Pathology correlates of a Papanicolaou diagnosis of low‐grade squamous intraepithelial lesion,cannot exclude high‐grade squamous intraepithelial lesion

BACKGROUND.

The objective of this study was to compare findings after a cytologic report of low‐grade squamous intraepithelial lesion, cannot exclude high‐grade squamous intraepithelial lesion (LSIL‐H) with findings after a report of low‐grade squamous intraepithelial lesion (LSIL).

METHODS.

A review of patient records revealed that 312 women had cytologic findings of LSIL‐H, and 324 consecutive women in a comparison group had cytologic findings of LSIL during 2005. Findings over 6 months after diagnosis were retrieved and analyzed using chi‐square tests, Fisher exact tests, and independent group t tests.

RESULTS.

Histology was available for 194 of 312 women (64%) with LSIL‐H and for 184 of 324 women (57%) with LSIL. Of these, 47 of 194 women (24%) with LSIL‐H had grade 2 cervical intraepithelial neoplasia or greater (CIN2+) versus 13 of 184 women (7%) with LSIL (P < .0001). No cancers were identified. High‐grade SIL cytology was reported in 2 of 105 women who had LSIL (2%) and in 4 of 93 women who had LSIL‐H (4%). Women with LSIL‐H who were positive for CIN2+ were younger than those without CIN2+ (25 years vs 30 years; P = .0067)

CONCLUSIONS.

Clinicians whose laboratories report LSIL‐H should manage women who have LSIL‐H with colposcopy, whereas only serial cytologic surveillance is required after a report of LSIL. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

Use of high-risk human papillomavirus testing in patients with low-grade squamous intraepithelial lesions

BACKGROUND

The role of testing for high‐risk human papillomavirus (HR HPV) when triaging women with a cytologic diagnosis of low‐grade squamous intraepithelial lesion (LSIL) has not been well established. The objective of the current study was to correlate the status of HR HPV with the incidence of cervical intraepithelial neoplasia 2 and more severe lesions (CIN 2+) on tissue follow‐up in women with LSIL.

METHODS

A total of 1046 women with LSIL and HR HPV testing were identified in the database of a large teaching hospital within a 12‐month period. HR HPV testing was performed using the Hybrid Capture 2 assay with 1 relative light unit/cutoff as the cutoff.

RESULTS

Of the 1046 women with LSIL and concurrent HR HPV testing, 82.3% tested positive for HR HPV, 91.1% of whom were women aged < 30 years and 73% of whom were women aged ≥ 30 years (P < .001). Cytologic and/or histologic follow‐up was available in 979 (93.6%) women; 25.5% had negative follow‐up, 62.5% were found to have CIN 1 lesions, and 12.0% had CIN 2+ lesions. The sensitivity and negative predictive value of HR HPV status as a marker of CIN 2+ lesions were 98.3% and 98.9%, respectively. The colposcopy rate was 73.3% and 96.9% for women aged ≥ 30 years and women aged < 30 years, respectively (P = .01).

CONCLUSIONS

Using 1 RLU/CO as the cutoff value, HR HPV testing was found to be highly sensitive for detecting CIN 2+ lesions in women with LSIL. The colposcopy rate was significantly lower in women aged ≥ 30 years compared with women aged < 30 years. Triaging with HR HPV testing may be indicated in women aged ≥ 30 years with LSIL cytology, but not in women aged < 30 years. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

Effectiveness of two strategies to follow-up ASC-US and LSIL screening results in The Netherlands using repeat cytology with or without additional hrHPV testing: a retrospective cohort study

Purpose

The purpose of the study was to assess the effectiveness of repeat cytology with and without additional high-risk human papilloma virus (hrHPV) testing after atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASC-US/LSIL) screening results.

Methods

In the Netherlands, ASC-US/LSIL is triaged by repeat cytology at 6 months or repeat cytology at 6 months with additional hrHPV testing. ASC-US/LSIL results from 13,734 screenees in 2008 were extracted from “Dutch Pathology Registry” including cytology, histology, and/or HPV follow-up results. Proportions of compliance, repeat cytology, referral, and detected cervical intraepithelial neoplasia (CIN) were assessed.

Results

With additional hrHPV testing, 46.8 % was send back to regular screening at 6 months, 28.6 % needed second repeat cytology, and 24.6 % was referred for colposcopy. Without additional hrHPV testing, this was 0.0, 76.1, and 23.9 %, respectively. With additional hrHPV testing, significantly higher proportions of persisting ASC-US/LSIL; compliance with repeat/referral advices; and histological detection of CIN0 (no CIN or cancer), CIN1, and CIN2 were found but equal proportions CIN3+.

Conclusions

Additional hrHPV testing shortens follow-up without altering CIN3+ detection. Detection of CIN0, CIN1, and CIN2 was higher, presumably by hrHPV-driven biased cytology and detection bias. Restricting additional hrHPV testing to older women, reading cytology without knowledge of hrHPV status, and addition of more specific triage tests could further improve the effectiveness of additional hrHPV testing.     

Clinical characteristics and treatment outcomes of gastric cancer patients with isolated para-aortic lymph node involvement

Background

Although gastric cancer with isolated para-aortic lymph node (PAN) involvement is considered an advanced disease, the clinical characteristics of it have not been comprehensively elucidated.

Patients and methods

We reviewed the medical records of 1,277 patients received palliative chemotherapy with advanced gastric cancer according to metastatic sites: PAN-only metastasis, single organ metastasis other than PAN, and multiple organ metastasis. Time to other organ metastasis (TTOM) was determined only in PAN-only metastasis group as the time interval between initial diagnosis of recurrence or de novo metastasis and confirming distant metastasis beyond PAN area.

Results

The median overall survival (OS) of patients with PAN-only metastasis was significantly longer than that of patients with single organ metastasis other than PAN or multiple organ metastasis (13.8?months vs. 11.4?months vs. 8.4?months; P?<?0.001). In the PAN-only metastasis group, patients with recurrent diseases showed longer TTOM beyond the PAN area (10.7 vs. 7.7?months; P?=?0.037) and OS (23.8 vs. 12.8?months; P?=?0.010) than those with de novo metastatic disease and it was validated by multivariate analysis.

Conclusion

Patients with isolated PAN metastasis showed an excellent prognosis compared with patients with metastasis at other sites and it was primarily evident in patients with recurrent PAN metastasis.     

Hyaluronan-Irinotecan improves progression-free survival in 5-fluorouracil refractory patients with metastatic colorectal cancer: a randomized phase II trial

Purpose

The objective of this study was to conduct a randomised phase II study in second-line metastatic colorectal cancer with the purpose of confirming preliminary clinical data indicating that the formulation of irinotecan with the drug carrier, hyaluronan (HA) reduced toxicity of the drug.

Methods

Irinotecan-na?ve patients were randomized to receive either irinotecan (350?mg/m²) or HA-Irinotecan (HA 1,000?mg/m² and irinotecan at 350?mg/m²) every 3?weeks for a maximum of eight cycles.

Results

Seventy-six patients (41 HA-Irinotecan and 35 irinotecan-alone) were enrolled. There was no significant difference in any individual, or overall, grade 3 or 4 toxicity. There was a trend for increased diarrhea in the HA-Irinotecan-treated patients (20 versus 9%; P?=?21), potentially explained by a disproportionate number of baseline toxicity-associated risk factors in this treatment group. The median number of cycles completed was six for HA-Irinotecan patients and two for irinotecan-alone patients (P?=?0.005). When compared to the control arm, HA-Irinotecan patients had a significantly longer median progression-free survival of 5.2 versus 2.4?months (P?=?0.017) and time to treatment failure (4 vs. 1.8?months; P?=?0.007). Median overall survival was 10.1?months for HA-Irinotecan compared to 8.0?months for irinotecan patients (P?=?0.196).

Conclusion

Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone.     

Association between cervical dysplasia and human papillomavirus in HIV seropositive women from Johannesburg South Africa

Objective

To examine the association between CD4 counts, HPV infection and the risk of cervical neoplasia among HIV-seropositive women.

Methods

A cross-sectional observational study was conducted among 1,010 HIV-seropositive women using cytology-based Pap smears. HPV DNA testing using Linear Array genotyping assay (Roche) was carried out in a subset of 191 patients. Multivariable-adjusted prevalence ratios (mPR) and 95% confidence intervals (CIs) were estimated with log-binomial regression.

Results

Among 1,010 HIV-seropositive women, the prevalence of AGC/ASCUS, LSIL and HSIL or greater was 8.3, 23.5 and 18.0%, respectively. The risk of cervical lesions was higher with CD4?<?200 cells/mm³ vs. CD4 levels?>?500/mm³. HPV types 16 (41.7%) and HPV 56 (22.2%) were the most common types in HSIL cases. Women with CD4 levels?<?200/mm³ had a higher prevalence of HPV types 16 (p?<?0.01) and 66 (p?=?0.04). No statistical relationship between cervical lesions and HAART use was found.

Conclusion

The burden of HPV infection and HSIL was high and correlated with HIV-induced immunosuppression. HPV 16 was the most common type in HSIL and increased in prevalence with greater immune suppression. Prophylactic HPV 16 vaccination could prevent approximately 40% of HSIL cases. Strengthening screening programs is imperative in this population.     

The clinical performance of APTIMA human papillomavirus and Hybrid Capture 2 assays in the triage of lesser abnormal cervical cytologies

Objective

This study was performed to evaluate the clinical performance of APTIMA human papillomavirus (AHPV) assay and Hybrid Capture 2 (HC2) assay in screening for cervical disease, especially in women with atypical squamous cell of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL).

Methods

A total of 411 women diagnosed with ASC-US or LSIL were referred and further triaged by HC2 test. Prior to colposcopy, liquid-based cytology specimens were collected for the AHPV assay. Sensitivity and specificity were established based on the histological findings of cervical intraepithelial neoplasia (CIN).

Results

In all 411 subjects, the positive detection rate of AHPV assay was 70.8% (95% confidence interval [CI], 66.4 to 75.2), which was significantly lower than the positive detection rate of 94.9% obtained using HC2 test (95% CI, 92.3 to 96.8). Only one CIN 3-positive case was detected among the 120 AHPV-negative women, which was then confirmed by Pap smear test to be LSIL. The sensitivities of AHPV and HC2 for CIN 3 were similar (94.1% and 100%, respectively). However, AHPV showed a significantly higher specificity than HC2 test (30.2% and 5.3%, respectively; p<0.001).

Conclusion

AHPV assay is effective in identifying CIN 3-positive cases because of its high specificity and lower false-negative rate. The use of AHPV for the triage of ASC-US and LSIL might help to reduce the referral rate of colposcopy during cervical cancer screening.     

Concurrent use of proton pump inhibitors or H2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia

Purpose

The impact of proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2 blockers) on the efficacy of nilotinib was evaluated.

Methods

Retrospective analyses were performed in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP; N?=?492) and in patients with imatinib-resistant or imatinib-intolerant Ph+ CML-CP (N?=?256) treated with nilotinib.

Results

In the newly diagnosed population, 87 (17.7?%) and 49 (10.0?%) patients received PPIs and H2 blockers, respectively. Major molecular response at 12?months was achieved by 59 (49.6?%) patients who received at least one PPI or H2 blocker (n?=?119) and 153 (41.0?%) patients who did not receive any comedication (n?=?373; P?=?0.13). PPIs and H2 blockers were used by 77 (30.1?%) and 17 (6.6?%) patients with imatinib-resistant or imatinib-intolerant CML-CP, respectively. Major cytogenetic response by 12?months was achieved by 55 (64.0?%) patients who received at least one PPI or H2 blocker (n?=?86) versus 98 (57.6?%) patients who did not receive any comedication (n?=?170; P?=?0.40); 39 (45.3?%) versus 65 (38.2?%), respectively, achieved complete cytogenetic response by 12?months (P?=?0.34). Similar findings were observed in patients who received comedication for >50?% of the time on nilotinib therapy. Nilotinib steady-state trough concentration was not affected by the presence of PPIs or H2 blockers.

Conclusions

Concurrent use of PPIs or H2 blockers did not affect the pharmacokinetics and efficacy of nilotinib in patients with Ph+ CML-CP.     

Galectin-3 genetic variants are associated with platinum-based chemotherapy response and prognosis in patients with NSCLC

Aim

To explore the association between the galectin-3 genetic polymorphisms and Platinum-based chemotherapy response as well as the prognosis of non-small cell lung cancer (NSCLC).

Method

Three hundred twenty patients with Stage III (A+B) or IV NSCLC were enrolled. A Platinum-based chemotherapy was given to each subjects and therapeutic effect was evaluated. The two galectin-3 genetic polymorphisms, namely, galectin-3 +191 A>C and +292 A>C, were genotyped.

Results

The polymorphic genotypes and the allele frequency of galectin-3 +191 A>C were not significantly different between responders and non-responders to chemotherapy. For galectin-3 +292 A>C, the AA genotype and A allele distribution were significantly higher in responders than in non-responders. Logistic regression analysis showed CC genotype of galectin-3 +292 presented higher risk of being non-responders compared with the AA genotype (OR?=?2.96, 95?% CI: 1.55?C5.47; P?<?0.001). The overall survival in patients with AA genotype of galectin-3 +292 were significantly longer than in those with CC genotype (25.6 vs. 19.5?months, P?=?0.013). The hazard ratio for CC genotype of galectin-3 +292 was 2.43 (95?% CI: 2.03?C3.98, compared with AA carriers, P?=?0.003).

Conclusion

The galectin-3 genetic polymorphisms of galectin-3 +292, rather than galectin-3 +191, were associated with the chemotherapy response and prognosis of NSCLC.     

Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin

Purpose

A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline.

Methods

During the 2000?C2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed.

Results

Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of ???or?<6?months was demonstrated to be significantly associated with the response to second-line chemotherapy (P?=?0.0026), progression-free survival (P?=?0.0003) and overall survival (P?=?0.025). The second-line chemotherapy similar to the first-line regimen was ineffective in all the 7 cases (100%) whose TFI was shorter than 6?months. Multivariate analysis showed that TFI was the most significantly important factor predicting the effectiveness of second-line chemotherapy (the adjusted hazard ratio of TFI on PFS and OS: 3.482, 95% CI, 1.641?C7.388, P?=?0.0012, and 2.341, 95% CI, 1.034?C5.301, P?=?0.042, respectively).

Conclusions

Our present study provides, for the first time, evidence that the majority of refractory or recurrent diseases, if they occur within 6?months of a first-line chemotherapy using taxane and platinum with or without anthracycline, are non-responsive to the current regimens of second-line chemotherapy.     

A protein profile study to discriminate CIN lesions from normal cervical epithelium

Background

Cervical intraepithelial neoplasia (CIN), a frequently encountered disease caused by Human Papilloma Virus (HPV) is often diagnosed in formaldehyde-fixed paraffin embedded (FFPE) punch biopsies. Since it is known that this procedure strongly affects the water-soluble proteins contained in the cervical tissue we decided to investigate whether a water-soluble protein-saving biopsy processing method can be used to support the diagnosis of normal and CIN.

Methods

Cervical punch biopsies from 55 women were incubated for 24 h at 4°C in RPMI1640 medium for protein analysis prior to usual FFPE processing and p16 and Ki67-supported histologic consensus diagnosis was assessed. The biopsy supernatants were subjected to surface-enhanced laser desorption-ionization time of flight mass spectrometry (SELDI-TOF MS) for identifying differentially expressed proteins. Binary logistic regression and classification and regression trees (CART) were used to develop a classification model.

Results

The age of the patients ranged from 26 to 40 years (median 29.7). The consensus diagnoses were normal cervical tissue (n?=?10) and CIN2-3 (n?=?45). The mean protein concentration was 1.00 and 1.09 mg/ml in the normal and CIN2-3 group, respectively. The peak detection and clustering process resulted in 40 protein peaks. Many of these peaks differed between the two groups, but only three had independent discriminating power. The overall classification results were 88%.

Conclusions

Water-soluble proteins sampled from punch biopsies are promising to assist the diagnosis of normal and CIN2-3.     

Cigarette smoke stimulates VEGF-C expression in cervical intraepithelial neoplasia (CIN) 1 and 2 lesions

Objective

Vascular endothelial growth factors (VEGFs) are involved in angiogenesis, but molecular links to the most important etiological agents, human papillomavirus (HPV) and smoking, need to be clarified.

Methods

Archival samples at the first diagnosis of 64 cervical intraepithelial neoplasia grade 1 or 2 (CIN 1/2) lesions were examined immunohistochemically using anti-VEGF-C and anti-Ki-67 antibodies. HPV types were identified from cervical samples by restriction fragment length polymorphism, which has been shown to identify at least 26 types of genital HPVs. Follow-up data were available for all patients with CIN lesions.

Results

Cervical intraepithelial neoplasia lesions regressed in 47 cases and were persistent in 17 cases. Twenty-two smokers, 8 former smokers, and 34 non-smokers were enrolled in the study. The median observation period was 52.3?months. Significantly higher VEGF-C expression was observed in 8 smokers with persistent CIN persistence (49.0?±?16.6%, P?P?=?0.030) than that in the others. HPV was detected in 56 of the 64 cases. Thirty-two patients had high-risk HPV, 13 had intermediate-risk HPV, and 2 had low-risk HPV. No significant difference was observed among the HPV risk groups in both average Ki-67 and VEGF-C expression.

Conclusions

These findings suggest that VEGF-C may play an important role in cigarette smoking-associated cervical carcinogenesis.     

Phase II study of S-1 monotherapy in patients with previously treated, advanced non-small-cell lung cancer

Background

In this phase II clinical trial, we evaluated the efficacy and safety of S-1 monotherapy in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We also measured plasma concentrations of 5-fluorouracil (5-FU) and 5-chloro-2,4-dihydroxypyridine components of S-1 and examined correlation with effectiveness and toxicity.

Methods

S-1 was given orally at a dose of 80?mg/m²/day for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity.

Results

We enrolled 30 patients. The response rate was 26.7% (8/30), and the disease control rate was 70% (21/30). Median progression-free survival (PFS) was 3.1?months, and median overall survival (OS) was 11.2?months. Mutations in the epidermal growth factor receptor (EGFR) gene were analyzed in 27 patients. The response rate was higher in patients with mutant EGFR (50.0%) than in those with wild-type EGFR (11.8%, P?=?0.0288). Median PFS was 4.8 and 2.5?months (P?=?0.038), and median OS was 22.4 and 8.4?months (P?=?0.071). There was no grade 4 toxicity in this study. Five patients had grade 3 non-hematologic toxicity, and there was a trend toward higher plasma concentrations of 5-FU in those patients than in another patients.

Conclusions

S-1 monotherapy is effective and well-tolerated treatment for previously treated advanced NSCLC.     

The role of human papillomavirus type 16/18 genotyping in predicting high‐grade cervical/vaginal intraepithelial neoplasm in women with mildly abnormal Papanicolaou results

BACKGROUND:

The authors compared the predictive value of type 16 and/or 18 human papillomavirus (HPV) versus non‐16/18 HPV types for high‐grade (grade ≥2) cervical neoplasm/vaginal intraepithelial neoplasm and carcinoma (CIN/VAIN2+) in women with mildly abnormal Papanicolaou (Pap) results (ie, atypical squamous cells of undetermined significance [ASCUS] or low‐grade squamous epithelial lesion [LSIL]).

METHODS:

The authors retrospectively selected Pap specimens with HPV testing results obtained from 243 women (155 with ASCUS and 88 with LSIL Pap results) in their Department of Pathology. HPV genotyping was performed using the EasyChip HPV blot assay. The Pap specimens with HPV16/18 and non‐16/18 HPV types were compared with follow‐up biopsy results. Follow‐up duration ranged from 1 month to 58 months (mean, 26 months).

RESULTS:

In total, 58 of 155 specimens (37%) that had ASCUS and 29 of 88 specimens (33%) that had LSIL were positive for HPV16/18. CIN/VAIN2+ biopsies were identified in 43 of 155 women (28%) with ASCUS and in 28 of 88 women (32%) with LSIL. Women with ASCUS and HPV16/18 had a significantly higher rate (43%) of CIN/VAIN2+ than women with ASCUS and non‐16/18 HPV types (19%; P = .003; odds ratio, 3.10; 95% confidence interval, 1.48‐6.53). There was no statistically significant difference in the rate of CIN/VAIN2+ between women who had LSIL and HPV16/18 (45%) and those who had LSIL and non‐16/18 HPV types (29%; P = .16; odds ratio, 1.96; 95% confidence interval, 0.77‐4.97).

CONCLUSIONS:

HPV genotyping for HPV16/18 improved risk assessment for women with ASCUS Pap results and may be used to predict the risk of CIN/VAIN2+ to better guide follow‐up management. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.     

Different relation between ERCC1 overexpression and treatment outcomes of two platinum agents in advanced biliary tract adenocarcinoma patients

Purpose

The aim of this study is to evaluate the effect of excision repair cross-complementation group 1 (ERCC1) expression on treatment outcomes in advanced biliary tract adenocarcinoma (ABTA) patients treated with platinum-based chemotherapy.

Methods

One hundred and six patients with histologically confirmed adenocarcinoma of biliary tract were enrolled at 5 institutions in South Korea between January 2002 and September 2008. Of 106 patients, 93 were assessed by immunohistochemistry from tissue specimens. Sixty-five patients were treated with cisplatin-based regimens and the other 28 treated with oxaliplatin-based ones.

Results

For total study population, no significant differences were noted in progression-free survival (PFS) and overall survival (OS) between ERCC1-negative and ERCC1-positive patients, respectively (4.2 vs. 2.9?months, p?=?0.116; 7.0 vs. 7.8?months, p?=?0.143). In patients treated with cisplatin-based regimens, median PFS and OS were significantly longer in ERCC1-negative group than in ERCC1-positive group, respectively (4.6 vs. 1.9?months, p?=?0.014; 9.1 vs. 7.9?months, p?=?0.017). Disease control rate (DCR) was better in patients with ERCC1 negative than in patients with ERCC1 positive (p?=?0.048). On the other hand, in patients treated with oxaliplatin-containing regimens, median PFS and OS tended to be longer in ERCC1-positive group, but these did not reach statistical significances. Response rate was better in patients with ERCC1 positive (p?=?0.005).

Conclusions

ERCC1 shows a significant prognostic value in ABTA patients treated with cisplatin. A survival benefit was observed in ERCC1-negative patients from cisplatin-containing chemotherapy but not from oxaliplatin-containing ones. The action mechanism of ERCC1 on cisplatin may be different from that on oxaliplatin.     

Prognostic factors in patients with advanced biliary tract cancer receiving chemotherapy

Purpose

Prognostic factors for patients with advanced biliary tract cancer receiving chemotherapy are presently not well established. Gallbladder cancer and intra-hepatic cholangiocarcinoma are previously reported prognostic factors of poor prognosis; however, tumor volume has not been analyzed in these previous reports.

Methods

We analyzed 56 consecutive patients with advanced biliary tract cancer who had received gemcitabine and S-1 combination chemotherapy as first-line palliative chemotherapy. Prognostic factors, including the baseline sum longest diameter (BSLD) representing tumor volume in Response Evaluation Criteria in Solid Tumor, were evaluated.

Results

By multivariate analysis, age ??70 (HR 3.01, 95% CI 1.25?C7.31, P?=?0.014) and larger BSLD (HR 1.09, 95% CI 1.01?C1.18, P?=?0.021) were statistically significant independent predictors of poor prognosis. Primary biliary site was not identified as a prognostic factor (P?=?0.728). Median survival times of patients with BSLDs????9.0?cm and BSLDs?>?9.0?cm were 18.7 and 8.8?months, respectively (P?=?0.024).

Conclusions

Age and BSLD were identified as strong prognostic factors for patients with advanced biliary tract cancer receiving chemotherapy. Tumor volume might be more important than primary biliary site for the prognosis of advanced biliary tract cancer.     

High recurrence risk and use of adjuvant trastuzumab in patients with small, HER2-positive, node-negative breast cancers

Background

Five randomized trials of adjuvant trastuzumab have reported significant improvements in recurrence-free survival (RFS) and overall survival. However, patients with node-negative tumors 1?cm or smaller were excluded from these trials. We assessed the recurrence risk and benefit of adjuvant therapy in such patients with small tumors.

Methods

We identified patients with node-negative breast tumors 1?cm or smaller between April 2003 and December 2007. Patients were categorized according to HER2 status and pathological tumor size (pT <5?mm vs. 5?C10?mm), hormone receptor (HR) status and adjuvant chemotherapy. The primary endpoint was RFS.

Results

Of 267 patients included in the analysis, 42 had HER2-positive tumors. The median follow-up was 4.3?years. RFS was worse in patients with HER2-positive tumors than HER2-negative tumors (90.5 vs. 97.7% at 5?years; P?=?0.031). In the group with HER2-positive tumors, there were no recurrences in patients with pT<5?mm, but 4 recurrences in those with pT 5?C10?mm. RFS was worse in patients with pT 5?C10?mm than pT <5?mm (79.0 vs. 100%, P?=?0.025). Furthermore 3 recurrences occurred in patients without adjuvant trastuzumab, and 1 recurrence occurred as soon as adjuvant trastuzumab was finished. Our results appear to establish the efficacy of adjuvant trastuzumab therapy. HR status and use of adjuvant chemotherapy were not significantly associated with RFS.

Conclusions

Patients with HER2-positive, node-negative breast tumors 1?cm or smaller (especially 0.5?C1.0?cm) have a significant recurrence risk and the decision to employ adjuvant trastuzumab therapy should be discussed with patients based on our results and those of other studies.     

Fifty percent patients avoid whole brain radiotherapy: stereotactic radiotherapy for multiple brain metastases. A retrospective analysis of a single center

Purpose

To summarize the outcomes of stereotactic radiotherapy (SRT), with or without whole-brain radiotherapy (WBRT), in the treatment of multiple brain metastasis and to explore the status of WBRT and SRT in the management of multiple brain metastasis.

Methods

From May 1995 to April 2010, 98 patients with newly diagnosed, multiple brain metastasis were treated in our center. Forty-four patients were treated with SRT alone for the initial treatment, and 54 were treated with SRT?+?WBRT. Kaplan?CMeier and Cox proportional hazards regression analyses were used for the survival analysis.

Results

The median survival time (MST) was 13.5?months. No difference was observed in MST between the SRT and the SRT?+?WBRT groups (p?=?0.578). The Karnofsky Performance Score at the time of treatment (p?=?0.025), the interval time between diagnosis of primary tumor and brain metastasis (P?=?0.012) and the situation of extracranial disease (p?=?0.018) were significant predictors of survival. The crude distant intracranial recurrence (DIR) rates were 47.7?% in the SRT group and 24.1?% in the SRT?+?WBRT group (p?=?0.018). In addition, 52.3?% patients in the SRT group were free from DIR and did not require WBRT in their whole lives.

Conclusions

Our data suggest that use of SRT as the initial treatment while reserving WBRT as the salvage therapy in case of distant intracranial recurrence made about 50?% of the patients avoid WBRT throughout the course of their lives and may be another optional treatment modality for multiple brain metastases.     

Immediate referral to colposcopy versus cytological surveillance for low‐grade cervical cytological abnormalities in the absence of HPV test: A systematic review and a meta‐analysis of the literature

We performed a systematic review and meta‐analysis to explore the optimum management strategy for women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low‐grade squamous intra‐epithelial lesions (LSIL/mild dyskaryosis) cytological abnormalities at primary screening in the absence of HPV DNA test. We searched MEDLINE, EMBASE and CENTRAL and included randomised controlled trials comparing immediate colposcopy to cytological surveillance in women with ASCUS/LSIL. The outcomes of interest were occurrence of different histological grades of cervical intraepithelial neoplasia (CIN) and default rates during follow‐up. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random‐effect model and with inverse variance weighting. Interstudy heterogeneity was assessed using I² statistics. Six RCTs were included. Immediate colposcopy significantly increased detection of unimportant abnormalities as opposed to repeat cytology (koilocytosis: 32 vs. 21%, RR: 1.49, 95% CI = 1.17–1.90); CIN1: 21 vs. 8%, RR: 2.58, 95% CI = 1.69–3.94). Although immediate colposcopy detected CIN2, CIN2+, and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN3+: 10.3 vs.11.9%, RR: 1.02, 95% CI = 0.53–1.97), with significant interstudy heterogeneity (p < 0.001, I² = 93%). Default risk was significantly higher for repeat cytology (6 months: 6.3 vs. 13.3%, RR: 3.85, 95% CI = 1.27–11.63; 12 months: 6.3 vs. 14.8%, RR: 6.39, 95% CI = 1.24–32.95; 24 months: 0.9 vs. 16.1%, RR: 19.1, 95% CI = 9.02–40.4). Detection of CIN2+ for cytological surveillance over two years is similar to that of immediate colposcopy, although patients may default. Colposcopy may be first choice when good compliance is not assured, but may increase detection of insignificant lesions. This emphasizes the need for a reflex triage test to distinguish women who need diagnostic work‐up from those who can return to routine recall.     

Effects of Long-Term Vitamin D Supplementation on Regression and Metabolic Status of Cervical Intraepithelial Neoplasia: a Randomized,Double-Blind,Placebo-Controlled Trial

We are not aware of any study examining the effects of long term vitamin D administration on regression and metabolic status of patients with cervical intraepithelial neoplasia grade 1 (CIN1). This study was performed to evaluate the effects of long-term vitamin D administration on regression and metabolic status of patients with CIN1. This randomized, double-blind, placebo-controlled trial was performed among 58 women diagnosed with CIN1. CIN1 diagnosis was performed based on specific diagnostic procedures of biopsy, pathological diagnosis, and colposcopy. Patients were randomly allocated into two groups to take 50,000 IU vitamin D3 supplements (n = 29) or placebo (n = 29) every 2 weeks for 6 months. Fasting blood samples were taken at the beginning of the study and end-of-trial to measure related markers. After 6 months of vitamin D administration, greater percentage of women in the vitamin D group had regressed CIN1 (84.6 vs. 53.8%, P = 0.01) than those in the placebo group. Long-term vitamin D supplementation increased serum-25(OH) vitamin D levels in the intervention group compared to the placebo group (+12.3 ± 11.4 vs. -0.1 ± 3.7 ng/mL, P < 0.001). In addition, vitamin D intake led to significant decreases in serum insulin levels (?5.3 ± 7.3 vs. +2.4 ± 5.9 μIU/mL, P < 0.001), homeostasis model of assessment-insulin resistance (?1.2 ± 1.6 vs. +0.5 ± 1.2, P < 0.001), homeostatic model assessment-Beta cell function (P = 0.005) and a significant elevation in quantitative insulin sensitivity check index (+0.03 ± 0.04 vs. -0.007 ± 0.02, P < 0.001) compared with the placebo group. Additionally, significant increases in plasma nitric oxide (NO) (+15.5 ± 10.3 vs. +4.0 ± 13.4 μmol/L, P = 0.001), total antioxidant capacity (TAC) (P = 0.04), total glutathione (GSH) (+11.8 ± 153.5 vs. -294.2 ± 595.1 μmol/L, P = 0.01) and a significant reduction in plasma malondialdehyde (MDA) levels (?0.8 ± 1.0 vs. -0.03 ± 1.4 μmol/L, P = 0.03) were observed following the administration of vitamin D supplements compared with the placebo group. In conclusion, vitamin D3 administration for 6 months among women with CIN1 resulted in its regression and had beneficial effects on markers of insulin metabolism, plasma NO, TAC, GSH and MDA levels. Clinical trial registration number www.irct.ir: IRCT201412065623N30.