Prognostic role of IDH mutations in gliomas: a meta-analysis of 55 observational studies

Background

IDH (Isocitrate dehydrogenase) mutations occur frequently in gliomas, but their prognostic impact has not been fully assessed. We performed a meta-analysis of the association between IDH mutations and survival in gliomas.

Methods

Pubmed and EMBASE databases were searched for studies reporting IDH mutations (IHD1/2 and IDH1) and survival in gliomas. The primary outcome was overall survival (OS); the secondary outcome was progression-free survival (PFS). Hazard ratios (HR) with 95% confidence interval (CI) were determined using the Mantel-Haenszel random-effect modeling. Funnel plot and Egger''s test were conducted to examine the risk of publication bias.

Results

Fifty-five studies (9487 patients) were included in the analysis. Fifty-four and twenty-seven studies investigated the association between IDH1/2 mutations and OS/PFS respectively in patients with glioma. The results showed that patients possessing an IDH1/2 mutation had significant advantages in OS (HR = 0.39, 95%CI: 0.34–0.45; P < 0.001) and PFS (HR = 0.42, 95% CI: 0.35–0.51; P < 0.001). Subgroup analysis showed a consistent result with pooled analysis, and patients with glioma of WHO grade III or II-III had better outcomes.

Conclusions

These findings provide further indication that patients with glioma harboring IDH mutations have improved OS and PFS, especially for patients with WHO grade III and grade II-III.     

The impact of body mass index on complication and survival in resected oesophageal cancer: a clinical-based cohort and meta-analysis

Background:

Body mass index (BMI) has been associated with the risk of oesophageal cancer. But the influence of BMI on postoperative complication and prognosis has always been controversial.

Methods:

In total, 2031 consecutive patients who underwent oesophagectomy between 1998 and 2008 were classified according to Asian-specific BMI (kg m⁻²) cutoff values. The impact of BMI on overall survival (OS) was estimated using the Kaplan–Meier method and Cox proportional hazard models. We performed a meta-analysis to examine the association of BMI with OS and postoperative complication.

Results:

Patients with higher BMI had more postoperative complication (P=0.002), such as anastomotic leakage (P=0.016) and cardiovascular diseases (P<0.001), but less incidence of chylous leakage (P=0.010). Logistic regression analysis showed that BMI (P=0.005) was a confounding factor associated with postoperative complication. Multivariate analysis showed that overweight and obese patients had a more favourable survival than normal weight patients (HR (hazard ratio) = 0.80, 95% CI (confidence interval): 0.70–0.92, P=0.001). Subgroup analysis showed that the association with higher BMI and increased OS was observed in patients with oesophageal squamous cell carcinoma (ESCC) (P<0.001), oesophageal adenocarcinoma (EA) (P=0.034), never-smoking (P=0.035), ever-smoking (P=0.035), never alcohol consumption (P=0.005), weight loss (P=0.003) and advanced pathological stage (P<0.001). The meta-analysis further corroborated that higher BMI was associated with increased complication of anastomotic leakage (RR (risk ratio)=1.04, 95% CI: 1.02–1.06, P=0.001), wound infection (RR=1.03, 95% CI: 1.00–1.05, P=0.031) and cardiovascular diseases (RR=1.02, 95% CI: 1.00–1.05, P=0.039), but decreased incidence of chylous leakage (RR=0.98, 95% CI: 0.96–0.99, P<0.001). In addition, high BMI could significantly improved OS (HR=0.78, 95% CI: 0.71–0.85, P<0.001).

Conclusion:

Preoperative BMI was an independent prognostic factor for survival, and strongly associated with postoperative complications in oesophageal cancer.     

Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients

Background:

Metastatic renal cell carcinoma (mRCC) prognostic models may be improved by incorporating treatment-induced toxicities.

Methods:

In sunitinib-treated mRCC patients (N=770), baseline prognostic factors and treatment-induced toxicities (hypertension (systolic blood pressure ⩾140 mm Hg), neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2), hand–foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points.

Results:

On-treatment neutropenia and hypertension were associated with longer PFS (P=0.0276 and P<0.0001, respectively) and OS (P=0.0014 and P<0.0001, respectively), independent of baseline prognostic factors, including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. By 12-week landmark analysis, neutropenia was significantly associated with longer PFS and OS (P=0.013 and P=0.0122, respectively) and hypertension or hand–foot syndrome with longer OS (P=0.0036 and P=0.0218, respectively). The concordance index was 0.65 (95% CI: 0.63−0.67) for IMDC classification alone and 0.72 (95% CI: 0.70−0.74) when combined with hypertension and neutropenia. Considering hypertension and neutropenia (developing both vs neither) changed IMDC-predicted median OS in each IMDC risk group (favourable: 45.3 vs 19.5 months; intermediate: 32.5 vs 8.0 months; poor: 21.1 vs 4.8 months).

Conclusions:

On-treatment neutropenia and hypertension are independent biomarkers of sunitinib efficacy and may add prognostic accuracy to the IMDC model.     

The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer

Background:

The importance of lymphocyte subtypes in determining outcome in primary operable ductal invasive breast cancer remains unclear. The aim of present study was to examine the relationship between tumour lymphocyte subsets infiltrate and standard clinico-pathological factors and survival in patients with primary operable invasive ductal breast cancer.

Methods:

The analysis of the inflammatory cell infiltrate, including lymphocyte subtypes, was undertaken using immunohistochemical techniques and visual quantitative and semi-quantitative techniques in 338 patients with ductal breast cancer.

Results:

The majority (91%) of patients had high grade inflammatory cell infiltrate. The median follow-up of the survivors was 164 months. During this period, 65 died of their cancer. On univariate analysis, tumour inflammatory cell infiltrate, macrophages infiltrate (P<0.05), lymphocytic infiltrate (P<0.001) and CD8+ T-lymphocytic infiltrate (P<0.01) were associated with improved cancer-specific survival, whereas neutrophil (P<0.05) and CD138+ B-lymphocytic infiltrate (P<0.001) were associated with poorer cancer-specific survival. On multivariate analysis, tumour lymphocytic infiltrate (P<0.001), macrophage infiltrate (P<0.05), CD8+ T-lymphocytic infiltrate (P<0.01) and CD138+ B-lymphocytic infiltrate (P<0.001) were independently associated with cancer survival. When the significant inflammatory cell types were included with tumour-based factors in multivariate analysis only tumour size (Hazard ratios (HR): 2.55, 95% confidence interval (CI): 1.53–4.27, P<0.001), Ki-67 index (HR: 2.08, 95% CI: 1.08–4.00, P<0.05), lymphovascular invasion (HR: 4.40, 95% CI: 2.07–9.35, P<0.001), macrophage infiltrate (HR: 0.49, 95% CI: 0.33–0.73, P<0.001), lymphocytic infiltrate (HR: 0.11, 95% CI: 0.05–0.23, P<0.001), CD8+ T-lymphocytic infiltrate (HR: 0.57, 95% CI: 0.38–0.87, P<0.001) and CD138+ B-lymphocytic infiltrate (HR: 2.86, 95% CI: 1.79–4.56, P<0.001) were independently associated with cancer survival.

Conclusion:

The majority of patients with invasive ductal breast cancer had high-grade inflammatory cell infiltrate. In these patients, inflammatory cells including macrophage and lymphocytic infiltrate, and subsets CD8+ T-lymphocytic infiltrate and CD138+ B-lymphocytic infiltrate had superior prognostic value, compared with hormone status and lymph node involvement in patients with primary operable invasive ductal breast cancer.     

The efficacy and safety of extended adjuvant temozolomide following concurrent radio-chemotherapy among Egyptian patients with newly diagnosed glioblastoma multiforme

Although concurrent radio-chemotherapy and adjuvant temozolomide (TMZ) treatment for 6 cycles has been established as a standard of care for newly diagnosed glioblastoma multiforme (GBM) patients, the recommended duration of adjuvant TMZ remains a matter of debate. Hereby, we aimed to report for the first time our experience from Upper Egypt through comparing survival and toxicity profile between two treatment modalities of adjuvant TMZ (> six cycles versus six cycles) and delineating factors of prognostic significance in Egyptian patients with newly diagnosed GBM treated by radiation therapy with concomitant and adjuvant TMZ. Between June 2016 and February 2018, the medical records of 121 patients were eligible to be retrospectively reviewed to extract the study relevant data. All patients received concurrent radio-chemotherapy, followed by TMZ for 6 cycles in 29 patients (Group 1) and for >6 cycles in 26 patients (Group 2). Patients in Group 1 had a median PFS of 15 months (95% CI: 10.215-19.785), while those in Group 2 had a median PFS of 18 months (95% CI: 16.611-19.389). After a median follow up duration of 20 months (range: 12-41), the median OS was 18 months (95% CI: 13.420-22.580) in Group 1 and 22 months (95% CI: 18.777-25.223) in Group 2. There was no statistically significant correlation between the number of chemotherapy cycles and PFS (P=0.513) or OS (P=0.867). The extent of surgical resection was the only independent prognostic factor for both PFS (P=0.015) and OS (P=0.028) by multivariate analysis. Three grade ≥3 hematologic toxicity were encountered in 3 patients. One in the six-cycle group (neutropenia), and two in the extended cycles group (one had neutropenia and the other one developed thrombocytopenia). No statistically significant difference in the toxicity profile between both groups. The results of our study suggest that extended TMZ therapy is safe and tolerable, however it did not significantly improve PFS or OS as compared to the standard six-cycle course. Larger randomized studies are required to shed more light on this issue.     

Critical weight loss is a major prognostic indicator for disease-specific survival in patients with head and neck cancer receiving radiotherapy

Background:

Pre-treatment weight loss (WL) is a prognostic indicator for overall survival (OS) in head and neck cancer (HNC) patients. This study investigates the association between WL before or during radiotherapy and disease-specific survival (DSS) in HNC patients.

Methods:

In 1340 newly diagnosed HNC patients, weight change was collected before and during (adjuvant) radiotherapy with curative intent. Critical WL during radiotherapy was defined as >5% WL during radiotherapy or >7.5% WL until week 12. Differences in 5-year OS and DSS between WL groups were analysed by Cox''s regression with adjustments for important socio-demographic and tumour-related confounders.

Results:

Before radiotherapy, 70% of patients had no WL, 16% had ⩽5% WL, 9% had >5–10% WL, and 5% had >10% WL. Five-year OS and DSS rates for these groups were 71%, 59%, 47%, and 42% (P<0.001), and 86%, 86%, 81%, and 71%, respectively (P<0.001). After adjustment for potential confounders, >10% WL before radiotherapy remained significantly associated with a worse OS (HR 1.7; 95% CI 1.2–2.5; P=0.002) and DSS (HR 2.1; 95% CI 1.2–3.5; P=0.007).The 5-year OS and DSS rates for patients with critical WL during radiotherapy were 62% and 82%, compared with 70% and 89% for patients without critical WL (P=0.01; P=0.001). After adjustment, critical WL during radiotherapy remained significantly associated with a worse DSS (HR 1.7; 95% CI 1.2–2.4; P=0.004).

Conclusion:

Weight loss both before and during radiotherapy are important prognostic indicators for 5-year DSS in HNC patients. Randomised studies into the prognostic effect of nutritional intervention are needed.     

Phosphorylated protein phosphatase 2A determines poor outcome in patients with metastatic colorectal cancer

Background:

Protein phosphatase 2A (PP2A) is a tumour suppressor frequently inactivated in human cancer and its tyrosine-307 phosphorylation has been reported as a molecular inhibitory mechanism.

Methods:

Expression of phosphorylated PP2A (p-PP2A) was evaluated in 250 metastatic colorectal cancer (CRC) patients. Chi-square, Kaplan–Meier and Cox analyses were used to determine correlations with clinical and molecular parameters and impact on clinical outcomes.

Results:

High p-PP2A levels were found in 17.2% cases and were associated with ECOG performance status (P=0.001) and presence of synchronous metastasis at diagnosis (P=0.035). This subgroup showed substantially worse overall survival (OS) (median OS, 6.0 vs 26.2 months, P<0.001) and progression-free survival (PFS) (median PFS, 3.8 vs 13.3 months, P<0.001). The prognostic impact of p-PP2A was particularly evident in patients aged <70 years (P<0.001). Multivariate analysis revealed that p-PP2A retained its prognostic impact for OS (hazard ratio 2.7; 95% confidence interval, 1.8–4.1; P<0.001) and PFS (hazard ratio 3.0; 95% confidence interval, 1.8–5.0; P<0.001).

Conclusions:

Phosphorylated PP2A is an alteration that determines poor outcome in metastatic CRC and represents a novel potential therapeutic target in this disease, thus enabling to define a subgroup of patients who could benefit from future treatments based on PP2A activators.     

Upfront Chemotherapy Followed by Stereotactic Body Radiation Therapy with or without Surgery in Older Patients with Localized Pancreatic Cancer: A Single Institution Experience and Review of the Literature

Objective: To report on clinical outcomes and toxicity in older (age ≥ 70 years) patients with localized pancreatic cancer treated with upfront chemotherapy followed by stereotactic body radiation therapy (SBRT) with or without surgery. Methods: Endpoints included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and toxicity. Results: A total of 57 older patients were included in the study. Median OS was 19.6 months, with six-month, one-year, and two-year OS rates of 83.4, 66.5, and 42.4%. On MVA, resection status (HR: 0.30, 95% CI 0.12–0.91, p = 0.031) was associated with OS. Patients with surgically resected tumors had improved median OS (29.1 vs. 7.0 months, p < 0.001). On MVA, resection status (HR: 0.40, 95% CI 0.17–0.93, p = 0.034) was also associated with PFS. Patients with surgically resected tumors had improved median PFS (12.9 vs. 1.6 months, p < 0.001). There were 3/57 cases (5.3%) of late grade 3 radiation toxicity and 2/38 cases (5.3%) of Clavien-Dindo grade 3b toxicity in those who underwent resection. Conclusion: Multimodality therapy involving SBRT is safe and feasible in older patients with localized pancreatic cancer. Surgical resection was associated with improved clinical outcomes. As such, older patients who complete chemotherapy should not be excluded from aggressive local therapy when possible.     

The Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Metastatic Testicular Cancer

We investigated the prognostic utility of pre-chemotherapy neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic germ cell tumors (GCTs) undergoing first-line chemotherapy. We utilized two institutional databases to analyze the pretreatment-derived NLR (dNLR). Predictive accuracy was evaluated using the Cox proportional hazard model adjusted for the international germ cell cancer collaborative group (IGCCCG) risk classification. Discriminatory accuracy was evaluated by determining the area under the receiver operating characteristic curve (AUROC). In total, 569 of 690 patients had available dNLR (IGCCCG: good, 64%; intermediate, 21%; poor, 16%). The 5-year and 10-year overall survivals (OSs) for good, intermediate, and poor risk groups were 96.2%, 92.8%, and 62.7% and 93.9%, 90.3%, and 62.7%, respectively. A dNLR of 2 provided the best discriminatory accuracy with an AUROC of 0.58 (95% CI: 0.52–0.65, p = 0.01) for progression-free survival (PFS), whereas for OS, a dNLR of 3 provided the best discriminatory accuracy with an AUROC of 0.62 (95% CI: 0.53–0.70, p < 0.01). A dNLR > 2 was associated with a hazard ratio (HR) of 1.99 (95% CI: 1.27–3.12, p < 0.01) for PFS, which lost its effect after adjustment for IGCCCG (HR: 1.44, 95% CI: 0.90–2.30, p = 0.13). For OS, a dNLR >3 was associated with an HR of 3.00 (95% CI: 1.79–5.01, p < 0.01), but lost its effect after adjustment for IGCCCG. Systemic inflammation plays a role in metastatic GCT, but its prognostic utility beyond established algorithms is limited. The general prognostic value of NLR can be seen across a number of tumors, although the consistency and magnitude of the effect differ according to cancer type, disease stage, and treatment received. We identified that an elevated NLR was associated with an adverse PFS and OS, but not independent of the IGCCCG risk classification. dNLRs >2 and >3 were associated with an adverse PFS and OS, respectively, in patients with metastatic GCT receiving first-line chemotherapy, but not independent of the IGCCCG risk classification.     

Prognostic value of MET protein overexpression and gene amplification in locoregionally advanced nasopharyngeal carcinoma

This study assessed the incidence and prognostic value of MET protein overexpression and gene amplification in locoregionally advanced nasopharyngeal carcinoma (NPC). Specimens from 376 consecutive patients with locoregionally advanced NPC were subjected to immunohistochemistry to analyze MET protein expression and fluorescence in situ hybridization to assess MET amplification status. In total, 139/376 (37.0%) patients had MET protein overexpression; of whom, 7/139 (5.0%) had MET amplification. MET overexpression was significantly associated with locoregional failure (P = 0.009), distant metastasis (P = 0.006) and death (P < 0.001); MET amplification was significantly associated with death (P = 0.021). A positive correlation was observed between MET copy number status and MET protein expression (r = 0.629, P < 0.001). Multivariate analysis demonstrated MET overexpression was an independent prognostic factor for overall survival (OS; HR, 1.99; 95% CI, 1.38–2.87; P < 0.001) and disease-free survival (DFS; HR, 1.85; 95% CI, 1.33–2.57; P < 0.001), and MET amplification was independently associated with poorer OS (HR, 4.24; 95% CI, 1.78-10.08; P < 0.001) and DFS (HR, 5.44; 95% CI, 2.44-12.09; P < 0.001). In conclusion, MET protein overexpression and gene amplification are independent prognostic factors for OS and DFS in locoregionally advanced nasopharyngeal carcinoma, and may provide therapeutic biomarkers to identify patients in whom MET inhibitors may be beneficial.     

High plasma fibrinogen level represents an independent negative prognostic factor regarding cancer-specific,metastasis-free,as well as overall survival in a European cohort of non-metastatic renal cell carcinoma patients

Background:

In recent years, plasma fibrinogen has been ascribed an important role in the pathophysiology of tumour cell invasion and metastases. A relatively small-scale study has indicated that plasma fibrinogen levels may serve as a prognostic factor for predicting clinical outcomes in non-metastatic renal cell carcinoma (RCC) patients.

Methods:

Data from 994 consecutive non-metastatic RCC patients, operated between 2000 and 2010 at a single, tertiary academic centre, were evaluated. Analyses of plasma fibrinogen levels were performed one day before the surgical interventions. Patients were categorised using a cut-off value of 466 mg dl⁻¹ according to a calculation by receiver-operating curve analysis. Cancer-specific (CSS), metastasis-free (MFS), as well as overall survival (OS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic impact of plasma fibrinogen level, a multivariable Cox regression model was performed for all three different endpoints.

Results:

High plasma fibrinogen levels were associated with various well-established prognostic factors, including age, advanced tumour stage, tumour grade and histologic tumour necrosis (all P<0.05). Furthermore, in multivariable analysis, a high plasma fibrinogen level was statistically significantly associated with a poor outcome for patients'' CSS (hazard ratio (HR): 2.47, 95% confidence interval (CI): 1.49–4.11, P<0.001), MFS (HR: 2.15, 95% CI: 1.44–3.22, P<0.001) and OS (HR: 2.48, 95% CI: 1.80–3.40, P<0.001).

Conclusion:

A high plasma fibrinogen level seems to represent a strong and independent negative prognostic factor regarding CSS, MFS and OS in non-metastatic RCC patients. Thus, this easily determinable laboratory value should be considered as an additional prognostic factor for RCC patients'' individual risk assessment.     

Association of supratotal resection with progression-free survival,malignant transformation,and overall survival in lower-grade gliomas

BackgroundSupratotal resection is advocated in lower-grade gliomas (LGGs) based on theoretical advantages but with limited verification of functional risk and data on oncological outcomes. We assessed the association of supratotal resection in molecularly defined LGGs with oncological outcomes.MethodsIncluded were 460 presumptive LGGs; 404 resected; 347 were LGGs, 319 isocitrate dehydrogenase (IDH)–mutated, 28 wildtype. All patients had clinical, imaging, and molecular data. Resection aimed at supratotal resection without any patient or tumor a priori selection. The association of extent of resection (EOR), categorized on volumetric fluid attenuated inversion recovery images as residual tumor volume, along with postsurgical management with progression-free survival (PFS), malignant (M)PFS, and overall survival (OS) assessed by univariate, multivariate, and propensity score analysis. The study mainly focused on IDH-mutated LGGs, the “typical LGGs.”ResultsMedian follow-up was 6.8 years (interquartile range, 5–8). Out of 319 IDH-mutated LGGs, 190 (59.6%) progressed, median PFS: 4.7 years (95% CI: 4–5.3). Total and supratotal resection obtained in 39% and 35% of patients with IDH1-mutated tumors. In IDH-mutated tumors, most patients in the partial/subtotal group progressed, 82.4% in total, only 6 (5.4%) in supratotal. Median PFS was 29 months (95% CI: 25–36) in subtotal, 46 months (95% CI: 38–48) in total, while at 92 months, PFS in supratotal was 94.0%. There was no association with molecular subtypes and grade. At random forest analysis, PFS strongly associated with EOR, radiotherapy, and previous treatment. In the propensity score analysis, EOR associated with PFS (hazard ratio, 0.03; 95% CI: 0.01–0.13). MPFS occurred in 32.1% of subtotal total groups; 1 event in supratotal. EOR, grade III, previous treatment correlated to MPFS. At random forest analysis, OS associated with EOR as well.ConclusionsSupratotal resection strongly associated with PFS, MPFS, and OS in LGGs, regardless of molecular subtypes and grade, right from the beginning of clinical presentation.     

Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials

Background

The aim of this study was to determine correlations between progression-free survival (PFS) and the objective response rate (ORR) with overall survival (OS) in glioblastoma and to evaluate their potential use as surrogates for OS.

Method

Published glioblastoma trials reporting OS and ORR and/or PFS with sufficient detail were included in correlative analyses using weighted linear regression.

Results

Of 274 published unique glioblastoma trials, 91 were included. PFS and OS hazard ratios were strongly correlated; R² = 0.92 (95% confidence interval [CI], 0.71–0.99). Linear regression determined that a 10% PFS risk reduction would yield an 8.1% ± 0.8% OS risk reduction. R² between median PFS and median OS was 0.70 (95% CI, 0.59–0.79), with a higher value in trials using Response Assessment in Neuro-Oncology (RANO; R² = 0.96, n = 8) versus Macdonald criteria (R² = 0.70; n = 83). No significant differences were demonstrated between temozolomide- and bevacizumab-containing regimens (P = .10) or between trials using RANO and Macdonald criteria (P = .49). The regression line slope between median PFS and OS was significantly higher in newly diagnosed versus recurrent disease (0.58 vs 0.35, P = .04). R² for 6-month PFS with 1-year OS and median OS were 0.60 (95% CI, 0.37–0.77) and 0.64 (95% CI, 0.42–0.77), respectively. Objective response rate and OS were poorly correlated (R² = 0.22).

Conclusion

In glioblastoma, PFS and OS are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis.     

Clinical significance of p95HER2 overexpression,PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies

Background:

Overexpression of p185HER2 is an established poor prognostic factor in breast cancer, portending an aggressive course and potential for early metastasis. On the other hand, monoclonal antibody trastuzumab is widely used in the clinic to target this overexpressed oncogene. Unfortunately, ∼30–40% of all patients overexpressing HER2 respond to trastuzumab, warranting further research regarding the structure and additional modulation of the receptor. In this study, we aimed to investigate the response to trastuzumab in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)) and a truncated receptor protein, p95HER2, retrospectively.

Materials and methods:

Paraffin-embedded primary tumour tissues of 100 HER2-positive metastatic breast cancer patients who received trastuzumab with combination cytotoxic chemotherapy were analysed with immunohistochemical method for p95HER2, p85 (PI3K) and PTEN. Relationship between variables were tested via χ², Fischer''s exact test and Mann–Whitney U tests, wherever appropriate. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan–Meier method and survival curves of subgroups were compared with log-rank test.

Results:

Percentage of patients was found to be 33%, 57% and 42% positive for p95 expression, PTEN and PI3K, respectively. p95-expressing tumours had statistically lower response rates for trastuzumab than tumours not expressing p95 (P=0.001). On the contrary, PTEN-expressing tumours had statistically higher response rates for trastuzumab than tumours not expressing PTEN (P=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for p95-expressing and not expressing tumours were 8 months (95% CI, 2.5–13.4 months) and 22 months (95% CI, 9.9–34 months), respectively (P=0.0001). Median PFS for PTEN-expressing and not expressing tumours were 15.3 months (95% CI, 12.6–34 months) and 12.1 months (95% CI, 7.9–16.2 months), respectively (P=0.04). Median OS for p95-expressing and not expressing tumours were 24 months (95% CI, 8.3–40.4 months) and 29.1 months (95% CI, 8.6–43.2 months), respectively (P=0.045). Median OS for PTEN-expressing and not expressing tumours were 25.1 months (95% CI, 7.5–40.1 months) and 26.8 months (95% CI, 8.1–42 months), respectively, which was not statistically significant (P=0.5). Level of PI3K expression had no effect on PFS and OS in our patient population. Presence of visceral metastases HR=2.38 ((95% CI, 1.2–4.5), P=0.009), p95 expression HR=2.1 ((95% CI, 1.1–3.7), P=0.03) and response to trastuzumab HR=2.2 ((95% CI, 1.18–4.47), P=0.014) are identified as factors independently affecting PFS. Response to trastuzumab HR=1.7 ((95% CI, 1.14–3.47), P=0.013) was identified as the single parameter influencing survival by Cox regression analysis.

Conclusions:

Presence of p95 predicted a poorer response to trastuzumab treatment, shorter PFS and OS in our HER2-positive metastatic breast cancer cohort. In addition, loss of PTEN predicted a poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.     

Clinicopathological and prognostic factors for long-term survival in Chinese patients with metastatic renal cell carcinoma treated with sorafenib: a single-center retrospective study

Data on long-term survival and prognostic significance of demographic factors and adverse events (AEs) associated with sorafenib, an orally administered multikinase inhibitor in Chinese population with advanced renal cell carcinoma (RCC) are limited. Outcome data from adult patients (n = 256) with advanced RCC who received sorafenib (400 mg twice daily) either as first-line or second-line therapy between April 2006 and May 2013 were analyzed retrospectively. The primary endpoint was median overall survival (OS), determined to be 22.2 (95% CI: 17.1–27.4) months, and the secondary endpoint was overall median progression-free survival (PFS), determined to be 13.6 (95% CI: 10.7–16.4) months at a median follow-up time of 61.8 (95% CI: 16.2–97.4) months. Analysis of the incidence of AEs revealed the most common side effect as hand-foot skin reactions (60.5%) followed by diarrhea (38.7%), fatigue (35.5%), alopecia (34.0%), rash (24.6%), hypertension (21.5%) and gingival hemorrhage (21.1%). Multivariate regression analysis revealed older age (≥ 58 years), lower Memorial Sloan-Kettering Cancer Center score, time from nephrectomy to sorafenib treatment, number of metastatic tumors and best response as significant and independent demographic predictors for improved PFS and/or OS (p ≤ 0.05). Alopecia was identified as a significant and independent predictor of increased OS, whereas vomiting and weight loss were identified as significant predictors of decreased OS (p ≤ 0.05). Sorafenib significantly improved OS and PFS in Chinese patients with advanced RCC. Considering the identified significant prognostic demographic factors along with the advocated prognostic manageable AEs while identifying treatment strategy may help clinicians select the best treatment modality and better predict survival in these patients.     

Pegylated liposomal doxorubicin in the management of ovarian cancer: A systematic review and metaanalysis of randomized trials

Ovarian cancer is the leading cause of death among gynecological tumors. Carboplatin/paclitaxel represents the cornerstone of front-line treatment. Instead, there is no consensus for management of recurrent/progressive disease, in which pegylated liposomal doxorubicin (PLD) ± carboplatin is widely used. We performed a systematic review and metaanalysis to evaluate impact of PLD-based compared with no-PLD-based regimens in the ovarian cancer treatment. Data were extracted from randomized trials comparing PLD-based treatment to any other regimens in the January 2000–January 2013 time-frame. Study end-points were overall survival (OS), progression free survival (PFS), response rate (RR), CA125 response, and toxicity. Hazard ratios (HRs) of OS and PFS, with 95% CI, odds ratios (ORs) of RR and risk ratios of CA125 response and grade 3–4 toxicity, were extracted. Data were pooled using fixed and random effect models for selected endpoints. Fourteen randomized trials for a total of 5760 patients were selected and included for the final analysis, which showed no OS differences for PLD-based compared with other regimens (pooled HR: 0.94; 95% CI: 0.88–1.02; P = 0.132) and a significant PFS benefit of PLD-based schedule (HR: 0.91; 95% CI: 0.86–0.96; P = 0.001), particularly in second-line (HR: 0.85; 95% CI: 0.75–0.91) and in platinum-sensitive (HR: 0.83; 95% CI: 0.74–0.94) subgroups. This work confirmed the peculiar tolerability profile of this drug, moreover no difference was observed for common hematological toxicities and for RR, CA125 response. PLD-containing regimens do not improve OS when compared with any other schedule in all phases of disease. A marginal PFS advantage is observed only in platinum-sensitive setting and second-line treatment.     

Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer

Background:

Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects.

Methods:

We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population.

Results:

Patients with low expression of VEGF-D (0, 1+) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CB+CBM), 0.21; 95% CI, 0.08–0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13–0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2+ PFS HR, 0.67; 95% CI, 0.45–1.00; OS HR, 0.82; 95% CI, 0.52–1.30; VEGF-D 3+ PFS HR, 0.77; 95% CI, 0.50–1.17; OS HR, 1.28; 95% CI, 0.79–2.09) (P interaction <0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression.

Conclusions:

The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.     

Prognostic significance of circumferential resection margin involvement following oesophagectomy for cancer and the predictive role of endoluminal ultrasonography

Background:

The optimum multimodal treatment for oesophageal cancer, and the prognostic significance of histopathological tumour involvement of the circumferential resection margin (CRM+) are uncertain. The aims of this study were to determine the prognostic significance of CRM+ after oesophagectomy and to identify endosonographic (endoluminal ultrasonography (EUS)) features that predict a threatened CRM+.

Methods:

Two hundred and sixty-nine consecutive patients underwent potentially curative oesophagectomy (103 surgery alone, 124 neoadjuvant chemotherapy (CS) and 42 chemoradiotherapy (CRTS)). Primary outcome measures were disease-free survival (DFS) and overall survival (OS).

Results:

CRM+ was reported in 98 (38.0%) of all, and in 90 (62.5%) of pT3 patients. Multivariate analysis of pathological factors revealed: lymphovascular invasion (HR 2.087, 95% CI 1.396–3.122, P<0.0001), CRM+ (HR 1.762, 95% CI 1.201–2.586, P=0.004) and lymph node metastasis count (HR 1.563, 95% CI 1.018–2.400, P=0.041) to be independently and significantly associated with DFS. Lymphovascular invasion (HR 2.160, 95% CI 1.432–3.259, P<0.001) and CRM+ (HR 1.514, 95% CI 1.000–2.292, P=0.050) were also independently and significantly associated with OS. Multivariate analysis revealed EUS T stage (T3 or T4, OR 24.313, 95% CI 7.438–79.476, P<0.0001) and use or not of CRTS (OR 0.116, 95% CI 0.035–0.382, P<0.0001) were independently and significantly associated with CRM+.

Conclusion:

A positive CRM was a better predictor of DFS and OS than standard pTNM stage.     

Reactor-based boron neutron capture therapy for 44 cases of recurrent and refractory high-grade meningiomas with long-term follow-up

BackgroundHigh-grade meningioma (HGM) is difficult to treat, and recurrent HGM after radiotherapy has an especially poor prognosis. We retrospectively analyzed the cases of 44 consecutive patients with recurrent and refractory HGM who were treated by reactor-based boron neutron capture therapy (BNCT).MethodsIn 2005–2019, we treated 44 recurrent and refractory HGMs by reactor-based BNCT. We analyzed the patients’ tumor shrinkage, overall survival (OS) after initial diagnosis, OS after BNCT, progression-free survival (PFS) post-BNCT, and treatment failure patterns.ResultsThe median OS (mOS) after BNCT and mOS after initial diagnosis were 29.6 (95% CI: 16.1–40.4) and 98.4 (95% CI: 68.7–169.4) months, respectively. The median follow-up after BNCT was 26 (6.4–103) months. The grade 2 (20 cases) and 3 (24 cases) post-BNCT mOS values were 44.4 (95% CI: 27.4–not determined) and 21.55 (10.6–30.6) months, respectively (P = .0009). Follow-up images were obtained from 36 cases at >3 months post-BNCT; 35 showed tumor shrinkage during the observation period. The post-BNCT median PFS (mPFS) of 36 cases was 13.7 (95% CI: 8.3–28.6) months. The post-BNCT mPFS values in patients with grade 2 and 3 disease were 24.3 (95% CI: 9.8–not determined) and 9.4 (6.3–14.4) months, respectively (P = .0024). Local recurrence was observed in only 22.2% of cases. These results showed good local tumor control and prolonged survival for recurrent HGM cases.ConclusionsMost of these cases had relatively large tumor volumes. The proportion of grade 3 patients was extremely high. Our patients thus seemed to have poor prognoses. Nevertheless, reactor-based BNCT exerted relatively good local control and favorable survival for recurrent and refractory HGMs.     

Quaternary cytoreductive surgery in ovarian cancer: does surgical effort still matter?

Background:

To evaluate surgical outcome and survival benefit after quaternary cytoreduction (QC) in epithelial ovarian cancer (EOC) relapse.

Methods:

We systematically evaluated all consecutive patients undergoing QC in our institution over a 12-year period (October 2000–January 2012). All relevant surgical and clinical outcome parameters were systematically assessed.

Results:

Forty-nine EOC patients (median age: 57; range: 28–76) underwent QC; in a median of 16 months (range:2–142) after previous chemotherapy. The majority of the patients had an initial FIGO stage III (67.3%), peritoneal carcinomatosis (77.6%) and no ascites (67.3%). At QC, patients presented following tumour pattern: lower abdomen 85.7% middle abdomen 79.6% and upper abdomen 42.9%. Median duration of surgery was 292 min (range: a total macroscopic tumour clearance could be achieved. Rates of major operative morbidity and 30-day mortality were 28.6% and 2%, respectively.Mean follow-up from QC was 18.41 months (95% confidence interval (CI):12.64–24.18) and mean overall survival (OS) 23.05 months (95% CI: 15.5–30.6). Mean OS for patients without vs any tumour residuals was 43 months (95% CI: 26.4–59.5) vs 13.4 months (95% CI: 7.42–19.4); P=0.001. Mean OS for patients who received postoperative chemotherapy (n=18; 36.7%) vs those who did not was 40.5 months (95% CI: 27.4–53.6) vs 12.03 months (95% CI: 5.9–18.18); P<0.001.Multivariate analysis indentified multifocal tumour dissemination to be of predictive significance for incomplete tumour resection, higher operative morbidity and lower survival, while systemic chemotherapy subsequent to QC had a protective significant impact on OS. No prognostic impact had ascites, platinum resistance, high grading and advanced age.

Conclusion:

Even in this highly advanced setting of the third EOC relapse, maximal therapeutic effort combining optimal surgery and chemotherapy appear to significantly prolong survival in a selected patients ‘group''.