Significant Unfavorable Prognostic Factor Research Articles

Later lines of systemic therapy in patients with metastatic colorectal cancer: real-world data from a setting with barriers to access cancer therapies.

Regorafenib and trifluridine/tipiracil (TFD/TPI) are oral systemic therapies with survival benefit in chemorefractory metastatic colorectal cancer (mCRC) patients, but they are not widely available worldwide. We aimed to evaluate the treatment patterns and outcomes of patients with limited access to these drugs. Retrospective study involving 510 patients with mCRC who were treated at five different centers in Brazil, from January 2011 to December 2019. We analyzed the characteristics and clinical outcomes of patients who were exposed to third-line and beyond systemic therapy (N=148). A total of 148 (29%) and 73 (14%) patients received third- and fourth-line therapies, respectively. Most patients had left-sided tumors (80%) and had undergone primary tumor resection (87%) and metastasectomy (62%). From the initiation of third-line therapy, median follow-up was 17.8 months and median overall survival (OS) was 13.1 months (95% confidence interval: 8.1-18.0) (58% of deaths). The most adopted therapies were reexposure to previous chemotherapy regimens (85% third-line and 71% fourth-line), followed by regorafenib (13% and 25%) and TFD/TPI (2% and 4%). In multivariable analysis, male patients and right-sided tumors were significant unfavorable prognostic factors for OS. In a real-world setting with barriers to accessing the standard of care of chemorefractory mCRC, reexposure to chemotherapy was the main therapeutic strategy, with potential negative influence on OS. Our study highlights how barriers hamper the achievement of health equity in cancer care and increases the awareness of patients and stakeholders, contributing to engaging them in ensuring equitable access to high-quality cancer care.

Results of treatment of patients 75 years or older with non-metastatic prostate cancer in real clinical practice

Aim. To evaluate the results of radical surgical treatment and radiotherapy in patients with non-metastatic prostate cancer at age ≥75 years.Materials and methods. The retrospective study included data from 151 patients ≥75 years with verified non-metastatic prostate cancer who underwent radical prostatectomy (RP) or external beam radiotherapy (EBRT). Median age was 81.0 (75.0–97.0) years. Median Charlson comorbidity index was 7 (4–12). Median baseline prostate specific antigen (PSA) level was 11.0 (1.8–172.0) ng/mL. Prostatic adenocarcinoma was verified (ISUP grade 4–5 – 30 (19.9 %)) in all patients. сТ category was сТ3–4 in 37 (24.5 %), cN1 category was diagnosed in 10 (6.6 %) patients. The groups of unfavorable intermediate, high and very high risk included 93 (61.6 %) patients. Radical treatmentwas performed in all cases: RP in 38 (25.2 %), EBRT in 113 (74.8 %) patients (109 (72.2 %) men completed EBRT). Adjuvant treatment was administered in 8 (21.1 %) patients who underwent surgery. In the EBRT group neoadjuvant androgen-deprivation therapy (ADT) was administered in 74 (65.5 %), adjuvant ADT in 79 (70.0 %) cases. Treatment groups were matched by the main characteristics (р >0.05 for all) excluding lower baseline PSA in the RP group (р = 0.013). Median follow-up was 46.2 (1.5–234.2) months for all patients.Results. RP complications were registered in 3 (7.8 %), EBRT complications – in 7 (6.2 %) patients. No serious or lethal adverse event was observed. Recurrences were diagnosed in 9 (23.7 %) patients after surgery and in 26 (23.9 %) of 109 patients who completed EBRT. In the total study population, 4-year recurrence-free, cancer-specific, overall, and cardiac-specific survival rates were 74.5; 96.3; 91.2 and 90.8 %, respectively. The only factor significantly decreasing overall survival was Charlson comorbidity index ³8 (р = 0.05). Significant decrease of recurrence-free survival was observed in the surgery group compared to the EBRT group (р = 0.032). It did not translate into decreased cancerspecific and overall survival (р >0.05 for all). There was no significant difference in cardiac-specific survival between the groups (р = 0.626). Significant unfavorable prognostic factors of recurrence-free survival in the EBRT group included сN1 category (р = 0.045), very high risk (р = 0.049), and EBRT dose.Conclusion. RP and EBRT in elderly patients with non-metastatic prostate cancer receiving treatment in real clinical practice have acceptable safety profile and provide effectiveness comparable to the historical data on patients not sampled by age. The optimal candidates for radical treatment are men with Charlson comorbidity index <8.

Prognostic factors among patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome: A retrospective cohort study using a nationwide inpatient database in Japan

IntroductionShiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome (STEC-HUS). Understanding its prognostic factors is essential for immediate interventions. We examined early-phase unfavorable prognostic factors among patients with STEC-HUS using a nationwide database. Material and methodsThis is a retrospective cohort study to analyze practice patterns and identify prognostic factors among patients with STEC-HUS. We used the Diagnosis Procedure Combination Database, which includes approximately half of the acute-care hospitalized patients in Japan. We enrolled patients who were hospitalized for STEC-HUS from July 2010 to March 2020. The composite unfavorable outcome included in-hospital death, mechanical ventilation, dialysis, and rehabilitation at discharge. Unfavorable prognostic factors were assessed using a multivariable logistic regression model. ResultsWe included 615 patients with STEC-HUS (median age, 7 years). Of them, 30 (4.9%) patients had acute encephalopathy and 24 (3.9%) died within 3 months of admission. Unfavorable composite outcome was observed in 124 (20.2%) patients. Significant unfavorable prognostic factors were age of 18 years or older, methylprednisolone pulse therapy, antiepileptic drug administration, and respiratory support within 2 days of admission. DiscussionPatients requiring early steroid pulse therapy, antiepileptic drugs, and respiratory support were considered to be in poor general condition; such patients should receive aggressive intervention to avoid worse outcomes.

Disparate outcomes for Black patients following neoadjuvant chemoradiation for rectal cancer are multifactorial in origin.

21 Background: Studies have shown that Black patients receiving chemoradiation (CRT) for locally advanced rectal cancer (LARC) have achieved clinical outcomes less satisfactory than those achieved by other racial groups, but the source of this disparity is poorly understood. This study investigated the demographic, geographic, socioeconomic, and clinical factors that underlie this disparity. Methods: We interrogated the National Cancer Database from 2004-2017 to identify patients with T3-T4 or N > 0 LARC treated with CRT prior to surgery. Response to CRT was determined by the rates of pathologic complete response (pCR) and tumor downstaging after treatment. Univariate analysis (UVA) was performed with chi-square and Fisher’s exact tests. Multivariate analysis (MVA) was then used to identify independent factors associated with improved pCR. Results: A total of 37,783 patient records were reviewed for the study (7.8% Black, 86.0% White, 6.1% Other). Black patients were younger (p < 0.0001), more often female (p < 0.0001), and more likely to live in metropolitan areas (p < 0.0001). LARC in Black patients was diagnosed at a higher clinical stage (p = 0.0007) and was more often treated with abdominoperineal resection in preference to low anterior resection (p < 0.0001). Black patients were more often uninsured or covered by Medicaid (p < 0.0001) and less often covered by commercial insurance (p < .0001). UVA demonstrated that Black patients achieved pCR and tumor downstaging at lower rates than White patients (11.6% vs 14.5%; 46.9% vs 51.8%, both p < 0.0001). On MVA, Black race (OR 0.8015, 95%CI 0.7101-0.9047), a rural location (OR 0.8211, 95% CI 0.7082-0.952), absence of commercial medical insurance (Medicaid OR 0.8394 95% CI 0.7456-0.9449; Medicare OR 0.8989 95% CI 0.8226-0.9823; No Insurance OR 0.6107 95% CI 0.5103-0.7309), and higher tumor grade and stage remained independent risk factors for a lower pCR. Additional significant unfavorable prognostic factors for pCR included younger age, male sex, lower hospital treatment volume, and higher tumor grade or stage. Similarly, Black race, lower hospital treatment volume, absence of commercial medical insurance, and higher grade or stage were significant unfavorable prognostic factors for downstaging. Neither lower income nor fewer years of education was associated with pCR or tumor downstaging. Conclusions: The results confirm a lower rate of response to CRT in Black patients with LARC. The identification of race as an independent risk factor after adjustment for sociodemographic, geographic, and clinical factors suggests that other unknown variables–including genetic differences unaddressed in this study–must be pursued comprehensively in future studies. The more advanced stage of rectal cancers in Black patients suggests that critical evaluation of current cancer screening methods may play a role in this effort.

P1574: ANTINEOPLASTIC THERAPY FOR HEMATOLOGIC MALIGNANCIES DURING COVID-19

Background: During the COVID-19 pandemic patients with hematologic malignancies frequently have to interrupt specific antineoplastic therapy as a result of a positive SARS-COV-2 RNA PCR result and for evidence of viral pneumonia on chest CT. However, delaying or withholding specific therapy for significant time may cause progression of a hematologic malignancy and increase the risks of tumor resistance. Aims: Analyze in-hospital overall survival and causes of death in COVID-19 patients during specific therapy for hematologic malignancies. Methods: During the period of March 2020 – November 2021, 192 patients with hematologic malignancies having coronavirus infection underwent specific antineoplastic therapy at the hematology unit of Moscow clinical hospital #52. We analyzed in-hospital overall survival and the causes of death, depending on the disease entity of a hematologic malignancy, disease status, patients’ age, Charlson comorbidity index and the intensity of specific antineoplastic therapy. The study included 93 patients with acute leukemias, 51 patients with non-Hodgkin’s lymphoma, 30 patients with chronic lymphocytic leukemia and 18 patients with multiple myeloma. Median age was 55 years (19-92 years). Results: In the acute leukemias group mortality was 25-82%, depending on the disease entity, disease status, age and intensity of the antineoplastic treatment. The most significant unfavorable prognostic factors were as follows: lack of acute leukemia remission (p=0.003), age above 65 years (p=0.002), Charlson comorbidity index > 6 (p<0,001). Infectious complications (24%) and severe coronavirus disease (60%) were the main causes of death in the acute leukemias group. In the group of patients who received chemotherapy for acute leukemia according to standard treatment protocols the rate of remission was higher, mortality was the lowest, and the risk of severe coronavirus disease was lower compared to patients who received specific antineoplastic therapy of lower intensity. In the non-Hodgkin’s lymphoma group mortality was 30%. In 90% cases of death patients had no remission of their underlying disease. Among the causes of death, the most common were lymphoma progression (46%) and severe COVID-19 (47%). In the chronic lymphocytic leukemia and multiple myeloma group in-hospital mortality was 27% and 17% respectively, and in 100% cases deaths were caused by severe coronavirus disease. Summary/Conclusion: The main risk factor for severe COVID-19 and death in patients with hematologic malignancies was lack of remission of the underlying disease. Therefore, specific antineoplastic therapy results in control over the neoplastic process, eventually reducing the risk of severe COVID-19. However, individual approach must be applied in the selection of antineoplastic treatment and its timing, and in evaluating the risks of coronavirus infection reactivation during immunosuppressive therapy.

Poor prognosis of patients with severe COVID-19 admitted to an infectious disease intensive care unit during the pandemic caused by the Delta variant in Japan.

During the surge of coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) delta variant, our institution operated an intensive care unit (ICU) for patients with severe COVID-19. The study aim was to determine the survival rate and treatment outcomes of patients with severe COVID-19 treated in the ICU during the surge. A total of 23 consecutive patients with severe COVID-19 were admitted to the ICU between August 5 and October 6, 2021. Patients received multidrug therapy consisting of remdesivir, tocilizumab, heparin, and methylprednisolone. The patients were divided into two groups based on the ordinal scale (OS): a non-invasive oxygen therapy (OS-6) group, and an invasive oxygen therapy (OS-7) group. There were 13 (57%) and 10 (43%) patients in the OS-7 and OS-6 groups, respectively. All patients were unvaccinated. Sixteen patients (70%) were male. The median age was 53 years; the median body mass index (BMI) was 30.3 kg/m2; and the median P/F ratio on admission was 96. The 30-day survival rate was 69% and was significantly poorer in the OS-7 group (54%) than in the OS-6 group (89%; p = 0.05). The prevalence of obesity (p = 0.05) and the Sequential Organ Failure Assessment (SOFA) score on admission (p < 0.01) were significantly higher in the OS-7 group. Seven patients in the OS-7 group (54%) developed bacteremia. A low P/F ratio on admission was a significant unfavorable prognostic factor (hazard ratio: 10.9; p = 0.03). The survival rate was poor, especially in patients requiring invasive oxygen therapy. More measures are needed to improve the treatment outcomes of patients with severe COVID 19.

The prognostic significance of neuroendocrine markers and somatostatin receptor 2 in hepatocellular carcinoma.

Prostatic and colon carcinomas with neuroendocrine differentiation are reported to behave more aggressively than those without such differentiation. In hepatocellular carcinomas (HCCs), however, only a few studies have reported the expression status of neuroendocrine markers and somatostatin receptor 2, the main target of a somatostatin analog. Furthermore, the prognostic significance of the markers in HCCs has not been fully explored. We evaluated the expression of the neuroendocrine makers (chromogranin A, synaptophysin, and CD56) and somatostatin receptor 2 (SSTR2) in 95 HCCs, and investigated the correlation between the expression of these markers and clinicopathological findings. Chromogranin A was immunolocalized in 2 cases, synaptophysin in 15 cases, CD56 in 11 cases, and SSTR2 in 19 cases. Immunoreactivity of synaptophysin and CD56 were the significant unfavorable prognostic factors in terms of 2-year disease-free survival (DFS) and the overall survival (OS) along with a high nuclear mitosis level (>10/10 high-power field), a larger tumor size (>5 cm), the presence of vascular and/or biliary invasion, and high TNM stage (III/IV). Multivariate Cox proportional hazards analysis identified synaptophysin as an independent prognostic factor for 2-year DFS and OS. Synaptophysin expression can be used to predict an unfavorable prognosis in patients with HCC.

Efficacy of EDP ± mitotane chemotherapy in the treatment of metastatic adrenocortical carcinoma. Predictive and prognostic factors of efficacy

Introduction. Adrenocortical carcinoma (ACC) is an orphan disease with an unfavorable prognosis. The most effective therapeutic option in the treatment of ACC is EDP plus mitotane combination chemotherapy. However, no studies comparing the efficacy of the EDP regimen with or without mitotane have been published.Materials and methods. A retrospective analysis of health records of patients with histologically confirmed metastatic ACC, who received at least one chemotherapy cycle with EDP ± mitotane. The study included 73 patients, 49 of which received a combination of EDP and mitotane and 24 were treated with EDP chemotherapy.Results. The objective response rate was 18,4 % in the EDP + mitotane group versus 4,1 % in the EDP group. Disease control was reported in 25 (51 %) and 13 (54,2 %) patients, respectively. No significant differences were found in progression-free survival (PFS) rates between the EDP and EDP + mitotane groups; the median PFS rate was 6,5 and 6,0 months, respectively. The median overall survival (OS) in the total population was 20,9 months; no significant differences were found between the groups. However, an increase in median PFS was observed in patients who achieved a therapeutic concentration of mitotane. Moreover, the achievement of therapeutic mitotane concentrations was the only factor significantly associated with improved PFS (HR 0.44, p = 0.006). Significant unfavorable prognostic factors associated with lower OS were Ki-67 level in the primary tumor &gt; 20 % (HR 10.5, p = 0.006) and more than 1 site of metastases (HR 3.82, p = 0.02).Conclusions. This study showed that the addition of mitotane to EDP chemotherapy does not improve the median PFS and OS in the total patient population, however, the achievement of therapeutic mitotane concentrations is significantly associated with improved progression-free survival.

A Retrospective Multicenter Analysis of the Safety and Efficacy of Brentuximab Vedotin (BV) As Monotherapy or in Combination with Bendamustine (BV-B) in Relapsed Refractory Classic Hodgkin Lymphoma (cHL) in Argentina

TITLE: A retrospective multicenter analysis of the safety and efficacy of Brentuximab Vedotin (BV) as monotherapy or in combination with Bendamustine (BV-B) in relapsed refractory Classic Hodgkin Lymphoma (cHL) in Argentina.PURPOSE: We performed a retrospective multicenter study in Argentina to collect information on patients (pts) with relapsed refractory cHL treated with BV as monotherapy or with its combination with BV-B. All patients that received either therapy were included with no exclusion criteria. The primary endpoint was response rate and EFS. Toxicity and OS were secondary end points. PATIENTS AND METHODS: Between 8/2011 and 2/2017, 112 pts met inclusion criteria, 93 had complete data and were evaluable for response, among these 71 pts received BV as monotherapy and 22 with BV-B. Median age for all pts was 29 (range 16-73).RESULTS: All 112 pts were evaluable for toxicity. In the group of 78 pts treated with BV 46 (59%) presented at least one adverse events (AE). With 13 (17%) of AE grade III-IV (4 grade IV peripheral neuropathy, 7 grade III-IV infections and 3 grade III neutropenia). In the group of 34 pts treated with BV-B, 17 (50%) had some AE, 11 pts (32%) presented grade III-IV AE: 2 peripheral neuropathy, 1 grade IV infection and 4 (12%) pts with SNC AE (1 seizures, 2 aseptic meningitis and 1 encephalopathy).With a median follow up of 13 months, pts treated with BV had a PFS of 41% and an OS of 75% at 1 yr. The outcome was better for those pts who achieved a CR, with a PFS of 80% and an OS 95%.In a multivariate analysis for obtaining CR after BV, considering: Bulky disease, 2 vs > 2 lines of prior treatment and primary refractory/early relapse vs late relapse, the only significant unfavorable prognostic factors was being primary refractory/first relapse within the first year (P=0.019).For the group of pts with BV-B the PFS was 42% with an OS of 95%, and 62% and 100% for those in CR.CONCLUSIONS: This is the first and only retrospective multicenter trial showing the Argentine experience with Brentuximab. Our findings add to the growing body of evidence supporting the efficacy of Bv as monotherapy and the high ORR and CR of the combination of Bv-B, and warrant a confirmatory randomized trial to re-examine the efficacy and toxicity of this drug combination over BV as monotherapy. [Display omitted] DisclosuresShanley:Gador: Speakers Bureau. Pavlovsky:Janssen: Honoraria, Speakers Bureau. Riveros:Janssen: Consultancy, Speakers Bureau; Raffo: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Pavlovsky:TAKEDA: Speakers Bureau.

Long-term results of fluorescence and indigo carmine blue dye-navigated sentinel lymph node biopsy.

Sentinel lymph node biopsy is widely applied for the management of clinically node-negative breast cancer, and a radioisotope with a blue dye are most often used as tracers. Fluorescence of indocyanine green could also potentially be used as tracer. This study aimed to demonstrate the long-term survival results of fluorescence-guided sentinel lymph node biopsy. Patients with clinically node-negative breast cancer who underwent surgery as initial treatment were included in this study. Both fluorescence of indocyanine green and indigo carmine blue dye were used as tracers. Axillary lymph node dissection was omitted unless metastasis was pathologically proven in sentinel nodes. Breast cancer recurrence and death were recorded and prognostic factors were identified using disease-free survival and overall survival data. A total of 565 patients were analyzed. There were 14 (2.5%) patients whose sentinel nodes could not be identified, yielding an identification rate of 97.5%. Axillary dissection was performed in 90 patients. Forty-three recurrences including 6 ipsilateral axilla recurrence and 13 deaths were observed during the median 83months of follow-up period. Seven-year disease-free and overall survival were 92.4% and 97.3%, respectively. Multivariate analyses demonstrated that pre-menopausal status and invasive lobular carcinoma were significant unfavorable prognostic factors of disease-free survival. Half of ipsilateral axilla recurrences occurred within 5years after surgery and these recurrences were correlated with inappropriate adjuvant therapy. Fluorescence-guided sentinel lymph node biopsy demonstrated favorable prognostic results and could be alternative to the radioisotope for clinically node-negative breast cancer.

Prognostic Value of Hepatitis B Virus Infection in Very Young Patients With Curatively Resected Breast Cancer: Analyses From an Endemic Area in China.

Background: Hepatitis B virus (HBV) infection has been associated with the risk and prognosis of many malignancies. Nevertheless, the association between HBV and the prognosis of breast cancer is unclear. The objectives of this study were to investigate the prognostic role of hepatitis B surface antigen (HBsAg) and to integrate HBsAg to establish nomograms for better prognostic prediction of very young patients with breast cancer.Methods: This analysis was performed retrospectively in a cohort of 1,012 consecutive very young (≤35 at diagnosis) patients who received curative resection for breast cancer. The significance of HBsAg in the prognosis of these patients was investigated. Univariate and multivariate analyses were used to identify independent variables for disease-free survival (DFS) and overall survival (OS). Nomograms were built based on those identified variables.Results: Overall, 140 of the 1,012 patients (13.8%) were seropositive for HBsAg. The median follow-up was 67.9 (95% CI, 64.4–71.4) months for the entire population. The HBsAg-positive cohort had significantly inferior DFS (HR, 1.66; 95% CI, 1.07–2.56; P = 0.021) and OS (HR, 1.75; 95% CI, 1.10–2.79; P = 0.016) as compared with the HBsAg-negative cohort. The rates of 10-year DFS and OS were 77.4 and 73.0% in the HBsAg-positive group and 84.1 and 85.6% in the HBsAg-negative group, respectively. In multivariable analysis, HBsAg status was identified as an independent significant unfavorable prognostic factor for DFS (P = 0.01) and OS (P = 0.04) in very young patients with breast cancer. Nomograms were established and displayed good calibration and acceptable discrimination. The C-index values for DFS and OS were 0.656 (95% CI: 0.620–0.691) and 0.738 (95% CI: 0.697–0.779), respectively. Based on the total prognostic scores (TPS) of the nomograms, 3 different prognosis groups were identified for DFS and OS.Conclusions: HBsAg is an independent unfavorable prognostic factor for DFS and OS in very young patients with curatively resected breast cancer, and nomograms integrating HBsAg provide individual survival prediction to benefit prognosis evaluation and individualized therapy.

Surgical extent and role of adjuvant radiotherapy of surgically resectable, low-grade parotid cancer.

Due to the rarity of low-grade parotid gland cancer and the diversity of histologic subtype, its optimal treatment modalities and prognostic factors have not been established yet. In this study, we aimed to identify the prognostic factors and adequate treatment modalities for patients with low-grade parotid gland cancer. We retrospectively analyzed clinico-pathologic data from 287 patients with low-grade parotid gland cancer from 1999 to 2018. Recurrence-free survival, disease-specific survival, and overall survival rates at 10years were 80.6%, 93.9%, and 84.4%, respectively. Among all patients, 56.1% received surgery alone, and the remaining 43.9% received surgery with adjuvant radiotherapy. Resection margin status and TNM stage were significant unfavorable prognostic factors. In patients with T1-2 tumor, surgical extent (total vs. less-than-total) did not show any significant effect on disease recurrence and patients' survival, and the disease was controlled well if a negative surgical margin was obtained after surgery, even with microscopic clear margin of<1mm. In patients with adverse pathologic features (positive margin, lymphovascular invasion, perineural invasion, extracapsular nodal spread, T3-4, and N1-3), adjuvant radiotherapy significantly decreased loco-regional recurrence. Oncological outcomes were good in patients with low-grade parotid gland cancer with surgery and radiotherapy. In patients with T1-2 low-grade parotid gland cancer, surgery alone showed good local control rate regardless of the extent of surgery, if a negative surgical margin was obtained after surgery. Adjuvant radiotherapy played a significant role in controlling loco-regional recurrence in patients with adverse pathologic features.

Prognostic Factors Among Children With Acute Encephalitis/Encephalopathy Associated With Viral and Other Pathogens.

Acute encephalitis/encephalopathy (AE) associated with viral and other pathogens leads to neurological sequelae and mortality. Knowing the prognostic factors is therefore important for immediate interventions. We examined early-phase unfavorable prognostic factors among children with AE using a nationwide database. We performed a retrospective cohort study using the Diagnosis Procedure Combination database, which includes approximately half of acute-care inpatients across Japan. We enrolled children aged ≤ 18 years who were hospitalized for AE and discharged from April 2010 to March 2018. The composite unfavorable outcome included the following at discharge: in-hospital death, tracheostomy, enteral tube feeding, and physical rehabilitation. Unfavorable prognostic factors were assessed using a multivariable Poisson regression model including patient characteristics, associated pathogens, and interventions within 2 days of admission adjusting for within-hospital clustering. This study included 9386 children with AE (median age, 3 years). A total of 241 (2.6%) in-hospital deaths occurred, and 2027 (21.6%) patients had the composite unfavorable outcome. Significant unfavorable prognostic factors were age 12-18 years, congenital anomalies, epilepsy, and Japan Coma Scale score of 100-300 at admission (ie, worse levels of consciousness). In contrast, herpes simplex virus infection and influenza virus infection were associated with favorable outcomes. We identified early-phase (within 2 days of admission) unfavorable prognostic factors among children with AE. These findings will help identify patients who may benefit from early aggressive therapeutic interventions.

Nrf2 expression in surgically resected lung adenocarcinomas: Its association with clinicopathologic features and driver oncogene alterations

Abstract Background Nrf2 is a transcription factor associated with cancer growth and chemotherapy resistance. Nrf2 expression levels may be associated with prognosis of lung cancer, but previous results have been inconsistent. Methods The expression of Nrf2 in 1037 surgically resected lung adenocarcinoma (LAD) specimens was evaluated by immunohistochemistry. Nrf2 positivity was defined based on the intensity of stained nucleus of tumor cells on the tissue microarray: negative, weakly positive and strongly positive. The correlations between the Nrf2 expression and the prognosis, clinicopathological features and driver oncogene alterations were analyzed. Results The Nrf2 expression was negative in 236 (23%) of 1037 tumors, weakly positive in 444 (43%) and strongly positive in 357 (34%). The proportion of Nrf2-positive tumors was significantly higher in patients with pathological stage I (81%), tumors with EGFR mutations (87%) or KRAS mutations (87%), tumors without ALK fusions (78%) or ROS1 fusions (78%). The Nrf2 expression was not associated with the age, gender and smoking status. In multivariate analysis (Logistic regression model), pathological stage I, positive EGFR or KRAS mutation status were significant predictors of Nrf2 positivity. The increased expression of Nrf2 was associated with longer overall survival regardless of driver oncogene status. In multivariate analysis (Cox proportional hazards model), advanced age, male gender, advanced pathological stage and negative EGFR mutation status were significant unfavorable prognostic factors. Conclusions LADs that positively express Nrf2 have unique clinicopathological features. The increased expression of Nrf2 is a favorable prognostic marker in surgically resected LAD. Legal entity responsible for the study The authors. Funding AMED. Disclosure All authors have declared no conflicts of interest.

Tumor-Associated Macrophages as Potential Prognostic Biomarkers of Invasive Breast Cancer.

PurposeTumor-associated macrophages (TAMs) are activated macrophages associated with tumor progression in various cancers. TAMs can polarize M1 or M2 type. M1 has a pro-inflammatory function and kills pathogens. Conversely, M2 shows immunosuppressive action and promotes tumor growth. There are various markers of TAMs. CD11c is considered as a specific marker of M1. CD163 is an optimal marker for M2. CD68 is known as a pan-macrophage marker. We evaluated the relationship between the clinicopathological parameters and immunohistochemical expressions of CD11c, CD163, and CD68 in invasive breast cancer (IBC), and the prognostic value of macrophage localization within the tumor stroma (TS) and tumor nest (TN).MethodsImmunohistochemistry of CD68, CD11c, and CD163 was analyzed on tissue microarrays of 367 IBCs. The number of CD68+, CD11c+, or CD163+ macrophages in TN vs. TS was counted by 2 pathologists. The correlations between the degree of macrophage (CD68+, CD11c+, or CD163+) infiltration and the clinicopathological parameters were analyzed. We also assessed the impact of macrophages (CD68+, CD11c+, or CD163+) on disease free survival (DFS) and overall survival (OS).ResultsHigh numbers of macrophages (CD68+, CD11c+, or CD163+) were associated with higher histologic grade, higher Ki-67 proliferating index, estrogen receptor negativity, and progesterone receptor negativity. High numbers of macrophages (CD11c+ or CD163+) in TS were associated with a larger tumor size. Furthermore, CD163+ macrophages in TN were an independent prognostic marker of reduced OS and DFS. Conversely, CD11c+ macrophages in TS were an independent prognostic marker for higher OS and DFS.ConclusionTAMs, including M2 type, are associated with tumor progression in IBC. They can also act as a significant unfavorable or favorable prognostic factor. In addition to simply analyzing the degree of TAM infiltration, it is also important to analyze the location of TAMs.

ELISA study of matrix metalloproteinases 2, 7, 9 and their type 2 tissue inhibitor in the tumors of gastric cancer patients: clinical and pathologic correlations

Background: Over the last 10 years the incidence of gastric cancer has declined significantly. Nevertheless, it remains one of the most prevalent malignancies both in Russia and worldwide. Therefore, the problems of early diagnostics, prognosis and individualized treatment choice are still on the agenda. Much attention is paid to the evaluation of molecular biological characteristics of the tumor, as well as to the development of multiparametric prognostic systems for gastric cancer based on its identified characteristics. An important place among potential tumor biological markers belongs to matrix metalloproteinases (MMPs) involved into all the stages of tumor progression, first of all, into the regulation of invasion and metastasizing.Aim: Comparative quantitative evaluation of some MMP family members (MMP-2, 7, and 9) and one of the tissue MMP inhibitors (TIMP-2) levels in the tumors and adjacent histologically unchanged mucosa in gastric cancer patients, the analysis of their associations with the main clinical and pathological features of the disease and its prognosis.Materials and methods: Sixty six (66) primary gastric cancer patients (32 male and 34 female) aged 24 to 82 years (median, 61 year) were recruited into the study. Twenty two (22) patients were with stage I of the disease, 11 with stage II, 28 with stage III, and 5 with stage IV. The concentrations of the proteins studied were measured in the tumor and unchanged mucosa extracts by standard direct ELISA kits (Quantikine®, R&amp;D Systems, USA).Results: Tumor MMP-2, 7 and 9 levels were significantly increased, compared to those in the adjacent histologically unchanged mucosa, in 80, 70 and 72% of gastric cancer patients, respectively, while the increase of TIMP-2 level found in 61% of the tumors was not statistically significant. Tumor MMP-2 and TIMP-2 content was increasing significantly with higher T index – size and advancement of the primary tumor (p &lt; 0.01 and p &lt; 0.05 respectively). Tumor MMP-2 level was also increasing in parallel with the N index (regional lymph node involvement; p &lt; 0.01); it was significantly higher in the patients with distant metastases than in those without them (p &lt; 0.05). Tumor MMP-9 and MMP-7 concentrations were not significantly associated with the indices of the tumor progression. The patients were followed up for 1 to 85 months (median, 18.3 months). According to the univariate analysis, high (&gt; 32.6 ng/mg protein) MMP-2 and low MMP-7 (&lt; 1.1 ng/mg protein) levels in the gastric cancer tissue represent statistically significant unfavorable prognostic factors for overall survival. Increased TIMP-2 level is associated with a non-significant decrease in the overall survival (p &gt; 0.05), whereas the MMP-9 level was unrelated to the gastric cancer prognosis. Only T index (p = 0.0034) and tumor MMP-7 content (p = 0.026) remained independent prognostic factors in the multivariate regression analysis.Conclusion: The majority of gastric cancer patients demonstrate a significant increase in the expression of three MMP family members, i.e. gelatinases (MMP-2 and 9), and matrilysin (MMP-7), in the tumors, as compared to adjacent histologically unchanged mucosa. Only MMP-2 levels were associated with the disease progression, increasing with higher TNM system indices. High MMP-2 and low MMP-7 content in the gastric cancer tissue are significant unfavorable prognostic factors for the overall survival in the univariate analysis, but only MMP-7 has retained its independent prognostic value in the multivariate assessment.

Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer.

The prognosis of biliary tract cancer (BTC) is unfavorable due to its chemoresistance. Hypoxia triggers epithelial-to-mesenchymal transition (EMT), which is closely related to drug resistance. In this study, we focused on the functional roles of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a hypoxia-induced gene, in BTC, and assessed the clinical significance of PLOD2. The expression of PLOD2 under hypoxia was assessed in BTC cell lines. Gemcitabine-resistant (GR) BTC cell lines were transfected with small interfering RNA (siRNA) against PLOD2, and EMT markers and chemoresistance were evaluated. PLOD2 expression was also characterized using immunohistochemistry in BTC clinical specimens following resection. Patient survival was analyzed and the role of PLOD2 expression was examined. The expression of PLOD2 was induced by hypoxia in vitro and was upregulated in BTC-GR cell lines, which had low expression of epithelial markers and high expression of mesenchymal markers. Downregulation of PLOD2 by siRNA resulted in improved chemoresistance, recovery of epithelial markers, and reduction of mesenchymal markers. In the resected BTC samples, PLOD2 expression was significantly correlated with lymph node metastasis (p = 0.037) and stage (p = 0.001). Recurrence-free survival (p = 0.011) and overall survival (p < 0.001) rates were significantly lower in patients with high expression of PLOD2. PLOD2 expression was an independent prognostic factor for overall survival (p = 0.019). The expression of PLOD2 influenced chemoresistance through EMT, and high expression of PLOD2 was a significant unfavorable prognostic factor in BTC patients. PLOD2 might be a potential therapeutic target for overcoming chemoresistance.

Pre-operative Plasma miR-21-5p Is a Sensitive Biomarker and Independent Prognostic Factor in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Surgical Resection.

Blood plasma microRNAs (miRNAs) are emerging as a clinically useful tool for non-invasive detection and prognosis estimation in various cancer types including pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to provide an independent validation of circulating miRNAs identified in previous studies as diagnostic and/or prognostic biomarkers in PDAC. Based on the literature search, 6 miRNAs were chosen as candidates for independent validation; miR-21-5p, miR-375, miR-155, miR-17-5p, miR-126-5p and miR-1290. Validation of these miRNAs was performed in a cohort of 25 patients with PDAC undergoing surgical resection and 24 healthy donors. Plasma levels of miRNAs were determined using quantitative real-time PCR. We confirmed significantly higher levels of all tested miRNA in blood plasma of PDAC patients in comparison to healthy controls with miR-21-5p showing the highest analytical performance (p<0.001; AUC>0.99). Increased levels of miR-21-5p (p=0.045) and miR-375 (p=0.013) were significantly associated with overall survival. Multivariate analysis demonstrated that miR-21-5p is a significant unfavorable prognostic factor independent on other clinical variables including adjuvant chemotherapy (hazard ratio 2.95; 95% CI 1.06-8.18; p=0.038). Our preliminary data indicate promising diagnostic and prognostic utility of plasma miR-21-5p in PDAC patients.

Expression and localization of CHI3L1 in monocyte derived dendritic cells

Chitinase-3-like-1 protein (CHI3L1) also called YKL-40, is a 40 kDa mammalian glycoprotein which is a heparin, chitin and collagen binding member of the mammalian chitinase-like proteins. Biological activities of CHI3L1 embrace regulation of cell proliferation, adhesion, angiogenesis, migration and activation. CHI3L1 is produced by variety of cells, including neutrophils, monocytes/macrophages, osteoclasts and Kupffer cells [1]. CHI3L1 secretion is induced by interferon (INF)-g and interleukin (IL)-6 and is an acute phase reactant associated with disease severity and mortality in a variety of infectious [2]. In this study, we have examined the expression and localization of CHI3L1 during the differentiation and maturation of monocyte derived dendritic cells by real time RT-PCR, Western Blot, Confocal Immunofluorescence, and Immunocytochemical assays. Potential nuclear localization signal (NLS) was determinated using the open source software cNLS Mapper and Chimera. Peripheral blood monocytes were differentiated toward immature DCs (iDC) and mature DCs (mDCs) through a combination of factors and cytokines. Our result showed, for the first time, that CHI3L1 is expressed during the process of differentiation and maturation of DCs in time dependent manner. Furthermore, CHI3L1 is evenly distributed in cytoplasm and in the nucleus of both the iDCs and mDCs. In conclusion, the discovery of CHI3L1 expression in DCs has opened new dilemma for designing DC-based cancer immunotherapeutic. In fact, on the light of these results one can’t exclude that as well as activated Tumor-associated macrophages (TAMs) also DCs infiltration could to be a significant unfavorable prognostic factor for cancer patients.

Elective nodal irradiation is not necessary in chemoradiotherapy for postoperative loco-regional recurrent esophageal cancer.

The purposes of the present study were to evaluate prognostic factors for patients with postoperative loco-regional recurrent esophageal cancer treated with chemoradiotherapy by multivariate analysis and to determine which irradiation is better, involved field irradiation or elective nodal irradiation, by matched-pair analysis. We reviewed records for 80 patients with postoperative loco-regional recurrent esophageal cancer treated by chemoradiotherapy between 2000 and 2014. The median follow-up period was 62.0 months. Thirty-one cases were treated with elective nodal irradiation and were randomly matched by risk factors to 49 cases treated with involved field irradiation (1:1). Fifty-one patients had disease recurrence again, and irradiated-field failure was observed in 26 patients. The 5-year overall survival rate was 30.5% with a median survival period of 26.5 months. Grade 3 or higher late toxicity was observed in only one patient. In multivariate analysis, short disease-free interval and anastomotic recurrence were statistically significant unfavorable prognostic factors for overall survival (hazard ratios: 2.1 and 2.5, respectively). Matched-pair analysis including disease-free interval, pattern of recurrence and number of recurrent regions revealed that overall survival rate and irradiated-field control rate in patients treated with involved field irradiation were significantly better than those in patients treated with elective nodal irradiation (P = 0.016 and P = 0.014, respectively). Short disease-free interval and anastomotic recurrence are unfavorable factors and elective nodal irradiation is not necessary in chemoradiotherapy for patients with postoperative loco-regional recurrent esophageal cancer.