Evaluation of Fine Needle Aspiration Cytopathology in Salivary Gland Tumors under Milan System: Challenges, Misdiagnosis Rates, and Clinical Recommendations.

(1) Background: Salivary gland tumors are rare in the head and neck. To determine the need and extent of surgical intervention, fine needle aspiration (FNA) is a widely accepted tool to approach salivary gland lesions. However, the FNA cytology varies between entities, while the lack of uniform terminology makes diagnosis more challenging. Since establishing the Milan system for reporting salivary gland cytopathology (MSRSGC) has become an increasingly accepted reporting standard, further examination and detailed recommendations were needed. (2) Methods: Between April 2013 and October 2021, 375 cases with FNA and salivary gland resection were retrospectively collected. All FNA specimens were reclassified according to the criteria of MSRSGC. After surgical excision, the FNA data were compared with the histological diagnosis to estimate the risk of malignancy (ROM), the risk of neoplasm (RON), and the diagnostic accuracy for each diagnostic category. (3) Results: Our cohort's distribution of ROM and RON was similar to the MSRSGC's recommendation. Carcinoma ex pleomorphic adenoma (CXPA) has the highest rate (66.7%) of misdiagnosed as a nonneoplastic lesion or benign salivary gland tumor. Pleomorphic adenoma (PA) and Warthin's tumor were the most common benign salivary gland tumors, while the cytology diagnosis of Warthin's tumor seems more challenging than PAs. (4) Conclusions: Despite the convenience and effectiveness of MSRSGC, we suggest close follow-up, re-biopsy, or surgical removal for salivary lesions even in Milan IVA-Benign for possibly missing FNA of malignancy, mixed lesions, or prevention of malignant transformation.

Oncocytic-type intraductal papillary mucinous neoplasm (IPMN)-derived invasive oncocytic pancreatic carcinoma with brain metastasis - a case report.

Pancreatic cancer is a lethal disease without effective treatments at present. It ranks as s as 4th and 5th in cancer-related mortality in the western countries and worldwide. Locally advanced pancreatic duct carcinoma (PDAC) and metastatic PDAC, usually found the metastases over liver, peritoneum, or lung, have been shown to be with dismal prognosis. Brain metastasis is a rare entity and most cases reported before were found post-mortem. Intraductal papillary mucinous neoplasms of the pancreas (IPMN) has been deemed as a precursor of PDAC with very slow progression rate. Here we reported a case diagnosed with IPMN-derived PDAC with brain metastasis. After surgeries for PDAC and brain metastasis, subsequent chemotherapy and radiotherapy were also given. One and half year after surgery, this patient is still living with good performance status, which may warrant individualization of therapeutic strategy for PDAC with only brain metastasis.

Inferiorly based nasolabial flap for reconstruction of full-thickness medium-sized lower lip and commissural defects following ablative cancer surgery.

BACKGROUND: Information regarding the design and usage of inferiorly based nasolabial flap for lower lip and commissural defect reconstruction following ablative cancer surgery remains limited. This study aimed to provide our design and experiences for such reconstructive purpose. METHODS: Patients with lower lip or oral commissural cancer who received curative surgery involving reconstruction with inferiorly based nasolabial flap were included. The demographic data and clinical outcomes of these patients were obtained by retrospective chart review. RESULTS: A total of eight patients were enrolled in this study. All patients received ablative surgery at the National Cheng Kung University Hospital during May 2019 to May 2021, with their surgical defects reconstructed with unilateral inferiorly based nasolabial flap successfully. Among the five patients with lower lip cancer, one had a limited area of necrosis at flap tip. Another patient had a small orocutaneous fistula that healed spontaneously. No trismus or oral incompetence was noted following recovery. For the three patients with commissural cancer, a second stage commisuroplasy was needed after primary reconstruction. One patient had limited wound dehiscence at mouth angle following surgery, resulting in mild oral incompetence. Although mild trismus was noted in these three commissural cancer patients, all patients resumed normal diet during follow-up. CONCLUSION: Inferiorly based nasolabial flap is an excellent local flap for lower lip reconstruction following cancer ablative surgery. It is also a viable option for reconstruction of oral commissural defects. Minimal donor side morbidity, good functional recovery, and esthetic outcomes can be achieved with meticulous flap design.

Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors.

PURPOSE: To investigate how single or fractionated doses of radiation change the microenvironment in transgenic adenocarcinoma of the mouse prostate (TRAMP)-C1 tumors with respect to vascularity, hypoxia, and macrophage infiltrates. EXPERIMENTAL DESIGN: Murine prostate TRAMP-C1 tumors were grown in C57BL/6J mice to 4 mm tumor diameter and were irradiated with either 25 Gy in a single dose or 60 Gy in 15 fractions. Changes in vascularity, hypoxia, and macrophage infiltrates were assessed by immunohistochemistry and molecular assays. RESULTS: Tumor growth was delayed for 1 week after both radiation schedules. Tumor microvascular density (MVD) progressively decreased over a 3-week period to nadirs of 25% and 40% of unirradiated tumors for single or fractionated treatment, respectively. In accord with the decrease in MVDs, mRNA levels of endothelial markers, such as CD31, endoglin, and TIE, decreased over the same time period after irradiation. Central dilated vessels developed surrounded by avascularized hypoxic regions that became infiltrated with aggregates of CD68+ tumor-associated macrophages, reaching a maximum at 3 weeks after irradiation. Necrotic regions decreased and were more dispersed. CONCLUSION: Irradiation of TRAMP-C1 tumors with either single or fractionated doses decreases MVD, leading to the development of disperse chronic hypoxic regions, which are infiltrated with CD68+ tumor-associated macrophages. Approaches to interfere in the development of these effects are promising strategies to enhance the efficacy of cancer radiotherapy.

Optimal Timing for Postsurgical Adjuvant Therapy in Patients with Gastric Cancer: A Propensity Score Matching Study.

Background: In clinical trials, adjuvant therapy (AT) has been shown to improve the prognosis in patients with gastric adenocarcinoma who undergo curative gastrectomy and adequate lymph node dissection. However, the optimal timing for initiating AT is still unclear. Method: We collected data from 538 patients with stage II-III gastric cancer who underwent curative gastrectomy and AT in two tertiary hospitals from 2006 to 2013. Patients were divided into the early group (≤8 weeks, n=393) and the late group (>8 weeks, n=145), based on the interval between gastrectomy and initiation of AT. Propensity score matching was applied according to baseline characteristics. Results: After 1:1 propensity score matching, an even distribution of characteristics in both groups (143:143) was achieved. The 5-year overall survival (OS) rates were 56.6% and 40.2% in the matched early and late groups, respectively (p=0.062), while the corresponding 5-year recurrence-free survival (RFS) rates were 57.6% and 46.4%, respectively (p=0.028). The time to AT initiation was correlated with RFS and had a positive association with OS. The 5-year distant metastasis-free survival was also significantly better (HR 0.682, 95% CI 0.472-0.985, p=0.040), suggesting an early AT results in a better outcome in patients. Conclusion: We observed that initiation of AT within 8 weeks of curative gastrectomy produces better disease control and may contribute to better overall survival.

Analysis of functional groups of differentially expressed genes in the peripheral blood of patients with cervical cancer undergoing concurrent chemoradiation treatment.

Chao, A., Wang, T. H., Lee, Y. S., Hong, J. H., Tsai, C. N., Chen, C. K., Tsai, C. S., Chao, A. S. and Lai, C. H. Analysis of Functional Groups Differentially Expressed Genes in the Peripheral Blood of Patients with Cervical Cancer Undergoing Concurrent Chemoradiation Treatment. Radiat. Res. 169, 76-86 (2008). We prospectively investigated the gene expression profiles of cervical cancer patients undergoing concurrent chemoradiation treatment. Up-regulated genes associated with anemia were analyzed. Peripheral blood of 20 patients (bulky stage IB-IVA cervical squamous cell carcinomas) undergoing concurrent chemoradiation treatment at four times was collected. Total RNA extracted by the PAXgene Blood RNA System was analyzed with microarrays and MetaCoretrade mark functional network analyses. Fifty-three genes were significantly differentially expressed during concurrent chemoradiation treatment. Fetal and embryonic hemoglobin genes were up-regulated when patients had been severely myelosuppressed. Twenty-eight genes correlated significantly with the hemoglobin genes are involved in responses to hypoxia and oxygenation, TGF-beta signaling, cell cycle suppression, G-protein signaling, and transcriptional regulation. c-Myc has the highest rank in transcriptional co-regulation. In addition, IGKV1D-13 was significantly down-regulated in patients with severe hematological toxicity. These approaches identified biological processes in peripheral blood modulated by concurrent chemoradiation treatment and subsequent anemia.

High pathologic complete response in HER 2-positive locally advanced breast cancer after primary systemic chemotherapy with weekly docetaxel and epirubicin.

BACKGROUND: To evaluate pathological complete response rate and to identify the predictor of response after primary systemic chemotherapy (PST) with weekly docetaxel and epirubicin for locally advanced breast cancer. METHODS: Sixty-three patients with locally advanced breast cancer received three cycles PST on day 1 and 8 of each 3-week cycle with epirubicin and docetaxel (epirubicin 45 mg/m(2) intravenous bolus, docetaxel 35 mg/m(2) in 100 ml normal saline infused 1 h), followed by surgery and adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil. The pathological complete response was defined as no invasive carcinoma in breast and axillary nodes after PST. RESULTS: The median tumor sizes (by ultrasound) before and after PST were 6.2 and 2.5 cm, respectively. The negative estrogen receptor (ER) by immunochemical stain was found in 33 (52.4%) patients and HER-2/neu-overexpression in 12 (19.0%) patients. Clinical overall response rate (ORR) was 89% (95% confidence intervals (95% CI: 81-97), including 38% complete response (95% CI: 26-50), sonographical ORR was 97% (95% CI: 93-100). The pathological complete response were found in 11 patients (18%, 95% CI: 9-27), and 15(24%, 95% CI: 13-35) patients achieved breast only pathological complete response. Nine (27.3%) of thirty-three ER (-) patients and 5 (41.7%) of 12 HER2-positive patients achieved pathological complete response. CONCLUSION: PST with weekly docetaxel and epirubicin were well-tolerated and very high pathological complete response rate was achieved in HER-2/neu-overexpression tumors.

Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth.

PURPOSE: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. METHODS AND MATERIALS: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. RESULTS: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNA expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1-2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. CONCLUSIONS: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo.

Value of dual-phase 2-fluoro-2-deoxy-d-glucose positron emission tomography in cervical cancer.

PURPOSE: The role of positron emission tomography (PET) with fluorine-18-labeled fluoro-2-deoxy-d-glucose (FDG) in cervical cancer has not yet been well defined. We conducted a prospective study to investigate its efficacy in comparison with magnetic resonance imaging and/or computed tomography (MRI-CT). MATERIALS AND METHODS: Patients with untreated locally advanced (35%) or recurrent (65%) cervical cancer were enrolled onto this study. In the first part of this study, 41 patients had a conventional FDG-PET (40 minutes after injection), and in the second part, 94 patients received dual-phase PET (at both 40 minutes and 3 hours after injection). The overall results of PET scans were compared with MRI-CT, and the two protocols of PET were also compared with each other. Lesion status was determined by pathology results or clinical follow-up. The receiver operating characteristic curve method with area under the curve (AUC) calculation was used to evaluate the discriminative power. RESULTS: Overall (N = 135), FDG-PET was significantly superior to MRI-CT in identifying metastatic lesions (AUC, 0.971 v 0.879; P =.039), although the diagnostic accuracy was similar for local tumors. Dual-phase PET was also significantly better than the 40-minute PET (n = 94). The latter accurately recognized 70% of metastatic lesions and the former detected 90% (AUC, 0.943 v 0.951; P =.007). Dual-phase FDG-PET changed treatment of 29 patients (31%; upstaging 27% and downstaging 4%). CONCLUSION: This study shows that dual-phase FDG-PET is superior to conventional FDG-PET or MRI-CT in the evaluation of metastatic lesions in locally advanced or recurrent cervical cancer.

Risk stratification of patients with advanced squamous cell carcinoma of cervix treated by radiotherapy alone.

PURPOSE: To identify prognostic factors for local and distant relapse and perform risk stratification for patients with advanced cervical cancer treated with radiotherapy (RT) alone. METHODS AND MATERIALS: A total of 1031 patients with Stage IB-IVA squamous cell carcinoma of the cervix treated with full-course RT but without any chemotherapy were included for analysis. Of these, 311 patients with nonbulky Stage IB-IIA disease were designated the reference group and the other 720 patients were the study group. The associations of stage, squamous cell carcinoma antigen (SCC-ag) level, hemoglobin level, age, cell differentiation, and pelvic lymph node status with treatment failure were evaluated. The independent prognostic factors were identified by multivariate analysis. The study group was further stratified into subgroups using combinations of these risk factors. RESULTS: In the study group, independent risk factors for local relapse were advanced stage and age <45 years. The 5-year local relapse-free survival rate was 86% for patients > or =45 years with bulky Stage IB-IIA or IIB disease, and was even greater, up to 90% if the SCC-ag level was <2. In contrast, it was 65% for patients with Stage IIIB who were <45 years old. The independent risk factors for distant failure were advanced stage, SCC-ag level >2, and positive pelvic lymph nodes. The 5-year distant relapse-free survival rate was 83% for patients with bulky Stage IB-IIA and IIB disease, SCC-ag level <2, and negative lymph nodes and 43% for patients with Stage III, SCC-ag level >2, and positive lymph nodes. CONCLUSION: The risk of treatment failure in advanced-stage cervical cancer patients treated by RT alone can be more precisely predicted by risk stratification. A certain subgroup of patients had better control than the others. The benefit of treating these relatively low-risk patients with additional treatment such as concurrent chemotherapy should be further evaluated in prospective studies or meta-analyses.

The Role of Pretreatment FDG-PET in Treating Cervical Cancer Patients With Enlarged Pelvic Lymph Node(s) Shown on MRI: A Phase 3 Randomized Trial With Long-Term Follow-Up.

PURPOSE: This report is the second analysis of a prospective randomized trial to investigate the impact of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) on cervical cancer patients with enlarged pelvic lymph nodes identified by magnetic resonance imaging. METHODS AND MATERIALS: Patients with newly diagnosed cervical cancer with enlarged pelvic lymph nodes but free of enlarged para-aortic lymph nodes (PALN) were eligible. Patients were randomized to receive either pretreatment FDG-PET (PET arm) or not (control arm). The whole pelvis was the standard irradiation field for all patients except those with FDG-avid extrapelvic findings. RESULTS: In all, 129 patients were enrolled. Pretreatment PET detected extrapelvic metastases in 7 patients. No new patient experienced treatment failure during the additional 4-year follow-up period. There were no significant differences between the PET arm and the control arm regarding overall survival, disease-free survival, and freedom from extrapelvic metastasis. In the control arm, 8 of 10 patients with PALN relapse had limited extrapelvic nodal failures; their 5-year disease-specific survival was 34.3%. By contrast, only 1 of 5 patients with PALN relapse in the PET arm experienced such limited failures; their 5-year survival rate was 0%. CONCLUSIONS: Although the pretreatment detection of PALN did not translate into survival benefit, it indeed decreased the need for extended-field concurrent chemoradiation therapy.

Recurrent squamous cell carcinoma of cervix after definitive radiotherapy.

PURPOSE: To study retrospectively the characteristics and survival of patients with recurrent squamous cell carcinoma (SCC) of the cervix after definitive radiotherapy (RT) and to identify subsets of patients who might benefit from aggressive salvage treatment. METHODS AND MATERIALS: Between 1990 and 1999, 1292 patients with Stage I-IVA SCC of the cervix underwent full-course RT. Of the 1292 patients, 375 (29%) had either local or distant failure and were included in this analysis. The 35 patients (2.7%) with both pelvic and distant relapse were excluded. In the 162 patients with local failure, 71 (44%) had persistent disease and 91 (56%) had a relapse after complete tumor regression. Of these 162 patients, 47 (29%) received salvage surgery. In the 213 patients with distant failure, 46 (22%) had isolated para-aortic lymph node (PALN) metastasis, and 35 (76%) of them were treated with concurrent chemoradiotherapy/RT. Patients with supraclavicular lymph node (SCLN) relapse usually underwent concurrent chemoradiotherapy. Palliative chemotherapy and/or RT were given by decision of the responsible attending physician. RESULTS: The independent prognostic factors for local failure were advanced stage and young age (<45 years) and, for distant failure, were advanced stage, positive pelvic lymph nodes, and high serum SCC-antigen levels. The 5-year overall survival rate was 10% and 11%, respectively, for patients with local or distant failure. For local relapse, the 5-year overall survival rate was 29% vs. 3% (p = 0.0001) for patients with vs. without salvage surgery and 22% vs. 9% vs. 4% for patients with tumors confined to the cervix, tumors extending but not beyond the cervix and adjacent tissues, and tumor extending beyond adjacent tissues but contained within the pelvis (p = 0.005). The survival rates, either with or without salvage surgery, were nearly identical between patients with persistent disease and those with relapse after complete regression. The 3-year overall survival rate was 34%, 28%, and 5% (p = 0.001), respectively, for patients with PALN relapse alone, SCLN relapse with or without PALN relapse, and relapse other than PALN and SCLN. Of the patients with PALN relapse alone, 27% survived >5 years. CONCLUSION: For recurrent SCC of the cervix after RT, patients with isolated PALN relapse salvaged by RT or combined chemoradiotherapy or those with cervical relapse salvaged by surgery can achieve long-term survival. Early detection of relapse with aggressive salvage treatment is important for achieving better outcome. Patients with persistent disease or relapse after complete remission had similar outcomes. Patients with SCLN relapse had a longer survival time than those with other metastases (except PALN), and palliative RT might be beneficial.

Preliminary report of using FDG-PET to detect extrapelvic lesions in cervical cancer patients with enlarged pelvic lymph nodes on MRI/CT.

PURPOSE: To evaluate, in a prospective study, the effects of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) on the detection of extrapelvic lesions, the design of whole pelvis or extended field radiotherapy, and subsequent failure patterns for patients with cervical cancer and enlarged pelvic lymph nodes (LNs) shown on MRI or CT. METHODS AND MATERIALS: Between April and December 2001, 19 consecutive patients underwent an additional FDG-PET examination before concurrent chemoradiotherapy. The inclusion criteria for the study were at least one enlarged pelvic LN > or =10 mm in its maximal dimension as shown on radiologic images and no extrapelvic tumors detected by conventional examination. The PET findings of the primary tumor, pelvic LNs, and extrapelvic lesions were investigated and compared with the MRI/CT findings. Tumor FDG uptake was quantitated with the maximal pixel standardized uptake value. RESULTS: Except for 1 patient with diabetes mellitus who was excluded from analysis, 18 cervical tumors had significant FDG uptake (maximal pixel standardized uptake value >8). A total of 39 pelvic LNs were reported, and the agreement of positive pelvic LNs between MRI/CT and PET was 79.5%. Five patients (28%) had positive paraaortic LNs on FDG-PET, and their treatment fields were extended to include the paraaortic region. In addition to the paraaortic LNs, 1 patient also had metastasis at the left supraclavicular node. After a minimum follow-up of 12 months (median 15.9), 4 patients (22.2%) developed new extrapelvic metastases. The disease-free survival rate was 78% at 12 months. CONCLUSION: FDG-PET is a useful tool to detect paraaortic LN metastasis and determine the appropriate treatment field for cervical cancer with enlarged pelvic LNs on MRI/CT. The preliminary data suggest that pretreatment FDG-PET can supplement conventional imaging studies, but still has limitations in the detection of microscopic disease.

Postoperative low-pelvic irradiation for stage I-IIA cervical cancer patients with risk factors other than pelvic lymph node metastasis.

PURPOSE: To retrospectively investigate whether postoperative low-pelvic radiotherapy (RT) is an appropriate treatment for node-negative, high-risk Stage I-IIA cervical cancer patients. METHODS AND MATERIALS: A total of 228 Stage I-IIA cervical cancer patients treated by radical surgery and postoperative RT were included in this study. All patients had histopathologically negative pelvic node metastasis, but at least one of the following risk factors: parametrial involvement, positive or close resection margins, invasion depth two-thirds or greater cervical stromal thickness. Seventy-nine patients (35%) received 30-50 Gy (median 44) to whole pelvis and a boost dose to the low pelvis (whole-pelvic RT group); the other 149 patients (65%) received low-pelvic RT only (low-pelvic RT group). For both groups, the total external RT dose to the low pelvis ranged from 40 to 60 Gy (median 50). The potential factors associated with survival, small bowel (gastrointestinal) complications, and leg lymphedema were analyzed, and patients who had a relapse in the upper pelvis were identified. RESULTS: The 5-year overall and disease-specific survival rate was 84% and 86%, respectively. After multivariate analysis, only bulky tumor (>or=4 cm) and non-squamous cell carcinoma were significantly associated with survival. Parametrial involvement, lymph-vascular invasion, 50.4 Gy to the low pelvis, but not old age and treatment technique (AP-PA vs. box), were significantly associated with gastrointestinal complications. Three patients (2%) in the low-pelvic RT group and 6 patients (8%) in the whole-pelvic RT group were found to have Grade III or higher small bowel complications (p = 0.023). Thirty-one percent of patients developed lymphedema of the leg. A dose to the low pelvis >50.4 Gy and an AP-PA field, but not whole-pelvic RT, old age, or the number of sampled lymph nodes, were associated with lymphedema of the leg. Five patients (3.6%) of the low-pelvic RT group and none of the whole-pelvic RT group developed upper pelvis relapse. Three of these 5 patients had upper pelvic relapse alone. CONCLUSION: Compared with whole-pelvic RT plus low-pelvic boost, low-pelvic RT alone significantly reduces the small bowel complications in node-negative, high-risk, Stage I-IIA cervical cancer patients. Although low-pelvic RT alone increases the incidence of upper pelvic relapse, its effect on survival is not substantial. Low-pelvic RT alone appears to be an appropriate treatment method for this group of patients.

Delayed (18)F-FDG PET for detection of paraaortic lymph node metastases in cervical cancer patients.

UNLABELLED: This prospective study investigated the usefulness of dual-phase (18)F-FDG PET scans (40 min and 3 h) in detecting paraaortic lymph node (PALN) metastasis for cervical cancer. METHODS: One hundred four consecutive cervical cancer patients (International Federation of Gynecology and Obstetrics staging Ib-IVb, recurrent or persistent tumors) were included. All patients received a whole-body (18)F-FDG PET scan at 40 min and an additional scan from the T11 level to the inguinal region at 3 h after injection of 370 MBq (18)F-FDG. The maximum standardized uptake value (SUV) and retention index (RI [%], obtained by subtracting the normalized SUV value obtained at 40 min from that at 3 h) of the lesions were determined. RESULTS: In all, 38 of the 104 patients were confirmed to have PALN metastases. For 31 patients (81.6%) with 13 upper (L1-L2 level) and 30 lower (L3-L4 level) PALNs, these metastases were detected with the 40-min scan. In addition, for 7 patients (18.4%) with 7 lower PALNs, metastases were found with the 3-h scan (RI = 12.6%). Two patients (3.0%) had 2 false-positive lesions initially (40 min) but were classified as benign with the 3-h scan. The sensitivity, specificity, and accuracy of (18)F-FDG PET scans at 40 min were 81.6%, 97.0%, and 91.3%, respectively. These quantities were all 100% when both the 40-min and 3-h scans were taken together. Eight patients (21.1%) had their treatment planning changed. We divided the 38 patients into 2 subgroups. Subgroup A included those with either only upper or only lower PALN metastases, and subgroup B included those with both upper and lower PALN metastases. In subgroup A, the SUV values were greater in the upper than in the lower PALNs in both the 40-min and 3-h images (P = 0.077). In subgroup B, there was no significant difference of SUV values between upper and lower PALNs in the 40-min (P = 0.433) and 3-h (P = 0.937) images. CONCLUSION: Our results showed that an additional 3-h scan is helpful for PALN detection of cervical cancer patients. A delayed image (3 h) is especially useful for lower PALN metastases.

Defining the priority of using 18F-FDG PET for recurrent cervical cancer.

UNLABELLED: PET with 18F-FDG has shown its potential in cervical cancer. For maximizing the benefits of this new imaging technology, we aimed to define the prognostic features of recurrent cervical cancer patients for selecting appropriate candidates using 18F-FDG PET. METHODS: Patients enrolled were from 2 independent prospective studies investigating the role of 18F-FDG PET in cervical cancer patients after definitive treatment with documented failure (CTRP-018) or unexplained elevated tumor marker serum levels (CTRP-016) and proven relapse after PET. A total of 55 eligible patients received PET and CT or MRI. Lesion status was determined from pathologic results or clinical follow-up. The benefits calculated were based on treatment that was modified because of the PET findings. The Cox proportional hazards ratio (HR) was used to select independent prognostic covariates. RESULTS: Thirty-six (65.5%) patients had treatment that was modified due to PET. Primary radiation (HR = 14.62; 95% confidence interval [CI] = 2.74-77.92), squamous cell carcinoma antigen (SCC-Ag) > or = 4 ng/mL (HR = 5.82; 95% CI = 1.53-22.04), and presence of symptoms (HR = 6.24; 95% CI = 1.99-19.61) at recurrence were significant factors associated with poor survival. A scoring system using these covariates defined 3 distinct prognostic groups: score < or = 1 (HR = 1.00); score = 2 (HR = 6.91; 95% CI = 1.49-32.14); and score = 3 (HR = 60.46; 95% CI = 9.68-378.09) (P < 0.0001). CONCLUSION: Using this risk score, 18F-FDG PET may offer maximal benefits by selecting appropriate recurrent cervical cancer patients for salvage therapy with precise restaging information.

Effects of pre-irradiation and SDF-1 suppression on the progression of murine astrocytoma cells grown in different stromal beds.

PURPOSE: To examine whether brain tumors grown in pre-irradiated (PreIR) thigh have a similar tumor bed effect (TBE) as in PreIR brain tissue. MATERIAL AND METHODS: Tumor growth delay and immunohistochemical (IHC) staining for CD31, an endothelial surface marker, and PIMO, a hypoxia marker, were used to study the TBE of a murine astrocytoma, ALTS1C1, or a stromal-derived factor-1 (SDF-1) gene-silenced astrocytoma, ALTS1C1-SDFkd, growing in different PreIR stroma beds. RESULTS: ALTS1C1 tumors growing in both PreIR brain and PreIR thigh had reduced microvascular density (MVD) and more chronic hypoxia, but tumor growth delay was only seen in PreIR brain tissue. In contrast, ALTS1C1-SDFkd tumors showed tumor growth delay in PreIR thigh, with little effect in PreIR brain tissue. CONCLUSIONS: This study cautions that both the tumor and the nature of the PreIR stromal bed are important when using pre-irradiation as a model of recurrent brain tumors after radiation therapy.

A retrospective review of the prognostic value of ALDH-1, Bmi-1 and Nanog stem cell markers in esophageal squamous cell carcinoma.

Stem cell markers are upregulated in various cancers and have potential as prognostic indicators. The objective of this study was to determine the expression of three stem cell markers, aldehyde dehydrogenase 1 (ALDH-1), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), and Nanog, in esophageal squamous cell carcinoma (ESCC) tissues. Immunohistochemistry was used to measure the expression of ALDH-1, Bmi-1, and Nanog in ESCC tissues from 41 patients who received pre-operative chemoradiation. We evaluated the relationship between expression of these markers, and clinicopathological features, tumor regression grade (TRG), and 5-year overall survival (OS). There were no significant associations of ALDH-1 or Bmi-1 expression with age, gender, clinical stage, and treatments (p>0.05). However, patients with Nanog-positive tumors were significantly older than those whose tumors were Nanog-negative (p = 0.033). TRG after treatment was significantly associated with expression of ALDH-1 (p = 0.001), Bmi-1 (p = 0.004), and Nanog (p<0.001). Although OS was significantly better in patients with low TRGs (p = 0.001), there were no significant correlations between ALDH-1, Bmi-1, or Nanog with OS. Expression of ALDH-1, Bmi-1, and Nanog correlated with TRG, but not OS. Further large studies are necessary to fully elucidate the prognostic value of these stem cell markers for ESCC patients.

Radiation therapy-induced tumor invasiveness is associated with SDF-1-regulated macrophage mobilization and vasculogenesis.

Radiation therapy (RT) remains the front-line treatment for high-grade gliomas; however, tumor recurrence remains the main obstacle for the clinical success of RT. Using a murine astrocytoma tumor cell line, ALTS1C1, the present study demonstrates that whole brain irradiation prolonged the survival of tumor-bearing mice, although the mice eventually died associated with increased tumor infiltration. Immunohistochemical (IHC) analysis indicated that RT decreased the microvascular density (MVD) of the primary tumor core, but increased the MVD of the tumor invasion front. RT also increased the number of tumor-associated macrophages (TAMs) and the expression of stromal cell-derived factor-1 (SDF-1) and hypoxia-inducible factor-1 (HIF-1) at the tumor invasion front. SDF-1 expression suppressed by siRNA (SDFkd tumors) showed a decrease in RT-enhanced tumor invasiveness, leading to prolonged survival of mice bearing these tumors. The invasion front in SDFkd tumors showed a lower MVD and TAM density than that in the islands of the control or irradiated ALTS1C1 tumors. Our results indicate that tumor-secreted SDF-1 is one key factor in RT-induced tumor invasiveness, and that it exerts its effect likely through macrophage mobilization and tumor revascularization.

Clinical behaviors and outcomes for adenocarcinoma or adenosquamous carcinoma of cervix treated by radical hysterectomy and adjuvant radiotherapy or chemoradiotherapy.

PURPOSE: To compare clinical behaviors and treatment outcomes between patients with squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix treated with radical hysterectomy (RH) and adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). METHODS AND MATERIALS: A total of 318 Stage IB-IIB cervical cancer patients, 202 (63.5%) with SCC and 116 (36.5%) with AC/ASC, treated by RH and adjuvant RT/CCRT, were included. The indications for RT/CCRT were deep stromal invasion, positive resection margin, parametrial invasion, or lymph node (LN) metastasis. Postoperative CCRT was administered in 65 SCC patients (32%) and 80 AC/ASC patients (69%). Patients with presence of parametrial invasion or LN metastasis were stratified into a high-risk group, and the rest into an intermediate-risk group. The patterns of failure and factors influencing survival were evaluated. RESULTS: The treatment failed in 39 SCC patients (19.3%) and 39 AC/ASC patients (33.6%). The 5-year relapse-free survival rates for SCC and AC/ASC patients were 83.4% and 66.5%, respectively (p = 0.000). Distant metastasis was the major failure pattern in both groups. After multivariate analysis, prognostic factors for local recurrence included younger age, parametrial invasion, AC/ASC histology, and positive resection margin; for distant recurrence they included parametrial invasion, LN metastasis, and AC/ASC histology. Compared with SCC patients, those with AC/ASC had higher local relapse rates for the intermediate-risk group but a higher distant metastasis rate for the high-risk group. Postoperative CCRT tended to improve survival for intermediate-risk but not for high-risk AC/ASC patients. CONCLUSIONS: Adenocarcinoma/adenosquamous carcinoma is an independent prognostic factor for cervical cancer patients treated by RH and postoperative RT. Concurrent chemoradiotherapy could improve survival for intermediate-risk, but not necessarily high-risk, AC/ASC patients.