IDH1/IDH2 Mutations Define the Prognosis and Molecular Profiles of Patients with Gliomas: A Meta-Analysis

Background

Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed.

Methodology and Principal Findings

An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25–0.42) and 0.38 (95% CI: 0.21–0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome.

Conclusion

Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.     

人脑胶质瘤中的IDH1/2突变

胶质母细胞瘤的基因组突变分析中发现的异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH1)突变对胶质瘤的认识具有突破性意义。随后,在胶质瘤中发现了IDH1的R132碱基和IDH2的R172碱基突变。IDH1突变较多的发生在WHOII-III级胶质瘤和继发胶质母细胞瘤中。这种突变改变了异柠檬酸脱氢酶的结构,从而使将异柠檬酸转化为a-酮戊二酸的能力丧失,而获得将a-酮戊二酸转化为2-羟基戊二酸这一新的酶活性。在临床中,IDH1和IDH2突变已经显示对胶质瘤患者有诊断和预后意义。同时,现今也发展了一些检测方法。     

MGMT Promoter Methylation Correlates with an Overall Survival Benefit in Chinese High-Grade Glioblastoma Patients Treated with Radiotherapy and Alkylating Agent-Based Chemotherapy: A Single-Institution Study

Promoter methylation of the O⁶-methylguanine-DNA-methyltransferase (MGMT) gene has been considered a prognostic marker and has become more important in the treatment of glioblastoma. However, reports on the correlation between MGMT and clinical outcomes in Chinese glioblastoma patients are very scarce. In this study, quantitative methylation data were obtained by the pyrosequencing of tumor tissues from 128 GBM patients. The median overall survival (OS) was 13.1 months, with a 1-year survival of 45.3%. The pyrosequencing data were reproducible based on archived samples yielding data for all glioblastomas. MGMT promoter methylation was detected in 75/128 cases (58.6%), whereas 53/128 (41.4%) cases were unmethylated. Further survival analysis also revealed that methylation was an independent prognostic factor associated with prolonged OS but not with progression-free survival (PFS) (p = 0.029 and p = 0.112, respectively); the hazard radios were 0.63 (95% CI: 0.42–0.96) and 0.72 (95% CI: 0.48–1.09), respectively. These data indicated that MGMT methylation has prognostic significance in patients with newly diagnosed high-grade glioblastoma undergoing alkylating agent-based chemotherapy after surgical resection.     

The Frequency and Clinical Significance of IDH1 Mutations in Chinese Acute Myeloid Leukemia Patients

Objective

Mutations in the gene encoding isocitrate dehydrogenease 1 (IDH1) occur in various hematopoietic tumors including acute myeloid leukemia (AML), myeloproliferative neoplasms and myelodysplastic syndromes. IDH1 mutations are significant in both diagnosis and prognosis of these conditions. In the present study we determined the prevalence and clinical significance of IDH1 mutations in 349 samples from newly diagnosed AML patients.

Results

Of the 349 AML patient specimens analyzed, 35 (10.03%) were found to have IDH1 mutations including 4 IDH1 R132 mutations and 31 non-R132 mutations. IDH1 non-R132 mutations were largely concentrated within AML-M₁ (35.72%, p<0.01). We identified five IDH1 mutations that were novel to AML: (1) c.299 G>A, p.R100Q; (2) c.311G>T, p.G104V; (3) c.322T>C, p.F108L; (4) c.356G>A, p.R119Q; and (5) c.388A>G, p.I130V. In addition, we identified three IDH1 mutations that were previously described in AML. The frequency of IDH1 mutations in AML patients with normal karyotype was 9.9%. IDH1 non-R132 mutations were concurrent with mutations in FLT3-ITD (p<0.01), CEBPA (p<0.01), and NRAS (p<0.01), as well as the overexpression of MN1 (p<0.01) and WT1(p<0.01). The overall survival (OS) in the patients with IDH1 non-R132 mutations compared to patients without IDH1 mutations don''t reach statistically significance (median 521 days vs median: not reached; n.s.).

Conclusion

IDH1 non-R132 mutations occurred frequently in newly diagnosed adult Chinese AML patients, and these mutations were associated with genetic alterations. The OS was not influenced by IDH1 non-R132 mutations in the present study.     

ASXL1 but Not TET2 Mutations Adversely Impact Overall Survival of Patients Suffering Systemic Mastocytosis with Associated Clonal Hematologic Non-Mast-Cell Diseases

Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) is a rare and heterogeneous subtype of SM and few studies on this specific entity have been reported. Sixty two patients with Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) were presented. Myeloid AHNMD was the most frequent (82%) cases. This subset of patients were older, had more cutaneous lesions, splenomegaly, liver enlargement, ascites; lower bone mineral density and hemoglobin levels and higher tryptase level than lymphoid AHNMD. Defects in KIT, TET2, ASXL1 and CBL were positive in 87%, 27%, 14%, and 11% of cases respectively. The overall survival of patients with SM-AHNMD was 85.2 months. Within the myeloid group, SM-MPN fared better than SM-MDS or SM-AML (p = 0.044,). In univariate analysis, the presence of C-findings, the AHNMD subtypes (SM-MDS/CMML/AML versus SM-MPN/hypereosinophilia) (p = 0.044), Neutropenia (p = 0.015), high monocyte level (p = 0.015) and the presence of ASXL1 mutation had detrimental effects on OS (p = 0.007). In multivariate analysis and penalized Cox model, only the presence of ASXL1 mutation remained an independent prognostic factor that negatively affected OS (p = 0.035). SM-AHNMD is heterogeneous with variable prognosis according to the type of the AHNMD. ASXL1 is mutated in a subset of myeloid AHNMD and adversely impact on OS.     

IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy

Isocitrate dehydrogenase 1 and 2 (IDH1/2) are enzymes recurrently mutated in various types of cancer, including glioma, cholangiocarcinoma, chondrosarcoma, and acute myeloid leukemia. Mutant IDH1/2 induce a block in differentiation and thereby contribute to the stemness and oncogenesis of their cells of origin. Recently, small-molecule inhibitors of mutant IDH1/2 have been Food and Drug Administration–approved for the treatment of IDH1/2-mutated acute myeloid leukemia. These inhibitors decrease the stemness of the targeted IDH1/2-mutated cancer cells and induce their differentiation to more mature cells. In this review, we elucidate the mechanisms by which mutant IDH1/2 induce a block in differentiation and the biological and clinical effects of the release into differentiation by mutant-IDH1/2 inhibitors. (J Histochem Cytochem 70:83–97, 2022)     

A Novel Nomogram for Predicting the Overall Survival in Patients with Unresectable HCC after TACE plus Hepatic Arterial Infusion Chemotherapy

Background and aimTransarterial chemoembolization combined with hepatic arterial infusion chemotherapy (TACE-HAIC) has shown encouraging efficacy in the treatment of unresectable hepatocellular carcinoma (HCC). We aimed to develop a novel nomogram to predict overall survival (OS) of patients with unresectable HCC treated with TACE-HAIC.MethodsA total of 591 patients with unresectable HCC treated with TACE-HAIC between May 2009 and September 2020 were enrolled. These patients were randomly divided into training and validation cohorts. The independent prognostic factors were identified with Cox proportional hazards model. The model's discriminative ability and accuracy were validated using concordance index (C-index), calibration plots, the area under the time-dependent receiver operating characteristic curve (AUC) and decision curve analyses (DCAs).ResultsThe median OS was 15.6 months. A nomogram was established based on these factors, including tumor size, vein invasion, extrahepatic metastasis, tumor number, alpha fetoprotein (AFP), and albumin-bilirubin (ALBI), to predict OS for patients with unresectable HCC treated with TACE-HAIC. The C-index of the nomogram were 0.717 in the training cohort and 0.724 in validation cohort. The calibration plots demonstrated good agreement between the predicted outcomes and the actual observations. The AUC values were better than those of three conventional staging systems. The results of DCA indicated that the nomogram may have clinical usefulness. The patients in the low-risk group had a longer OS than those in intermediate-risk and high-risk groups (P<0.001).ConclusionA prognostic nomogram was developed and validated to assist clinicians in accurately predicting the OS of patients with unresectable HCC after TACE-HAIC.     

The NPM1 Mutation Type Has No Impact on Survival in Cytogenetically Normal AML

NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1-mutated AML patients treated in the AMLCG99 trial. Complete remission rates, overall survival and relapse-free survival were not significantly different between patients with NPM1 type A or rare type mutations. The NPM1 mutation type does not seem to play a role in risk stratification of cytogenetically normal AML.     

Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy Improves Survival for Patients with Peritoneal Carcinomatosis from Colorectal Cancer: A Phase II Study from a Chinese Center

Background

Peritoneal carcinomatosis (PC) is a difficult clinical challenge in colorectal cancer (CRC) because conventional treatment modalities could not produce significant survival benefit, which highlights the acute need for new treatment strategies. Our previous case-control study demonstrated the potential survival advantage of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) over CRS alone. This phase II study was to further investigate the efficacy and adverse events of CRS+HIPEC for Chinese patients with CRC PC.

Methods

A total of 60 consecutive CRC PC patients underwent 63 procedures consisting of CRS+HIPEC and postoperative chemotherapy, all by a designated team focusing on this combined treatment modality. All the clinico-pathological information was systematically integrated into a prospective database. The primary end point was disease-specific overall survival (OS), and the secondary end points were perioperative safety profiles.

Results

By the most recent database update, the median follow-up was 29.9 (range 3.5–108.9) months. The peritoneal cancer index (PCI) ≤20 was in 47.0% of patients, complete cytoreductive surgery (CC0-1) was performed in 53.0% of patients. The median OS was 16.0 (95% confidence interval [CI] 12.2–19.8) months, and the 1-, 2-, 3-, and 5-year survival rates were 70.5%, 34.2%, 22.0% and 22.0%, respectively. Mortality and grades 3 to 5 morbidity rates in postoperative 30 days were 0.0% and 30.2%, respectively. Univariate analysis identified 3 parameters with significant effects on OS: PCI ≤20, CC0-1 and adjuvant chemotherapy over 6 cycles. On multivariate analysis, however, only CC0-1 and adjuvant chemotherapy ≥6 cycles were found to be independent factors for OS benefit.

Discussion

CRS+HIPEC at a specialized treatment center could improve OS for selected CRC PC patients from China, with acceptable perioperative safety.     

PTCH1 Gene Mutations in Keratocystic Odontogenic Tumors: A Study of 43 Chinese Patients and a Systematic Review

Background

The keratocystic odontogenic tumor (KCOT) is a locally aggressive cystic jaw lesion that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). PTCH1, the gene responsible for NBCCS, may play an important role in sporadic KCOTs. In this study, we analyzed and compared the distribution pattern of PTCH1 mutations in patients with sporadic and NBCCS-associated KCOTs.

Methods

We detected PTCH1 mutations in 14 patients with NBCCS-associated KCOTs and 29 patients with sporadic KCOTs by direct sequencing. In addition, five electronic databases were searched for studies detecting PTCH1 mutations in individuals with NBCCS-associated or sporadic KCOTs, published between January 1996 and June 2013 in English language.

Results

We identified 15 mutations in 11 cases with NBCCS-associated KCOTs and 19 mutations in 13 cases with sporadic KCOTs. In addition, a total of 204 PTCH1 mutations (187 mutations from 210 cases with NBCCS-associated and 17 mutations from 57 cases with sporadic KCOTs) were compiled from 78 published papers.

Conclusions

Our study indicates that mutations in transmembrane 2 (TM2) are closely related to the development of sporadic KCOTs. Moreover, for the early diagnosis of NBCCS, a genetic analysis of the PTCH1 gene should be included in the new diagnostic criteria.     

CYP2A6 Polymorphisms Associate with Outcome of S-1 Plus Oxaliplatin Chemotherapy in Chinese Gastric Cancer Patients

Gastric carcinoma is a heterogeneous malignant disease involving genetic factors. To identify predictive markers for gastric cancer treatment in Chinese patients, we evaluated the association between polymorphisms of the gene encoding cytochrome P450 2A6(CYP2A6) and outcomes of S-1 plus oxaliplatin(SOX) chemotherapy treatment. Clinical data on 60 consecutive gastric cancer patients receiving SOX regimen were collected prospectively. We sequenced all exons of CYP2A6 and a total of 22 different polymorphisms were detected in the present study. Comprehensive analyses of these genetic polymorphisms were performed to determine their association with both safety and efficacy of SOX regimen. Our results showed that polymorphisms of CYP2A6 were associated with the safety and efficacy of SOX treatment. Among them, missense mutations CYP2A6 rs60823196 and rs138978736 could be possible risk factors(P 0.05) for severe diarrhea induced by SOX, whereas CYP2A6 rs138978736 could be a conceivable predictor for overall survival of patients treated with SOX adjuvant chemotherapy. Further large-scale randomized prospective studies are warranted to confirm these findings.     

Association of Pretreatment Anemia with Pathological Response and Survival of Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: A Population-Based Study

Background

Anemia related to adjuvant chemotherapy might predict compromised survival in patients with breast cancer. The present population-based study was to investigate the correlation of pretreatment anemia with pathological response and long-term prognosis of breast cancer patients receiving neoadjuvant chemotherapy (NCT).

Methods

From 1999 to 2011, a total of 655 patients with operable or locally advanced breast cancer who underwent NCT before definitive surgery were reviewed. The patients were subdivided into anemic (baseline hemoglobin (Hb)<12.0g/dL) and non-anemic (Hb≥12.0g/dL) groups. Comparison was made between anemic and non-anemic groups concerning the rate of pathological complete response (pCR), relapse-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS). Logistic and Cox regression models were utilized to determine the predictive value of pretreatment anemia in outcomes of patients undergoing NCT.

Results

166 women (25.3%) were anemic before treatment. Patients in the anemic group were less likely to achieve pCR in NCT than their non-anemic counterparts (odds ratio (OR) 0.428, 95% confidence interval (CI) 0.198–0.927, p = 0.031). Patients with baseline anemia displayed inferior 10-year RFS (59.1% vs 66.0%, p = 0.022 by log-rank), OS (75.3% vs 90.9%, p<0.001) and CSS (82.4% vs 94.4%, p<0.001) compared with those without. After adjustment for confounders, pretreatment anemia was demonstrated to correlate with elevated risk of relapse (hazard ratio (HR) 1.453, 95% CI 1.077–1.962, p = 0.015), cancer-specific mortality (HR 2.961, 95% CI 1.679–5.222, p<0.001) and all-cause mortality (HR 2.873, 95% CI 1.757–4.699, p<0.001).

Conclusions

Pretreatment anemia was associated with worse pathological response to NCT as well as survival status in breast cancer. Further studies are warranted to identify optimal interventions and improve the prognosis of this subgroup.     

The Impact of Delayed Chemotherapy on Its Completion and Survival Outcomes in Stage II Colon Cancer Patients

Background

Delayed chemotherapy is associated with inferior survival in stage III colon and stage II/III rectal cancer patients, but similar studies have not been performed in stage II colon cancer patients. We investigate the association between delayed and incomplete chemotherapy, and the association of delayed chemotherapy with survival in stage II colon cancer patients.

Patients and Methods

Patients (age ≥66) diagnosed as stage II colon cancer and received chemotherapy from 1992 to 2005 were identified from the linked SEER–Medicare database. The association between delayed and incomplete chemotherapy was assessed using unconditional and conditional logistic regressions. Survival outcomes were assessed using stratified Cox regression based on propensity score matched samples.

Results

4,209 stage II colon cancer patients were included, of whom 73.0% had chemotherapy initiated timely (≤2 months after surgery), 14.7% had chemotherapy initiated with moderate delay (2–3 months), and 12.3% had delayed chemotherapy (≥3 months). Delayed chemotherapy was associated with not completing chemotherapy (adjusted odds ratio (OR): 1.33 (95% confidence interval: 1.11, 1.59) for moderately delayed group, adjusted OR: 2.60 (2.09, 3.24) for delayed group). Delayed chemotherapy was associated with worse survival outcomes (hazard ratio (HR): 1.75 (1.29, 2.37) for overall survival; HR: 4.23 (2.19, 8.20) for cancer-specific survival).

Conclusion

Although the benefit of chemotherapy is unclear in stage II colon cancer patients, delay in initiation of chemotherapy is associated with an incomplete chemotherapy course and poorer survival, especially cancer-specific survival. Causal inference in the association between delayed initiation of chemotherapy and inferior survival requires further investigation.     

The Impact of Hospice Care on Survival and Healthcare Costs for Patients with Lung Cancer: A National Longitudinal Population-Based Study in Taiwan

Background

The healthcare costs of cancer care are highest in the last month of life. The effect of hospice care on end-of-life (EOL) healthcare costs is not clearly understood.

Purpose

The purpose of this study was to evaluate the effect of hospice care on survival and healthcare costs for lung cancer patients in their final month of life.

Methods

We adopted Taiwan’s National Health Insurance Research Claims Database to analyze data for 3399 adult lung cancer patients who died in 1997–2011. A logistic regression analysis was performed to determine the predictors of high healthcare cost, defined as costs falling above the 90th percentile. Patients who received hospice cares were assigned to a hospice (H) group and those who did not were assigned to a non-hospice (non-H) group.

Results

The patients in the H group had a longer mean (median) survival time than those in the non-H group did (1.40 ± 1.61 y (0.86) vs. 1.10 ± 1.47 (0.61), p<0.001). The non-H group had a lower mean healthcare cost than the H group (US $1,821 ± 2,441 vs. US $1,839 ± 1,638, p<0.001). And, there were a total of 340 patients (10%) with the healthcare costs exceeding the 90th percentile (US $4,721) as the cutoff value of high cost. The non-H group had a higher risk of high cost than the H group because many more cases in the non-H group had lower costs. Moreover, the risk of high health care costs were predicted for patients who did not receive hospice care (odds ratio [OR]: 3.68, 95% confidence interval [CI]: 2.44–5.79), received chemotherapy (OR: 1.51, 95% CI: 1.18–1.96) and intubation (OR: 2.63, 95% CI: 1.64–4.16), and those who had more emergency department visits (OR: 1.78, 95% CI: 1.24–2.52), longer hospital admission in days (OR: 1.08, 95% CI: 1.07–1.09), and received radiotherapy (OR: 1.33, 95% CI: 1.00–1.78). Lower risks of high health care costs were observed in patients with low socioeconomic status (OR: 0.58, 95% CI: 0.40–0.83), or previous employment (OR: 0.66, 95% CI: 0.47–0.92). After propensity-score matching, the patients of the non-H group had a higher mean cost and a higher risk of high cost. Similar results were obtained from logistic regression analysis in propensity score-matched patients.

Conclusions

The survival of the hospice group was longer than non-H group, and patients in the non-H group were 3.74 times more likely to have high healthcare costs at EOL. The positive predictors for high health care costs were patients who did not receive hospice care, who received chemotherapy and intubation, who had more emergency department visits and longer hospital admission, and who received radiotherapy. Negative predictors were patients who had a low socioeconomic status or previous employment. The issue of how to reduce the high health care costs for patients with lung cancer in the last month of life is a challenge for policy makers and health care providers.     

Prognostic Impact of Diabetes Mellitus on Overall Survival in a Nationwide Population-Based Cohort of Patients With Pancreatic Cancer

Objective: Diabetes mellitus (DM) is a risk factor for pancreatic cancer but its prognostic impact remains controversial. We aimed to investigate the association between long-standing DM and the risk of mortality.Methods: This population-based cohort study analyzed data from the national healthcare database in Taiwan. We identified all patients diagnosed with pancreatic cancer and excluded those who were diagnosed with DM with-in 2 years of the cancer diagnosis. Eligible patients were grouped into long-standing DM (>2 years) and nondiabetic controls, and were compared for overall survival using a Cox proportional hazard model. Sensitivity tests stratified by cancer stages (as indicated by specific treatment) were performed.Results: Patients with long-standing DM were significantly older (mean age, 71.38 years versus 66.0 years; P<.0001) and had a higher Charlson comorbidity index (9.53 versus 6.78; P<.0001) and diabetes comorbidity severity index (2.38 versus 0.82; P<.0001) compared with the non-DM controls. Although the unadjusted analysis showed a higher risk of mortality in the patients with long-term DM (crude hazard ratio &lsqb;HR], 1.26; 95% confidence interval &lsqb;CI], 1.20 to 1.33; P<.0001), the association became insignificant after adjustment for age, sex, and comorbidity index (adjusted HR, 1.01; 95% CI, 0.95 to 1.06, P = .84). Subgroup analyses also showed no association between long-term DM and mortality in various subgroups stratified by cancer treatment.Conclusion: After adjusting for associated comorbidities and complications, long-standing DM per se was not an independent prognostic factor for overall survival in this nationwide population-based cohort with pancreatic cancer.Abbreviations: CCI = Charlson Comorbidity Index; CI = confidence interval; DCSI = Diabetes Complication Severity Index; DM = diabetes mellitus; HR = hazard ratio; ICD = International Classification of Diseases; NHIRD = National Health Insurance Research Database; RCIPD = Registry for Catastrophic Illness Patient Database     

Mutation Analysis of IDH1 in Paired Gliomas Revealed IDH1 Mutation Was Not Associated with Malignant Progression but Predicted Longer Survival

Recurrence and progression to higher grade lesions are characteristic behaviorsof gliomas. Though IDH1 mutation frequently occurs and is considered as an early event in gliomagenesis, little is known about its role in the recurrence and progression of gliomas. We therefore analysed IDH1 and IDH2 statusat codon 132 of IDH1 and codon 172 of IDH2 by direct sequencing and anti-IDH1-R132H immunohistochemistry in 53 paired samples and their recurrences, including 29 low- grade gliomas, 16 anaplastic gliomas and 8 Glioblastomas. IDH1/IDH2 mutation was detected in 32 primarytumors, with 25 low- grade gliomas and 6 anaplastic gliomas harboring IDH1 mutation and 1 low- grade glioma harboring IDH2 mutation. All of the paired tumors showed consistent IDH1 and IDH2 status. Patients were analyzed according to IDH1 status and tumor-related factors. Malignant progression at recurrence was noted in 22 gliomas and was not associated with IDH1 mutation. Survival analysis revealed patients with IDH1 mutated gliomas had a significantly longer progression-free survival (PFS) and overall survival (OS). In conclusion, this study demonstrated a strong tendency of IDH1/IDH2 status being consistent during progression of glioma. IDH1 mutation was not a predictive marker for malignant progression and it was a potential prognostic marker for gliomas of Chinese patients.     

Impact of Postoperative Chemoradiotherapy versus Chemotherapy Alone on Recurrence and Survival in Patients with Stage II and III Upper Rectal Cancer: A Propensity Score-Matched Analysis

Purpose

To compare the impact of postoperative chemoradiotherapy (CRT) versus adjuvant chemotherapy alone on recurrence and survival in patients with stage II and III upper rectal cancer undergoing curative resection.

Materials and Methods

From our institutional database, 190 patients who underwent primary curative resection between 2003 and 2010 for stage II or III upper rectal cancer were identified. None of the patients received preoperative CRT. Of these, 136 patients received postoperative chemotherapy alone (the CTx group) and 54 patients received postoperative CRT (the CRT group). The CRT group had poorer prognostic features (pT4, pN2, poor differentiation, or involved resection margin) compared with the CTx group. To reduce the impact of treatment selection bias on treatment outcomes, propensity score-matching analysis was used.

Results

The matched cohort consisted of 50 CRT and 50 CTx patients with a median follow-up period of 76 and 63 months, respectively. In the matched cohort, CRT resulted in an improved 5-year local control (98.0% vs. 85.2%, p = 0.024) and overall survival rate (89.9% vs. 69.8%, p = 0.021) compared with CTx. In the subgroup analysis to identify subpopulations of patients that benefit most from receiving CRT, local recurrence did not occur in patients who did not have poor prognostic features regardless of the receipt of CRT. For patients with any poor prognostic features, CRT resulted in an improved 5-year local control compared with CTx (96.4% vs. 70.7%, p = 0.013).

Conclusions

After adjusting for clinicopathologic factors by propensity score-matching, postoperative CRT was associated with improved local control and overall survival in stage II and III upper rectal cancer. Our results suggest that surgery followed by chemotherapy alone is acceptable for patients who did not have poor prognostic features, while additional radiotherapy should be given for patients who have any poor prognostic features.     

Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study

Background

Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.

Methods and Findings

Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population.Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22–1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12–1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86–1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located.

Conclusions

HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic. Please see later in the article for the Editors'' Summary.