Complete Histologic Regression Research Articles

336. IMPACT OF TIME TO SURGERY AFTER CHEMORADIOTHERAPY ON TUMOR REGRESSION AND SURVIVAL IN THE MULTICENTER RANDOMIZED CONTROLLED NEORES II TRIAL

Abstract Time to surgery after termination of neoadjuvant chemoradiotherapy for esophageal cancer has traditionally been 4–6 weeks. Observational studies have suggested that delay of surgery for up to three months may lead to improved tumor regression and better outcomes. NeoRes II is the first randomized trial to address this in esophageal cancer. No difference in surgical morbidity or mortality between early and delayed surgery was reported in a previous publication from the trial. A multicenter clinical trial with randomized 1:1 allocation of standard time to surgery of 4–6 weeks, or delay of surgery to 10–12 weeks, after termination of chemoradiotherapy. The primary endpoint was complete histological tumor regression in patients with adenocarcinoma. Secondary endpoints included tumor regression grade, tumor free resection margins and overall survival in all patients, and stratified by histological subtype. In total 249 patients were randomized, 204 with adenocarcinoma and 45 with squamous cell carcinoma. There was no significant difference in histological complete response between adenocarcinoma patients allocated to standard time to surgery (20.6%) compared to delayed (25.6%) surgery (P = 0.18). Tumor free resection margin was achieved in 97.4% after standard time to surgery and 97.1% after delayed surgery (P = 1.0). The median follow-up time for survival was 51 months. Delayed time to surgery was associated with a 35% higher overall mortality, hazard ratio 1.35 (95% CI:0.94–1.95), (P = 0.11). No significant difference in complete histological tumor regression or tumor free resection margins comparing standard and delayed time to surgery after chemoradiotherapy was observed. There was a non-significant trend towards inferior overall survival after delayed surgery, suggesting caution in delaying surgery for more than 6 weeks after neoadjuvant chemoradiotherapy.

Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): The AVANA study.

3511 Background: Preop CTRT is considered the standard of care in the management of LARC. RT can induce antigen release from a low neoantigen-burden tumor (such as a mismatch repair proficient colorectal cancer) and activate dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response. In LARC patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. Based on such considerations, we have designed the AVANA study to investigate the role of Ave in combination with preop CTRT in LARC. Methods: This is an Italian multi-center, phase II study. Pts with resectable LARC, defined by the presence of at least one of the following features: cN+, cT4, high risk cT3, received standard preop CTRT (capecitabine 825 mg/sqm/bid 5 days/week+ 50.4 Gy in 28 fractions over 5.5 weeks) plus 6 cycles of Ave 10 mg/Kg every 2 weeks. Surgery with total mesorectal excision was performed at 8-10 weeks after the end of CTRT. The primary end-point was the pCR rate, defined as complete histological regression with no available tumor cells ypT0N0. Secondary end-points were R0 resection rate, tumor downstaging, local recurrence, sphincter preservation rate, progression-free survival, overall survival, safety profile, and the evaluation of exploratory predictive and/or prognostic biomarkers. Assuming as null hypothesis p0 a pCR rate of 15%, a significance level of 5% (one-side), and a power of 80%, a sample size of 101 pts was needed to detect an absolute increment of 10% in pCR rate (from 15% to 25%). The experimental regimen is considered for further studies if, in at least 22 pts, we observe a pCR. Results: From April 2019 to November 2020, a total of 101 resectable LARC pts were enrolled in 10 Italian Centers. The median age was 63 years (23-82), 62 (61.4%) pts were male, 93 (92%) had ECOG PS 0. At baseline, 94 (93%) and 16 (16%) pts had cN+ and cT4 LARC, respectively. All pts completed the induction phase. Out of 96 pts evaluable for pathological response, 22 (23%) pts achieved a pCR and 59 (61.5%) pts a major pathological response (a central review is ongoing). At this time, microsatellite status is available only in 39 pts, of which only one was instable. The rate of grade 3-4 non-immune and immune-related adverse events was 8% and 4%, respectively. Avelumab was early interrupted in 9 pts out 101, mainly due to toxicity. Conclusions: The combination of preop CTRT plus Ave showed a promising activity and a feasible safety profile. According to our statistical considerations, the experimental regimen will be considered for further studies. Updated results will be presented during the Congress. Sponsored by GONO and partially supported by Merck. EUDRACT 2017-003582-10. Clinical trial information: NCT03854799.

PP264 Effectiveness And Safety Of Pressurized Intraperitoneal Aerosol Chemotherapy For Peritoneal Carcinomatosis: A Systematic Review

IntroductionPressurized intraperitoneal aerosol chemotherapy (PIPAC) is a minimally invasive therapeutic option for stage IV or terminal stage peritoneal carcinomatosis, which has a very low survival rate. PIPAC is aimed at patients whose only therapeutic alternative is systemic chemotherapy because they are unable to undergo other treatments, such as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. PIPAC consists of a micro-pump connected to a double-contrast injector, which is used to apply cytotoxic agents laparoscopically using pressurized aerosols. The objective of this study was to update the evidence regarding the effectiveness and safety of PIPAC.MethodsA systematic review (SR) was conducted by searching PubMed, Embase, and The Cochrane Library database. ClinicalTrials.gov and the European Union Drug Regulating Authorities Clinical Trials Database were consulted to identify registered clinical studies. All articles published up to April 2019 were considered for inclusion. Abstracts, letters, single case studies, non-clinical and animal studies, and studies published in languages other than English or Spanish were excluded. Validated checklists were used to assess the quality of the included studies.ResultsSeventeen studies were included (three SRs and fourteen cases series) and eighteen ongoing clinical trials were identified. The quality of the SRs and cases series studies was low and moderate, respectively. Adverse events were categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events as grade 1–2 (mild-moderate: 11% to 40% of patients) and grade 3–4 (severe-fatal: 0% to 37% of patients). Overall complete histological regression according to the Peritoneal Regression Grading Score and the Peritoneal Cancer Index occurred in at least sixty percent of patients. The survival time ranged from 11 to 16 months.ConclusionsEffectiveness data for PIPAC were promising, with high carcinomatosis regression rates. Most studies showed a moderate safety profile, with generally mild to moderate complications (nausea, abdominal pain, and vomiting). This is an advantage over systemic chemotherapy, which has severe systemic side effects. Economic evaluation studies are needed to estimate the cost effectiveness and cost utility of this technology. Diffusion of PIPAC is expected, but the criteria used to select patients in the studies carried out so far must be considered, as well as the need to follow strict safety protocols for preventing leakage of aerosolized cytotoxic drugs.

Neoadjuvant vismodegib in the management of locally advanced periocular basal cell carcinoma.

Vismodegib, a hedgehog pathway inhibitor, has been used in the management of locally advanced basal cell carcinoma (BCC) not suitable for surgery or radiation therapy. We report our experience using neoadjuvant vismodegib for locally advanced periocular BCC, followed by surgical excision. Our aim was to assess the effect on the extent of surgical excision and histological response. A retrospective case series of patients treated with neoadjuvant vismodegib, for the management of locally advanced periocular BCC prior to surgical excision, with intraoperative margin control. Patients were treated until a maximum clinical response was seen. The difference between the estimated surgical margins prior to vismodegib and the eventual margins used was compared. Fine (1 mm) vertical sections through the excised tumour were performed to assess the histological response and look for a multifocal tumour. Eight Caucasian patients had neoadjuvant treatment with vismodegib for a median duration of 6 months. Some clinical response was seen in all cases but was only partial in 6/8 patients. Histological evaluation of the excised specimen showed residual BCC in 6/8 cases and thus 2/8 showed complete histological regression. Two cases showed squamous differentiation. Side effects occurred in 7/8 patients all which resolved on cessation of therapy. The mean follow-up was 13.4 ± 5.2 months. Neoadjuvant treatment of periocular BCC showed a mixed clinical and histological response. Final surgical excision achieved clear margins in all patients with no recurrence at 13 months and a reduction in predicted defect size, but possible squamous differentiation in two cases.

Mo1291 SIMPLIFIED VERSUS STANDARD REGIMEN FOR FOCAL RADIOFREQUENCY ABLATION OF SHORT SEGMENT DYSPLASTIC BARRETT’S ESOPHAGUS ARE EQUALLY EFFECTIVE: SHOULD WE KEEP IT SIMPLE?

Focal radiofrequency ablation (RFA) of Barret’s esophagus islands using a simplified regimen (3x15 J/cm2, without cleaning) has proven to be as effective as the standard regimen (2x15 J/cm2, followed by cleaning, 2x15 J/cm2). However, studies using a lower radiofrequency energy (12 J/cm2) and specifically short segment Barrett’s (SSBE) are limited. Our aim was to compare the short-term efficacy of the simplified protocol regimen using 12 J/cm2 to the standard regimen for ablating SSBE. All SSBE patients that underwent focal RFA from January 2015 to November 2019 at Tampa General Hospital were reviewed. The patients undergoing simplified regimen (3×12 J/cm2, without cleaning) or the standard regimen were compared. Demographic data, length of Barrett’s, number of RFA sessions, level of dysplasia, and procedure time were included. The primary outcome was complete endoscopic and histological regression of dysplasia and intestinal metaplasia. Secondary outcomes included rate of stenosis, total procedure time and total number of sessions. Patient that received circumferential radiofrequency ablation, cryotherapy, previous mucosa resection or history of adenocarcinoma were excluded. Out of 139 patients, a total of 20 patients met inclusion criteria. 10 underwent the simplified and standard protocol each. Patient characteristics are available in Table 1. Patient characteristics were similar in both groups including the median Prague Score (C0M2 simplified vs C1M2 standard), high-grade dysplasia (30% simplified vs 60% standard), and presence of islands (40% simplified vs 30% standard). There was no difference in the biopsy-proven complete eradication between the two groups (40% simplified vs 50% standard, p=0.337), endoscopic surface regression (40% simplified vs. 70% standard, p=0.098), and procedure time (22 min simplified vs. 19 min standard, p=0.659).There was a significant difference in the number of RFA sessions required (1.9 simplified vs 3.3 standard, p=0.05). Two patients developed stenosis in the standard group, one requiring dilation. No patients in the simplified group developed stenosis. Compared to the standard method, the simplified method of RFA using 12 J/cm2 is as effective for treatment of SSBE. Our data, while limited due to a small sample size, did show a decrease in the total number of RFA sessions required to achieve eradication in the simplified group. Additionally, we did not find a higher rate of stenosis in the simplified group. Larger, randomized controlled trials are needed to confirm these findings further.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Impact of the histological regression grade of the primary tumor and regional lymph nodes after neoadjuvant chemoradiotherapy on survival of patients with gastric cancer: two case reports

Background . Stomach cancer remains one of the most common malignancies worldwide, with high incidence rates and low rates of long-term treatment outcomes. Neoadjuvant therapy currently is increasingly being considered the standard therapy for locally advanced gastric and cardioesophageal cancers. A complete pathological response of the tumor has been reported to be observed in 8-20 % of patients. However, there is no guarantee that the evidence of pathological complete response will improve the cure results in all patients, and very little is known about prognostic factors after neoadjuvant therapy. Case descriptions . Two clinical cases of locally advanced gastric cancer were described. The patients were treated with neoadjuvant chemoradiotherapy followed by D2 gastrectomy. Accelerated hyperfractionated radiotherapy (1 + 1.5 Gy/ day) to a total dose of 45 Gy at intervals of 4-5 hours was administered concurrently with chemotherapy (capecitabine: 1850 mg/m 2 orally twice daily at 12-hour interval; oxaliplatin: 85 mg/m 2 intravenously on days 1 and 21). Histological examination revealed complete histological regression of the primary tumor in two cases. However, in one of the cases, metastases in regional lymph nodes with grade 2 histological tumor regression were revealed. In the first case, the patient is still alive with no evidence of disease recurrence at over 6-years after treatment. In the second case, the patient died of the disease progression 3 years after treatment. Conclusion. The data obtained are consistent with the few published studies reporting that pathological complete response to neoadjuvant therapy of not only the primary tumor but also regional lymph nodes is the key point determining the effectiveness of the combined modality treatment.

Simplified versus standard regimen for focal radiofrequency ablation of dysplastic Barrett's oesophagus: a multicentre randomised controlled trial

For focal radiofrequency ablation of Barrett's oesophagus, a simplified regimen (3 × 15 J/cm2, without cleaning) has proven to be as effective as the standard regimen (2 × 15 J/cm2, followed by cleaning, followed by 2 × 15 J/cm2). However, this simplified regimen seemed to be associated with a higher stenosis rate. Therefore, we lowered the radiofrequency energy and hypothesised that this new simplified regimen would be as effective and safe as the standard regimen. This randomised non-inferiority trial included patients with dysplastic Barrett's oesophagus or residual Barrett's oesophagus after endoscopic resection or circumferential radiofrequency ablation, in five European tertiary referral centres. Patients were randomly assigned (1:1) to the new simplified regimen (3 × 12 J/cm2, without cleaning) or the standard regimen, with variable block sizes of four, six, and eight patients, stratified by participating hospital. Focal radiofrequency ablation was done every 3 months, up to a maximum of three treatments, until all Barrett's oesophagus was eradicated. The primary outcome was complete endoscopic and histological regression of dysplasia and intestinal metaplasia after two focal radiofrequency ablation treatments, assessed in the intention-to-treat population. Non-inferiority was assessed on the basis of the difference between groups in the median percentage of Barrett's oesophagus surface regression, with a non-inferiority margin of -15%. This study is registered with www.trialregister.nl, number NTR4994, and is completed. Between March 25, 2015, and July 25, 2016, 84 patients were randomly assigned to treatment: 44 to receive the simplified regimen and 40 to receive the standard regimen. One patient assigned to the simplified regimen and four assigned to the standard regimen were excluded because they weree found not to be eligible; therefore the final intention-to-treat population consisted of 43 patients in the simplified ablation group and 36 in the standard ablation group. Complete endoscopic and histological regression of dysplasia and intestinal metaplasia after two focal radiofrequency ablation treatments was achieved in 32 (74%, 95% CI 59-87) patients treated with the simplified protocol, versus 30 (83%, 95% CI 67-94) patients treated with the standard protocol (p=0·34). Median Barrett's oesophagus surface regression after two focal radiofrequency ablation sessions was 98% (IQR 95-100) in the simplified regimen group and 100% (97-100) in the standard regimen group. The difference between medians was 2% (95% CI -0·562 to 3·162); thus the simplified regimen was deemed non-inferior to the standard regimen. Stenoses requiring dilatation were observed in four (9%) of 43 patients in the simplified regimen group and four (11%) of 36 in the standard regimen group. Post-procedural bleeding requiring repeat endoscopy occurred in one (2%) patient in the simplified ablation group and three (8%) patients in the standard ablation group. One patient (2%) in the simplified treatment group died 36 days after the second radiofrequency ablation procedure, due to an unknown cause. Based on the results of this study, we conclude that the simplified regimen is the preferred regimen for focal radiofrequency ablation of Barrett's oesophagus. None.

ED14.04 Is There a Role for Surgery in SCLC?

ED14.04 Is There a Role for Surgery in SCLC?

Hope in the Long Road Toward the Development of a Therapeutic Human Papillomavirus Vaccine.

A pool of long synthetic peptides derived from HPV16 proteins induce objective partial or complete histologic regression of lesions in more than 50% of patients with high-grade vulvar (VuVIN3) and vaginal intraepithelial neoplasia (VaIN3). The intensity of T-cell response induced by the vaccine was correlated with clinical response. Clin Cancer Res; 22(10); 2317-9. ©2016 AACRSee related article by van Poelgeest et al., p. 2342.

The effect of topical diclofenac 3% and calcitriol 3 μg/g on superficial basal cell carcinoma (sBCC) and nodular basal cell carcinoma (nBCC): A phase II, randomized controlled trial

Nonsteroidal anti-inflammatory drugs and vitamin-D derivatives can target signaling pathways activated in basal cell carcinoma (BCC). We investigated the efficacy of topically applied diclofenac sodium 3% gel, calcitriol 3μg/g ointment, and a combination of both in superficial BCC (sBCC) and nodular BCC. Patients with a primary, histologically proven sBCC (n=64) or nodular BCC (n=64) were randomized to topical diclofenac, calcitriol, combination of both, or no topical treatment (control group). After self-application twice daily under occlusion (8weeks), tumors were excised. Primary outcome wasposttreatment expression levels of proliferation (Ki-67) and antiapoptosis (B-cell lymphoma [Bcl-2])immunohistochemical markers. Secondary outcomes were histologic clearance, adverse events, application-site reactions, and patient compliance. sBCC treated with diclofenac showed a significant decrease in Ki-67 (P<.001) and Bcl-2 (P=.001), and after combination therapy for Ki-67 (P=.012). Complete histologic tumor regression was seen in 64.3% (P=.0003) of sBCC (diclofenac) and 43.8% (P=.007) of sBCC (combination therapy) compared with 0.0% of controls. No significant changes were found in nodular BCC. Application-site reactions were mostly mild to moderate. The sample size was small. Our results suggest that topical diclofenac is a promising new treatment for sBCC. Its mode of action differs from available noninvasive therapies, and thus has an additive value.

Value and limits of non-robotic transoral oropharyngectomy for local control of T1-2 invasive squamous cell carcinoma of the tonsillar fossa

BackgroundAn analysis of the value and limits of non-robotic transoral oropharyngectomy for local control of T1-2 squamous cell carcinoma of the tonsillar fossa. MethodsA retrospective series of 111 T1 and 133 T2 (N0: 129; N1: 52; N2: 53; N3: 10). Induction chemotherapy and postoperative radiation therapy were used in 63.5% and 29.5% of cases, respectively. Actuarial analysis of local failure, impact of various variables upon local failure and consequences of local failure upon other oncological events and survival are documented. ResultsThe 5-year actuarial local failure estimate was 10.4% and 14.2% for T1 and T2 tumors, respectively. The 5-year actuarial local failure estimate was significantly reduced when resection margins were safe or yielded dysplasia (P=0.008) and when induction chemotherapy achieved complete histologic regression (P=0.013). Salvage treatment achieved a 97.2% and 93.2% overall local control rate in T1 and T2 tumors, respectively. The 5-year actuarial nodal failure estimate was 35.1% in patients with local failure versus 10.8% without (P=0.0001). The 5-year actuarial metachronous second primary estimate was 7% in patients with local failure versus 33.2% without (P=0.016). The impact of local failure on survival (5-year actuarial survival estimate: 67.3% without and 46.4% with local failure) was not significant. ConclusionIn T1-2 squamous cell carcinoma of the tonsillar fossa, non-robotic transoral oropharyngectomy appeared to be highly effective in terms of local control. The high incidence of head and neck metachronous second primaries further advocates the use of this treatment option in order to reserve radiation therapy to such cases.

Morphologic and Histologic Changes in Gastric Adenomas After Helicobacter pylori Eradication: A Long-Term Prospective Analysis.

Helicobacter pylori infection causes gastric neoplasia via development of chronic atrophic gastritis and intestinal metaplasia. The effect of H. pylori eradication on pre-existing gastric neoplasias is still controversial. The aim of this study was to use long-term observation to clarify morphologic and histologic changes in gastric adenomas following H. pylori eradication. Twenty-seven patients with gastric adenomas (revised Vienna classification category 3 or 4.1) who underwent successful H. pylori eradication between April 1996 and December 1997 were followed up at regular intervals with endoscopic and histologic examination. The association between macroscopic and histologic regressions of the lesions and the following patient and lesion characteristics was assessed with univariate analysis: follow-up period, age, sex, serum pepsinogen level, lesion size, lesion location, and histologic gastritis. The mean follow-up period was 91.9 months (range 44-181 months). Twelve lesions (44.4%) showed macroscopic regression, of which 7 (25.9% of the total) also showed histologic regression, with the mean duration from H. pylori eradication to complete macroscopic and histologic regression being 19.9 months. The other 15 lesions (55.6%) remained stable macroscopically and histologically, of which 6 (22.2% of the total) progressed to malignancy during the follow-up period. Univariate analysis revealed that female sex (p = .005), smaller lesion size (p = .025), higher baseline serum pepsinogen II level (p = .041), and absence of intestinal metaplasia in the greater curvature of the corpus (p = .026) were significantly associated with complete regression. Helicobacter pylori eradication may induce regression in some gastric adenomas.

Assessment of the Effect of Treatment with Neoadjuvant Chemotherapy on Breast Cancer Axillary Lymph Node

Summary Neoadjuvant chemotherapy is the standard of care for patients with locally advanced breast cancer (LABS). The aim of this study was to determine the effects of neoadjuvant chemotherapy on metastatic and nonmetastatic breast cancer axillary lymph nodes (ALNs). Seventy-seven patients with LABS and cytologically documented ALN metastases were treated in two prospective trials. Patients had breast surgery with level I and level II axillary dissection followed by additional chemotherapy or radiation treatment. Clinical nodal status was determined by physical examination and compared with histological and immunohistochemical findings. The regressive changes in primary tumor and ALNs were achieved using scoring systems. Objective clinical response in primary tumor was seen in 48.05% of patients. Histologic evidence of regression was noted in 46 cases (59.75%), with complete histologic regression achieved in 5 cases (6.49%). The number of cases according to the ALNs regression scoring system was as follows: 0 grade - viable metastases without effect - 21 patients (30%); 1 grade - cytotoxic effect in metastases - 20 patients (28.58%), 2 grade - micrometastasis - only3 patients (4.28%); 3 grade - no residual metastatic disease - 1 patient (1.43%); 4 grade - negative ALNs before and after treatment - 25 patients (35.71%). Nodular fibrotic area and iron-loaded macrophages suggested previous presence of tumor metastasis. There was significant relationship between histologic regression in the primary tumor and the presence of effect of cytotoxic agents on ALNs metastases (r=0.9123; p&lt;0.00001). As chemotherapy is widely used in the treatment of breast carcinoma, pathologists should be aware of chemotherapy-induced changes in metastatic and in non­metastatic ALNs.

Naturally occurring systemic immune responses to HPV antigens do not predict regression of CIN2/3

Essentially all squamous cervical cancers and their precursor lesions, high grade cervical intraepithelial neoplasia (CIN2/3), are caused by persistent human papillomavirus (HPV) infection. However, not all CIN2/3 lesions progress to cancer. In a brief, observational study window monitoring subjects with CIN2/3 from protocol entry (biopsy diagnosis) to definitive therapy (cervical conization) at week 15, in a cohort of 50 subjects, we found that 26% of CIN2/3 lesions associated with HPV16, the genotype most commonly associated with disease, underwent complete histologic regression. Nonetheless, HPV16-specific T cell responses measured in peripheral blood obtained at the time of study entry and at the time of conization were marginally detectable directly ex vivo, and did not correlate with lesion regression. This finding suggests that, in the setting of natural infection, immune responses which are involved in elimination of cervical dysplastic epithelium are not represented to any great extent in the systemic circulation.

Outcome and Histopathologic Regression in Oral Squamous Cell Carcinoma after Preoperative Radiochemotherapy

Preoperative radiochemotherapy has been reported to enhance tumor response and to improve long-term survival in advanced squamous cell carcinoma of the head and neck. This retrospective study evaluates regression rate and long-term survival in 228 patients with primary oral squamous cell carcinoma treated by neoadjuvant radiochemotherapy and radical surgery. All patients with biopsy-proven, resectable oral squamous cell carcinoma - TNM stages II-IV without distant metastasis - received preoperative treatment consisting of fractioned irradiation of the primary and the regional lymph nodes with a total dose of 40 Gy and additional cisplatin (n = 160) or carboplatin (n = 68) during the 1st week of treatment. Radical surgery and neck dissection followed after a delay of 10-14 days. The study only included cases with histologically negative resection margins. After a median follow-up of 5.2 years, 53 patients (23.2%) had experienced local-regional recurrence. The median 2-year disease-specific survival (DSS) rate was 86.2%. 5-year DSS and 10-year DSS were 76.3% and 66.7%, respectively. Complete histological local tumor regression after surgery (ypT0) was observed in 50 patients (21.9%) and was independent of pretreatment tumor classification. Uni- and multivariate survival analysis revealed that ypT- and ypN-stage were the most decisive predictors for DSS. Preoperative radiochemotherapy with cisplatin/carboplatin followed by radical surgery attains favorable long-term survival rates. This applies especially to cases with complete histological tumor regression after radiochemotherapy, which can be assumed for one of five patients.

A Phase I Trial of a Human Papillomavirus DNA Vaccine for HPV16+ Cervical Intraepithelial Neoplasia 2/3

To evaluate the safety and immunogenicity of a therapeutic human papillomavirus (HPV)16 DNA vaccine administered to women with HPV16+cervical intraepithelial neoplasia (CIN)2/3. This phase I trial incorporated the standard '3+3'' dose-escalation design with an additional 6 patients allocated to the maximally tolerated dose. Healthy adult women with colposcopically directed, biopsy-proven HPV16+ CIN2/3 received 3 i.m. vaccinations (0.5, 1, or 3 mg) of a plasmid expressing a Sig-E7(detox)-heat shock protein 70 fusion protein on days 0, 28, and 56, and underwent standard therapeutic resection of the cervical squamocolumnar junction at day 105 (week 15). The safety and immunogenicity of the vaccine and histologic outcome based on resection at week 15 were assessed. Fifteen patients were evaluable (3 each at 0.5 and 1mg, 9 at 3 mg). The vaccine was well tolerated: most adverse events were mild, transient injection-site discomfort; no dose-limiting toxicities were observed. Although HPVE7-specific T-cell responses to E7 detected by enzyme-linked immunospot assays (IFN-gamma) were of low frequency and magnitude, detectable increases in response subsequent to vaccination were identified in subjects in the second and third cohorts. Complete histologic regression occurred in 3 of 9 (33%; 7-70% confidence interval) individuals in the highest-dose cohort. Although the difference is not significant, it is slightly higher than would be expected in an unvaccinated cohort (25%). This HPV16 DNA vaccine was safe and well tolerated. Whereas it seems possible to elicit HPV-specific T-cell responses in patients with established dysplastic lesions, other factors are likely to play a role in lesion regression.

GASTRIC MALT LYMPHOMA AND HELYCOBACTER PYLORI INFECTION

Introduction: Gastric MALT lymphoma accounts aproximately 7% of all gastric tumors. Women are mostly affected by this disease (mean age 60 years). The aim of this study was to determine the incidence of gastric MALT lymphoma in the Endoscopy Unit of the Department of Gastroenterology Of University Clinical Center Tuzla, the degree of histological malignancy and correlation with the Helycobacter pylori infection and then to evaluate the effectiveness of triple-antibiotic therapy (protonic pump inhibitors and antacides) in treatment of these cases. Patients and methods: All the patiens in the study were performed with gastroscopy and mucosal tissue biopsy in the Endoscopy Unit of the Department of Gastroenterology of UKC Tuzla. PHD and IHH analysis of the given material were performed in the Patology Department of UKC Tuzla. The blood analyses on H. Pylori were done in the Department of Microbiology of UKC Tuzla. Results: 112 patients with gastric tumors were involved in this study, 91 of whom suffered from malignant tumors, six of them had MALT lymphoma (five of them had confirmed H. pylori infection, four had histologically confirmed low-grade tumors and two was categorised as high grade malignancies). Histological lesions were classified according to the actual Ann Arbor classification. Patients with high malignancy risk underwent the operative procedures, and then were treated by polychemiotherapy (CHOP protocole, VI-VIII cikluses). All the patients with confirmed H. pylori infection were treated with antibiotics for 2-4 months, after which complete eradication was accomplished in all cases. Patients histologicaly diagnosed with low grade malignancy showed complete histological regression. In addition to that, after triple antibiotic therapy none of the patients presented with the disease transformation into another histological form. Discussion and Conclusion: The results of this study prooved high incidence in use of triple antibiotic therapy in treatment of patients who suffer from MALT lymphoma with confirmed H. pylori infection. Besides, it is very important to emphasise the fact that patients had no side-effects during polychemiotherapy which was used to treat all the patients regardless of their histological type and malignancy degree of MALT lymphoma.

Surgery in the tri-modality treatment of small cell lung cancer.Stage-dependent survival

Patients with small cell lung cancer (SCLC) are frequently denied surgical treatment despite growing body of evidence for a longer duration of remission and overall survival, if surgical intervention is integrated in a tri-modality therapy concept including chemotherapy, surgery, and radiotherapy. A retrospective analysis was performed using data derived from 95 patients with SCLC operated upon over a period of 9 years. A subset of these patients was primarily operated upon and being diagnosed as SCLC only after thoracotomy, received radio-/chemotherapy postoperatively (n=64, group I). The second cohort had surgery after neoadjuvant chemotherapy which was continued postoperatively in addition to thoracic and cranial radiotherapy (n=31, group II). The patients in the second group were further divided into two subgroups: complete histological regression of tumor tissue in the mediastinal lymph nodes (group IIA), and those with persistent mediastinal lymph nodal involvement detected after thoracotomy (group IIB). Group I patients had stage I or II disease, whereas group II patients had clinical stage IIIA or IIIB. The overall 30-day mortality rate was as low as 5%. The median survival was 31.3 months for patients in group I, 31.7 months for adjuvant surgery with complete regression of mediastinal nodes (group IIA), and 12.4 months for adjuvant surgery without regression of mediastinal nodes (group IIB). Surgical intervention is promising and warrants prospective trials to be evaluated as an important adjunct to multi-modality therapy regimen in SCLC as regards to its impact on relapse free and overall survival.

Completely regressed primary cutaneous malignant melanoma with nodal and/or visceral metastases: A report of 5 cases and assessment of the literature and diagnostic criteria

Partial regression of primary cutaneous malignant melanoma is not uncommon and may predict a higher likelihood of metastasis and decreased survival. Complete histologic regression of a primary cutaneous melanoma is a rarer occurrence, with only 34 cases reported in the English-language or English language-summarized literature. We detail 4 cases of complete histologic regression of primary cutaneous melanoma, discovered at presentation with metastatic disease. A pigmented lesion or its remnant, coupled with historical information, was strongly suggestive of cutaneous melanoma. Histologic examination of the lesions, using multiple levels and immunohistochemical stains, failed to reveal residual melanoma. Our cases are typified by the presence of metastasis of melanoma to regional lymph nodes, with the absence of other suspect skin lesions or malignancies. In addition, we present a fifth case involving a completely regressed lesion on the scalp in a patient with cerebral melanoma metastasis and comment on the implications of this case to accepted diagnostic criteria, proposing that consideration of modification to the criteria be entertained. The concept of completely regressed primary cutaneous melanoma is reviewed and the literature critically appraised. When one considers a diagnosis of completely regressed primary cutaneous melanoma, cases must be well documented and biopsy proven. Patients with metastatic melanoma and an occult primary lesion require a thorough skin examination, with serious consideration given to the possibility of completely regressed cutaneous melanoma.

Is levonorgestrel intrauterine system effective for treatment of early endometrial cancer? Report of four cases and review of the literature

Background Intrauterine progesterone therapy potentially provides a simple alternative treatment for women with Stage I Grade I endometrial cancers who are at high risk for surgery. The case histories of four women with early endometrial cancer primarily treated with levonorgestrel intrauterine system (Mirena) are reported and the literature reviewed. Cases Four women had Stage I grade 1 endometrial adenocarcinoma with positive progesterone receptor. All were assessed to be in American Society of anaesthesiologists risk class IV. After insertion of mirena intrauterine system, one woman (25%) had complete histological regression of disease within 6 months. One of three women who did not respond to treatment subsequently had a vaginal hysterectomy, which showed endometrial cancer with superficial myometrial invasion. Conclusion This report raises doubts about the effectiveness of intrauterine progesterone therapy as a definitive alternative for the treatment of early endometrial cancer.