two of those patients developed associated local recurrence 7-8 months after radiotherapy. CONCLUSION: SNMM has a poor prognosis due to its high metastatic potential. Based on our numerically small report and data from literature we concluded that primary radiotherapy alone assured complete remission and even 5-year disease-free survival in only a few individual patients.

Prognostic factors in Polish patients with BRCA1-dependent ovarian cancer.

BACKGROUND: Treatment outcomes appear to be better for ovarian cancer (OC) patients carrying the BRCA1/2 germline mutation than for patients with sporadic OC. However, most published data are for North American, British and Jewish populations. There have been very few studies on treatment outcomes in Central and Eastern European patients with OC. The aim of this study was to analyse prognostic factors in Polish patients with BRCA1-dependent OC (BRCA1-OC). METHODS: The records of patients with OC treated with surgery and chemotherapy at the Centre of Oncology in Kraków, Poland, between 2004 and 2009 were reviewed. Based on family history, a group of 249 consecutive patients fulfilling the criteria for risk of hereditary OC were selected and tested for the germline BRCA1 mutation. Response to combination therapy (surgery and chemotherapy) in the BRCA1-OC group was assessed based on clinical examination, imaging and serum CA125. RESULTS: Germline BRCA1 mutations were detected in 69 of the 249 patients, but three of these patients failed to complete the study. Finally, 66 patients with BRCA1-OC were included in the study group. The median age of the study patients was 49.5 years. All had undergone primary or interval cytoreductive surgery and chemotherapy. Progression occurred in 48 (72.7 %) of the 66 patients and median time to progression was 20 months. The 5-year overall survival rate in was 43.9 % and median survival time was 32.3 months. On multivariate analysis, the endometrial subtype of OC and serum CA125 < 12.5 U/ml at the end of treatment were independent, positive prognostic factors for 5-year overall survival. CONCLUSION: Prognostic factors for favourable treatment outcomes in Polish patients with BRCA1-OC do not appear to differ from those in patients with sporadic OC. The incidence of the endometrial subtype of OC was relatively high (34.9 %) among women in the study. This was unexpected and has not been reported previously. This subtype of OC was an independent prognostic factor for favourable treatment outcomes.

Urine NGAL is useful in the clinical evaluation of renal function in the early course of acute pancreatitis.

INTRODUCTION: Acute Kidney Injury (AKI) is a serious early complications in patients with acute pancreatitis (AP) that signifcantly increases mortality rates compared to patients without AKI. The early diagnosis of AKI during its treatable phases and implementation of appropriate treatment protocols can improve outcomes for this group of patients. A promising biomarker for AKI is neutrophil gelatinase-associated lipocalin (NGAL). AIM: This study evaluated the diagnostic value of NGAL concentrations in serum and in urine for patients developing AKI as an early complication of AP compared to AP patients without AKI. MATERIAL AND METHODS: The study group composed of 65 patients (34 men and 31 women) with a mean age of 62.2 ± 16 years with AP and hospitalized in the Surgery Department of the Direct Hospital in Sucha Beskidzka, Poland between January and December 2014. Serum NGAL (sNGAL) levels were measured with the BioVendor ELISA kit, and urine NGAL (uNGAL) with the Abbott ARCHITECT Analyzer. RESULTS: In the early phase of AP, 11 patients (17%) developed AKI, including 10 patients with stage 1 and one with stage 2. AKI was associated with more severe AP, higher BISAP scores, the need for more intensive treatment, longer hospital stays and higher mortality. Both serum and urine NGAL concentrations were signifcantly higher in patients with AKI throughout the study and signifcantly predicted AKI in simple and multiple logistic regression adjusted for age, sex and comorbidities. Serum and urine NGAL concentrations were signifcantly correlated with levels of serum urea, creatinine, urine albumin, and the maximum change in serum creatinine. Serum and urine NGAL levels also correlated positively with direct neutrophil counts and CRP concentrations throughout the study. CONCLUSIONS: The measurement of NGAL levels, particularly in urine, is simple, easy to interpret, routinely available, and clinically useful in the assessment of dynamic changes in kidney function for patients with AP.

Methods and results of local treatment of brain metastases in patients with breast cancer.

This article presents methods and results of surgical treatment and radiation therapy of brain metastases in breast cancer patients (brain metastases from breast cancer BMF-BC). Based on the literature data, it was shown that patients with single BMF-BC, aged less than 65 years, with Karnofsky score (KPS) of 70 or more and with cured or controlled extracranial disease are the best candidates to surgical treatment. Irrespective of the extracranial disease control status, there are indications for surgery in patients with symptomatic mass effect (tumour diameter larger than 3 cm) and patients with obstructive hydrocephalus from their BMF-BC. Stereotactic radiosurgery (SRS) has some advantages over surgery, with similar effectiveness: it may be used in the treatment of lesions inaccessible to surgery, the number of lesion is not a limiting factor if each lesion is small (< 3) and adequate doses can be delivered, it is not contraindicated in patients with active extracranial disease, it does not interfere with ongoing systemic treatment, and it does not require general anaesthesia or hospitalisation. A disadvantage of SRS, as compared to whole brain radiotherapy (WBRT), in patients with BMF-BC is the possibility of subsequent development of new lesion in the non-irradiated field. Thus the majority of the BMF-BC patients are not good candidates to surgery or SRS; WBRT alone or combined with a systemic treatment still plays a major role in the treatment of these patients.

Methods and results of locoregional treatment of brain metastases in patients with non-small cell lung cancer.

This article presents methods and results of surgery and radiotherapy of brain metastases from non-small cell lung cancer (BMF-NSCLC). Patients with single BMF-NSCLC, with Karnofsky score ≥ 70 and controlled extracranial disease are the best candidates for surgery. Stereotactic radiosurgery (SRS) is recommended in patients with 1-3 BMF-NSCLC below 3-3.5 cm, with minor neurological symptoms, located in parts of the brain not accessible to surgery, with controlled extracranial disease. Whole brain radiotherapy (WBRT) following SRS reduces the risk of local relapse; in selected patients median survival reaches more than 10 months. Whole brain radiotherapy alone is a treatment in patients with multiple metastases, poor performance status, uncontrolled extracranial disease, disqualified from surgery or SRS with median survival 3 to 6 months. There is no doubt that there are patients with BMF-NSCLC who should receive only the best supportive care. There is a debate in the literature on how to select these patients.

Monocyte chemoattractant protein-induced protein 1 impairs adipogenesis in 3T3-L1 cells.

Monocyte chemoattractant protein-induced protein 1 (MCPIP1) encoded by the ZC3H12a gene (also known as Regnase-1) is involved in the regulation of degradation of mRNA of inflammatory modulators and for processing of pre-miRNA. These functions depend on the presence of the PIN domain. Moreover, MCPIP1 was described as a negative regulator of NF-κB and AP-1 signaling pathways although mechanisms underlying such activity remain unknown. We aimed at determining the role of MCPIP1 in adipogenesis. Here, we present evidence that Mcpip1 transcription is transiently activated during 3T3-L1 transition from pre- to adipocytes. However Mcpip1 protein expression is also strongly decreased at day one after induction of adipogenesis. Knockdown of Mcpip1 results in an upregulation of C/EBPß and PPARγ mRNAs, whereas overexpression of MCPIP1 reduces the level of both transcription factors and impairs adipogenesis. MCPIP1-dependend modulation of C/EBPß and PPARγ levels results in a modulation of the expression of downstream controlled genes. In addition, decreased C/EBPß, but not PPARγ, depends on the activity of the MCPIP1 PIN domain, which is responsible for RNase properties of this protein. Together, these data confirm that MCPIP1 is a key regulator of adipogenesis.

Malignant phyllodes tumor of the breast: treatment and prognosis.

Surgery remains the mainstay of the treatment in patients with malignant phyllodes tumor of the breast (MPTB); however, the extent of surgery (breast conserving surgery [BCS] versus mastectomy) and the role of adjuvant radiotherapy have been controversial. We report a single institution's experience with MPTB. We discuss controversial therapeutic aspects of this rare tumor. Seventy patients with MPTB treated primarily with surgery were evaluated. The mean age was 50 years (21-76), and the mean size of the tumor was 6 cm. Thirty-four (48.6%) patients were treated with total mastectomy, and 36 (51.4%) were treated with BCS (lumpectomy or wide local excision). Microscopic surgical margins were free of tumor in all cases. In 64 (91.4%) patients, margins were ≥1 cm. Remaining 6 (8.6%) patients treated with BCS margins were <1 cm and subsequently radiotherapy was performed. Among 70 patients, 58 (82.9%) had no evidence of disease (NED) after 5 years. The extent of surgery was not significantly related to the 5-year NED survival rates (82.4% in patients who underwent mastectomy and 83.3% in patients who underwent BCS only or BCS with adjuvant irradiation). The 5-year NED survival rates in BCS (tumor-free margin ≥1 cm) and BCS with irradiation (tumor-free margin <1 cm) groups were identical (83.3%). Our data support the potential use of BCS in patients with MPTB. Mastectomy is indicated only if tumor-free margins cannot be obtained by BCS. Adjuvant radiotherapy may be considered if tumor-free margins are <1 cm.

Mucinous breast cancer - clinical characteristics and treatment results in patients treated at the Oncology Centre in Kraków between 1952 and 2002.

AIM OF THE STUDY: To present the characteristics and clinical outcomes in 94 patients with mucinous breast cancer treated at the Oncology Centre in Krakow between 1952 and 2002. MATERIAL AND METHODS: Stage I or II carcinomas were found in 66 patients (69.4%) of the presented group and in the remaining 28 patients (29.8%) stage III disease was diagnosed. In 27 cases regional lymph nodes were involved. All patients had been treated with surgery: mastectomy (90 patients) or breast-conserving treatment (4 patients). Radiotherapy was administered in 14 patients, adjuvant chemo-therapy in 14 patients, and endocrine therapy in 39 patients. RESULTS: The maximum follow-up was 257 months. Ten-year survival was as follows: 75.7% (overall survival), 82.5% (disease-free survival). During the follow-up, 4 patients developed local recurrence, 5 patients developed metastases. Second primary cancer was found in 8 patients. CONCLUSIONS: The presented results confirm the good prognosis in patients treated for mucinous breast cancer. The diagnosis of early-stage breast cancer based on mammography can allow breast-conserving treatment.

Non-metastatic primary neuroendocrine neoplasms of the breast: a reference cancer center's experience of a heterogenous entity.

Background: Primary neuroendocrine neoplasms of the breast (Br-NENs) are rare. The classification has been updated in recent years making interpretation of the data published challenging. It is unclear whether neuroendocrine differentiation is associated with poorer prognosis and what treatment approaches should be applied. Methods: The database for breast cancer patients treated between 2009 and 2022 at the Maria Sklodowska-Curie National Research Institute of Oncology Branch Krakow was explored to search for Br-NENs. Patients' medical and pathological data were collected and analyzed. Results: We included 22 females with Br-NEN without metastases at the time of diagnosis. The median age was 64 years (range: 28-88), Of the cases, 18 were hormone receptor positive, all were HER-2 negative, the median Ki67 was 27% (10-100%). The median tumor size at the time of diagnosis was 29.5mm (7-75mm), 9 patients were N-positive. DCIS was present in 5 cases. Only one case was negative for chromogranin and synaptophysin staining, but data were missing for 4 cases. Nine patients received adjuvant chemotherapy, mainly based on anthracyclines and taxanes, while 16 received adjuvant hormonal therapy and 15 received postoperative radiotherapy. Radical surgery was performed in all patients, but two underwent suboptimal tumorectomy. One patient had local recurrence, three experienced metastatic disease, all involving the lungs, but these patients are still alive. The median follow-up was 96 months (8-153). Two patients died, with a follow up time of no recurrence >4 years. Our results were compared to twelve case series collecting clinical data on Br-NENs, with median patient number of 10.5 (range: 3-142). Conclusion: Br-NENs represent a heterogenous group of diseases, lacking data from prospective studies or clinical trials. There are no established treatment standards tailored for Br-NENs. Our patients' cohort exhibited a favorable prognosis, potentially attributed to lower tumor stage and Ki67 index compared to other reported case series. We suggest that radical surgery and postoperative radiotherapy be administered akin to standard treatment for breast cancer of no special type. ESMO also advocates for this approach in systemic treatment, although we recommend considering platinum-based chemotherapy for patients with poorly differentiated Br-NENs exhibiting high Ki67.