Decreased Disease Recurrence Research Articles

Adding mitomycin (MM) to bacillus Calmette-Guérin (BCG) as adjuvant intravesical therapy for high-risk, non–muscle-invasive urothelial bladder cancer (NMIBC): BCGMM; ANZUP 1301.

TPS4617 Background: Adjuvant intravesical BCG decreases disease recurrence and progression in high-risk, NMIBC, however recurrence occurs in 30% of those affected, despite optimal therapy. Meta-analyses evaluating addition of intravesical MM to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Phase 3 randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will determine the effects of adding MM to the standard BCG after resection of high-risk NMBIC. This is the largest study evaluating this approach in high-risk NMIBC, is of particular relevance given the current BCG shortage, and has the potential to change global practice. Methods: This open-label phase 3 trial is randomizing 500 participants stratified by stage, site of disease, and presence of carcinoma in-situ, in a 1:1 ratio to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG weeks 1, 2, 4, 5, 7, 8; months 4, 5, 7, 8 + MM weeks 3, 6, 9; months 3, 6, 9, see figure below). This provides 85% power to detect an absolute improvement of 10% in 2-year disease free survival (DFS) at 2p = 0.05. Stage 1 (n = 130) was to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, established feasibility. Stage 2, including an additional 370 participants, will provide information on DFS, time to recurrence and progression, overall survival, and identification of potential predictive biomarkers, is estimated to complete accrual by Q2 2023. Progress As of Jan 2023, 484 of 500 planned participants have been recruited from 16 Australian and 1 UK site. In stage 1, successful treatment completion, defined as 75% or more of planned treatment doses, was achieved by 76% in the experimental group (BCGMM) versus 60% in the control group (BCG alone). Clinical trial information: NCT02948543 .

Phase II trial of neoadjuvant osimertinib for surgically resectable EGFR-mutated non-small cell lung cancer.

8508 Background: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) effective in treating advanced EGFR-mutated non-small cell lung cancer (NSCLC). Adjuvant osimertinib significantly decreases disease recurrence in stage IB-IIIA EGFR-mutated NSCLC. However, the benefit of neoadjuvant osimertinib prior to surgical resection remains unknown. Methods: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (AJCC V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (NCT03433469). Patients received osimertinib 80 mg orally daily for up to two 28-day cycles prior to surgical resection. The primary endpoint was major pathological response (mPR) rate (≤10% residual viable tumor). 27 evaluable patients provide 87% power to detect a mPR rate of 50% with α = 0.05. Secondary endpoints included pathological response (PR) rate (≤50% residual viable tumor), pathological complete response (pCR) rate, unconfirmed objective response rate (ORR), rate of lymph node downstaging, unanticipated delays to surgery, surgical complication rate, disease-free survival (DFS), overall survival (OS), safety, and tumor mutational profile. Results: A total of 27 patients with early-stage (8 stage IA/B, 10 stage IIA/B, 9 stage IIIA) EGFR-mutated (11 exon 19 del, 16 L858R) NSCLC were treated with neoadjuvant osimertinib for a median 56 days prior to surgical resection. 24 (89%) patients underwent subsequent surgery; 3 (11%) patients were converted to definitive chemoradiotherapy. The mPR rate was 15% (4/27 patients) by intention-to-treat analysis. The PR rate was 48% (13/27). No pCR’s were observed. Partial responses by radiography were observed in 52% (14/27) of patients and stable disease in 44% (12/27) of patients. Lymph node downstaging was achieved in 44% (4/9) of patients with positive lymph nodes. Median DFS after surgical resection was 32 months (95% CI 26-not reached) with a median follow-up of 11 months. OS data are immature. Significant adverse events occurred in 3 patients with grade 2 (G2) dyspnea, grade 3 (G3) pulmonary embolism, and G3 atrial fibrillation. One patient developed G2 treatment-related pneumonitis that resolved without steroids. Perioperative complications occurred in 38% (9/24) of patients; most involved rapidly reversible postoperative G2 atrial fibrillation (6/9) unrelated to study drug. Tumors were evaluable for genetic alterations from 16 patients. 4/6 patients who did not achieve a PR had tumors that harbored loss of function mutations in RBM10 as compared to 0/10 patients who achieved a PR (p < 0.01). Conclusions: Neoadjuvant osimertinib in surgically resectable EGFR-mutated NSCLC achieved a 15% mPR, which did not meet the primary endpoint. Treatment was safe and may induce pathological responses and lymph node-downstaging of disease. Co-mutations in RBM10 may limit response. Clinical trial information: NCT03433469 .

EOMES+ Tr1-like Cells Are Enriched in Areas of NLPHL Group II (Patterns D to F) Supporting the Role of Tregs in Disease Recurrence/Progression

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma subtype characterized by proliferation of lymphocyte-predominant (LP) cells associated with a distinct tumor microenvironment. Six major histopathological growth patterns (A to F) have been described by Fan and colls., based on the cellular composition of the tumor microenvironment and its relationship with the LP cells. Group I (patterns A to C) is comprised of nodules rich in small B-cells and follicular dendritic cells and have been associated with low-risk of disease recurrence/progression, while group II (patterns D to F) is rich in small T-cells, lack follicular dendritic cells and have a higher risk of disease recurrence/progression. Although multiple studies have characterized the tumor microenvironment and its relationship with tumor biology in classic Hodgkin lymphoma and other lymphoma types, these studies are limited for NLPHL. Regulatory T-cells (Tregs), a highly immunosuppressive subset of CD4+ T cells, represent a key cellular player in the tumor microenvironment by limiting antitumor immune responses. Emerging studies suggest substantial heterogeneity in the immunophenotype and suppressive capacities of Tregs. For example, classic Tregs are positive for CD4, CD25 and FOXP3; however, a highly immunosuppressive subset of Tregs, named Tr1-like cells has been recently identified and characterized by a distinctive immunophenotype (CD4+, EOMES+, GZMK+ but Foxp3- CD25-) and distinct cytokine expression. Tr1-like are highly relevant in cancer because they seem to be clonally expanded in solid tumors and its presence and number correlates with disease progression (Bonnal et al. Nat Immunol, 2021). Here, we aimed to investigate the Tregs composition (classic and EOMES+ Tr1-like) in the tumor microenvironment of NLPHL and more specifically, to determine cell densities of Tregs in relation with the different histopathological growth patterns of NLPHL. We hypothesize that the number of Tregs will be higher in those immunoarchitectural patterns with the higher risk of disease recurrence/progression. Patients with a diagnosis of NLPHL between 2017 and 2021 with formalin-fixed paraffin embedded tissue biopsies available in our institution were included in the study. All cases were submitted to a previously optimized and validated multiplex IF panel which was specifically developed to assess classic and EOMES+ Tr-1 like Tregs. The panel included CD3, CD4, CD8, CD20, CD25, EOMES, Foxp3, and Granzyme K. Reactive tonsils were used as a positive control. The slides were imaged using Vectra Polaris system (Akoya Biosciences, Marlborough, MA) and up to 10 representative regions of interest (ROI) were selected from each case. The data was consolidated using Spotfire software. The nonparametric Mann-Whitney test was used to compare ROI representing group I and group II histologic areas. Eleven patients with available pretreatment samples were identified. The majority were male (n=7, 63%), with advanced stage of disease (n=7, 63% Stage III/IV); all patients were alive at last follow-up (median: 42 months). A total of 109 ROIs were analyzed (n=54 in group I and n=55 in group II) with a mean number of 22,723 cells/case, and a mean analyzed area of 1.6 mm2/case. The population of CD4+ T-cells was significantly increased in group I (patterns A-C) when compared to group II (patterns D to F) (median, 640 vs 2100, p=0.0013). Interestingly, the group II was associated with a significantly higher cell density of CD4+ EOMES+ Tr1-like cells when compared to group I (median, 0 vs 1010, p<0.0001) (Figure 1). Although not statistically significant, classical Tregs (CD3+CD4+Foxp3+) were also increased in the group II (median, 24.64 vs 67.77, p=0.094). In summary, increased cell densities of Tregs and specifically EOMES+ Tr1-like are strongly associated with architectural patterns of high-risk for disease recurrence and progression in NLPHL. Our data provide a biological rational to focus on these subset populations in efforts to decrease disease recurrence and progression in NLPHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Humanized Ovarian Cancer Patient-Derived Xenografts for Improved Preclinical Evaluation of Immunotherapies.

Simple SummaryEpithelial ovarian cancer (EOC) is a heterogenous disease and new combination therapies are employed to improve treatment, decrease disease recurrence, and avoid the development of treatment resistance. Immunotherapy has been suggested to boost the immune system and improve the prognosis of EOC patients. However, overall low response rates and missing reliable biomarkers to stratify patients to their best-suited personalized treatment regime hinder the successful implementation. Our aim is to advance the development and characterization of humanized patient-derived xenograft models aiding to unravel the function and interaction of the unique tumor microenvironment and the immune system in EOC. These developed and clinically relevant humanized models of EOC have the potential to test various immune cell-targeting combination therapies and identify mechanisms in heterogenous EOC cohorts to ultimately allow patient stratification.High-grade serous ovarian cancer (HGSOC) has poor prognosis and new treatment modalities are needed. Immunotherapy, with checkpoint inhibitors, have demonstrated limited impact. To evaluate the suitability for immunotherapeutics, contextualized preclinical models are required to secure meaningful clinical translation. Therefore, we developed and characterized humanized patient-derived xenograft (hu PDX) murine models of HGSOC, which were established by orthotopic implantation of tumor cell suspensions and intravenous injection of CD34+ cells isolated from umbilical cord blood samples. The developing human immune system in NSG and NSGS mice was followed longitudinally by flow cytometry and characterized by mass cytometry with a panel of 34 surface markers. Molecular imaging of tumor burden, survival analysis, and characterization of tumor-infiltrating immune cells was performed to assess the treatment response to anti-PD-1 (nivolumab) monotherapy. Successful generation of hu PDX models was achieved. Mice treated with nivolumab showed a decrease in tumor burden, however no significant survival benefit was identified when compared to untreated controls. No correlation was seen between PD-L1 expression and CD8 T cell infiltration and response parameters. As the characterization showed an immune infiltration of predominantly myeloid cells, similar to what is observed in HGSOC patients, the models may have the potential to evaluate the importance of myeloid cell immunomodulation as well.

Immunotherapy versus targeted therapy in the adjuvant setting for resected stage III melanoma: A single institution study.

e21578 Background: Both immunotherapy (IO) and targeted therapy (TT) are approved as adjuvant (Adj) treatment for stage III melanoma, as they have proven to significantly decrease disease recurrence. While there is evidence to suggest overall survival (OS) benefit with TT, data demonstrating OS advantage with Adj IO is lacking. There are no prospective head-to-head trials to date comparing these two treatment modalities. Our aim is to determine whether Adj IO equally improves outcomes compared to Adj TT. Methods: We retrospectively analyzed 104 patients (pts) with resected stage III melanoma who received Adj IO or TT from 1/2016 - 12/2021. Relapse free survival (RFS), distant metastasis free survival (DMFS) and OS rates were assessed between the 2 groups. Results: Of 104 pts, 78 received IO (91% nivolumab, 7% pembrolizumab, 2% other) and 26 pts TT (100% dabrafenib/trametinib). Median follow up was 21 months. At data cutoff, among the 26 pts who received TT, 50% completed 1 year of planned therapy, whereas 50% discontinued TT prematurely (42% due to adverse events [AEs], 8% due to disease relapse). Among the 78 pts who received IO, 70% completed 1 year of planned treatment or continued to receive IO at the end of the study, whereas 30% discontinued IO prematurely (18% due to disease relapse, 12% due to AEs). Relapsed disease was noted in 6/26 (23%) and 27/78 (34.6%) pts of the TT and IO groups, respectively. With regards to location of recurrence, in the TT group 2/6 pts relapsed locally and 4/6 distally, whereas in the IO group 14/27 pts relapsed locally and 13/27 distally. The estimated median RFS of the TT vs IO groups was not reached (NA) (95% Cl: 17 months, NA) vs. 30 months (95% CI: 17 months, NA) respectively, which was not statistically significant (p = 0.49). Comparison of DMFS rate was found not to be statistically significant between the 2 groups (p = 0.86). Finally, median OS was NA in either group. At the end of the study 91% and 90.5% of the pts in the TT and IO arms, respectively, were still alive. The most common AEs in the TT group were fatigue (23%), fever (23%), nausea/vomiting (19%), whereas in the IO group were fatigue (22%), hypothyroidism (14%), diarrhea/colitis (10%), pruritic rash (9%). Conclusions: Both TT and IO appear to equally decrease disease recurrence, locally or distally, when given as Adj therapy for stage III melanoma. Prospective, randomized control trials with longer follow up and larger sample size are warranted to determine any difference in potential OS benefit.[Table: see text]

Prophylactic Central Neck Dissection in Papillary Thyroid Carcinoma: All Risks, No Reward

BackgroundCentral neck dissection (CND) remains a controversial intervention for papillary thyroid carcinoma (PTC) patients with clinically negative nodes (cN0) in the central compartment. Proponents state that CND in cN0 patients prevents locoregional recurrence, while opponents deem that the risks of complications outweigh any potential benefit. Thus, there remains conflicting results amongst studies assessing oncologic and surgical outcomes in cN0 PTC patients who undergo CND. To provide clarity to this controversy, we sought to evaluate the efficacy, safety, and oncologic impact of CND in cN0 PTC patients at our institution. Materials and MethodsSix hundred and ninety-five patients with PTC who underwent thyroidectomy at our institution between 1998 and 2018 were identified using an institutional cancer registry and supplemental electronic medical record queries. Patients were stratified by whether or not they underwent CND; identified as CND(+) or CND(-), respectively. Patients were also stratified by whether or not they received adjuvant radioactive iodine (RAI) therapy. Patient demographics, pathologic results, as well as surgical and oncologic outcomes were reviewed. Standard statistical analyses were performed using ANOVA and/or t-test and chi-squared tests as appropriate. ResultsAmong the 695 patients with PTC, 492 (70.8%) had clinically and radiographically node negative disease (cN0). The mean age was 50 ± 1 years old and 368 (74.8%) were female. Of those with cN0 PTC, 61 patients (12.4%) underwent CND. CND(+) patients were found to have higher preoperative thyroid stimulating hormone (TSH) values, 2.8 ± 0.8 versus 1.5 ± 0.2 mU/L (P = 0.028) compared to CND(-) patients. CND did not significantly decrease disease recurrence, development of distant metastatic disease (P = 0.105) or persistence of disease (P = 0.069) at time of mean follow-up of 38 ± 3 months compared to CND(-) patients. However, surgical morbidity rates were significantly higher in CND(+) patients; including transient hypocalcemia (36.1% versus 14.4%; P < 0.001), transient recurrent laryngeal nerve (RLN) injury (19.7% vers us 7.0%; P < 0.001), and permanent RLN injury (3.3% versus 0.7%; P < 0.001). ConclusionsThe majority of patients at our institution with cN0 PTC did not undergo CND. This data suggests that CND was not associated with improvements in oncologic outcomes during the short-term follow-up period and led to increased postoperative morbidity. Therefore, we conclude that CND should not be routinely performed for patients with cN0 PTC.

Comparisons of survival outcomes between bevacizumab and olaparib in BRCA-mutated, platinum-sensitive relapsed ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG 3052).

ObjectiveTo compare survival outcomes between bevacizumab (BEV) and olaparib (OLA) maintenance therapy in BRCA-mutated, platinum-sensitive relapsed (PSR) high-grade serous ovarian carcinoma (HGSOC).MethodsFrom 10 institutions, we identified HGSOC patients with germline and/or somatic BRCA1/2 mutations, who experienced platinum-sensitive recurrence between 2013 and 2019, and received second-line platinum-based chemotherapy. Patients were divided into BEV (n=29), OLA (n=83), and non-BEV/non-OLA users (n=36). The OLA and non-BEV/non-OLA users were grouped as the OLA intent group. We conducted 1:2 nearest neighbor-matching between the BEV and OLA intent groups, setting the proportion of OLA users in the OLA intent group from 65% to 100% at 5% intervals, and compared survival outcomes among the matched groups.ResultsOverall, OLA users showed significantly better progression-free survival (PFS) than BEV users (median, 23.8 vs. 17.4 months; p=0.004). Before matching, PFS improved in the OLA intent group but marginal statistical significance (p=0.057). After matching, multivariate analyses adjusting confounders identified intention-to-treat OLA as an independent favorable prognostic factor for PFS in the OLA 65P (adjusted hazard ratio [aHR]=0.505; 95% confidence interval [CI]=0.280−0.911; p=0.023) to OLA 100P (aHR=0.348; 95% CI=0.184−0.658; p=0.001) datasets. The aHR of intention-to-treat OLA for recurrence decreased with increasing proportions of OLA users. No differences in overall survival were observed between the BEV and OLA intent groups, and between the BEV and OLA users.ConclusionCompared to BEV, intention-to-treat OLA and actual use of OLA maintenance therapy were significantly associated with decreased disease recurrence risk in patients with BRCA-mutated, PSR HGSOC.

Pre- and postsurgical medical therapy for endometriosis surgery.

Pre- and postsurgical medical therapy for endometriosis surgery.

Herpetic Uveitis – The Masquerader

Although a large proportion of anterior uveitis is noninfectious, viruses are regarded as an important cause of infectious anterior uveitis. Herpes viruses are common infectious causes of hypertensive anterior uveitis. PCR analysis of aqueous sample collected at the slit lamp under aseptic conditions for viral DNA is commonly used technique to confirm the diagnosis during the acute phase. Anterior uveitis may be shortened by the prompt use of therapeutic doses of antiviral therapy and maintenance therapy may be effective in decreasing disease recurrence. In eyes with raised IOP, topical antiglaucoma medications can be given. Eyes with severe elevation of IOP may require oral carbonic anhydrase inhibitors, and filtration surgery may be indicated in medically uncontrolled glaucoma with optic neuropathy.

Adding mitomycin to Bacillus Calmette-Guérin as adjuvant intravesical therapy for high-risk, nonmuscle-invasive urothelial bladder cancer (BCGMM; ANZUP 1301).

TPS602 Background: Adjuvant intravesical bacillus Calmette-Guérin (BCG) decreases disease recurrence and progression in people with high-risk, non-muscle invasive urothelial bladder cancer (NMIBC), however recurrence occurs in 30% despite optimal therapy. Recent meta-analyses evaluating addition of intravesical mitomycin (MM) to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Good quality randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will be the largest study to date evaluating this approach in people with high-risk NMIBC. Methods: This open-label phase 3 trial aims to randomize 500 participants, stratified by stage, site of disease, and presence of carcinoma in-situ, to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG + MM weekly x9 then monthly x9). This study is powered to detect a 10% improvement in 2-year disease free survival (DFS) at 5% level of significance with 85% power. Stage 1 of this study, designed to recruit 130 patients to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, has completed enrolment and successfully established feasibility of this trial protocol. Stage 2, aiming for a further 370 patients, will inform on additional endpoints including differences in DFS, time to recurrence and progression, overall survival, and potential predictive biomarkers, is estimated to complete accrual in December 2020. Successful treatment completion, defined as 75% or more of planned treatment doses, has been achieved in 76% of patients treated in the experimental arm of Stage 1, compared to 60% in those allocated BCG alone. Clinical trial information: NCT02948543.

Re: Adjuvant Pelvic Radiation is Associated with Improved Survival and Decreased Disease Recurrence in Pelvic Node-Positive Penile Cancer after Lymph Node Dissection: .

Re: Adjuvant Pelvic Radiation is Associated with Improved Survival and Decreased Disease Recurrence in Pelvic Node-Positive Penile Cancer after Lymph Node Dissection: .

The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for Anal Squamous Cell Cancers (Revised 2018).

The American Society of Colon and Rectal Surgeons is dedicated to ensuring high-quality patient care by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus. The Clinical Practice Guidelines Committee is composed of society members who are chosen

Surgical management decreases disease recurrence risk in recurrent pyogenic cholangitis.

Recurrent pyogenic cholangitis (RPC) has a high risk of disease recurrence. We present our experience with RPC and examine the factors associated with disease recurrence. We performed a retrospective review of all patients with RPC treated at two tertiary institutions between January 1990 and December 2013. Patients with liver atrophy and/or abscess were categorized as being associated with parenchymal disease (PD). We studied 157 patients with a median age of 59.0 (interquartile range (IQR): 47.0-70.0) years and a median follow-up duration of 71.0 (IQR: 26.0-109.0) months. There were 64 (40.8%) and 93 (59.2%) patients with and without associated PD, respectively. Disease recurrence rate was 43.9% in our overall cohort through the course of follow-up. Surgical treatment was an independent prognostic factor for decreased disease recurrence risk (hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.18-0.87, P = 0.021). Stratified analysis revealed that liver resection was prognostic for lower risk of disease recurrence among patients with PD (HR 0.38, 95% CI 0.15-0.94, P = 0.036), while biliary bypass was prognostic for lower risk of disease recurrence among patients without PD (HR 0.30, 95% CI 0.15-0.61, P = 0.001). The overall post-operative complication rate among surgically treated patients was 31.1%, and the presence of bilobar stones was found to be independently associated with higher odds of post-operative complications (odds ratio 3.51, 95% CI 1.26-9.81, P = 0.017). Surgical treatment is associated with decreased recurrence risk in RPC, but with significant post-operative morbidity. Where surgery is deemed appropriate, patients with and without PD are likely to benefit from liver resection and biliary bypass, respectively.

Surgical Management Decreases Disease Recurrence Risk in Complicated Recurrent Pyogenic Cholangitis

Surgical Management Decreases Disease Recurrence Risk in Complicated Recurrent Pyogenic Cholangitis

Adjuvant pelvic radiation is associated with improved survival and decreased disease recurrence in pelvic node-positive penile cancer after lymph node dissection: A multi-institutional study

PurposeFew studies have examined the role of radiation therapy in advanced penile squamous cell carcinoma. We sought to evaluate the association of adjuvant pelvic radiation with survival and recurrence for patients with penile cancer and positive pelvic lymph nodes (PLNs) after lymph node dissection. Materials and methodsData were collected retrospectively across 4 international centers of patients with penile squamous cell carcinoma undergoing lymph node dissections from 1980 to 2013. Further, 92 patients with available adjuvant pelvic radiation status and positive PLNs were analyzed. Disease-specific survival (DSS) and recurrence were analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards model. Results43% (n = 40) of patients received adjuvant pelvic radiation after a positive PLN dissection. Median follow-up was 9.3 months (interquartile range: 5.2–19.8). Patients receiving adjuvant pelvic radiation had a median DSS of 14.4 months vs. 8 months in the nonradiation group, respectively (P = 0.023). Patients without adjuvant pelvic radiation were associated with worse overall survival (hazard ratio [HR] = 1.7; 95% CI: 1.01–2.92; P = 0.04) and DSS (HR = 1.9; 95% CI: 1.09–3.36; P = 0.02) on multivariable analysis. Median time to recurrence was 7.7 months vs. 5.3 months in the radiation and nonradiation arm, respectively (P = 0.042). Patients without adjuvant pelvic radiation was also independently associated with higher overall recurrence on multivariable analysis (HR = 1.8; 95% CI: 1.06–3.12; P = 0.03). ConclusionsAdjuvant pelvic radiation is associated with improved survival and decreased recurrence in this population of patients with penile cancer with positive PLNs.

The Wertheim hysterectomy: Development, modifications, and impact in the present day

Ernst Wertheim was a pioneer in the history of the surgical treatment of cervical cancer. His English-language manuscript “The extended abdominal operation for carcinoma uteri (based on 500 operative cases),” which was published in 1912, detailed his standardization of the radical hysterectomy and formed the basis of the current treatment for early stage cervical cancer. We contextualize the Wertheim hysterectomy, emphasizing medical advances that allowed for its development and subsequent modification. We then discuss modifications to the originally proposed procedure, including a maximally extended parametrical resection pioneered by Takayama, and the addition of the Taussig en bloc lymph node dissection by Meigs, both of which afforded an improved mortality profile due to decreased disease recurrence. Finally, we discuss progress that has been made in the present day, such as the development of nerve-sparing and fertility-sparing surgeries, as well as the introduction of the robotic platform. In this way, we hope to provide a historical background for the Wertheim hysterectomy—a cornerstone of gynecologic oncology.

Restoring miR122 in human stem-like hepatocarcinoma cells, prompts tumor dormancy through Smad-independent TGF-β pathway.

miR122 is the prevalent miRNA in adult healthy liver and it is responsible for liver stem cell differentiation towards hepatocyte lineage. Its expression is frequently lost in hepatocellular carcinoma (HCC). We studied the effects of restoring miR122 expression in a distinctive cell line derived from human HCC-BCLC9 cells-with a solid stem-like cell profile, high tumor initiating ability and undetectable miR122 expression. We generated a stable BCLC9 cell line that expresses miR122 (BCLC9-miR122). Restitution of miR122 in BCLC9 cells, decreases cell proliferation rate and reduces significantly tumor size in vivo. BCLC9-miR122 cells down-regulate expression of MYC, KLF4, FOXM1, AKT2 and AKT3 genes and up-regulate FOXO1 and FOXO3A gene expression. In addition, miR122 transfected cells decreased AKT2 kinase activation while decreased FOXO1 and FOXO3A protein inactivation. Reduction in tumor size in BCLC9-miR122 associated with an increase in p38MAPK protein expression and activation leading to a low phospho-ERK1/2 to phospho-p38 ratio. Treatment of miR122 positive cells with an inhibitor of TGFBR1 activation, abolished tumor dormancy program and recovered cell proliferation rate through a Smad-independent TGF-β response.HCC stem-like cells can be directed towards cell differentiation and tumor dormancy by restoring miR122 expression. We demonstrate, for the first time, that dormancy program is achieved through a Smad-independent TGF-β pathway. Reestablishing miR122 expression is a promising therapeutic strategy that would work concurrently reducing tumor aggressiveness and decreasing disease recurrence.

Outcomes of Video-Assisted Thoracic Surgical Decortication in 274 Patients with Tuberculous Empyema

The present work aimed to retrospectively assess the outcomes associated with decortication by video-assisted thoracic surgery (VATS) in patients with tuberculous empyema. Patients (n = 274) who underwent decortication by VATS for surgical management of pleural empyema between January 2000 to 2010 were included. Pre-, intra-, and postoperative characteristics were observed for all patients, which were followed up for 12 months to evaluate surgical outcomes such as postoperative complications and disease recurrence. No patients required conversion to thoracotomy, and no death or postoperative bleeding was reported. The mean operation time was 104.5 ± 20.4 min, with 271.5 ± 41.3 ml intraoperative blood loss and median length of hospital stay of 7.2 ± 3 .4 days. Of the 274 patients, 262 were followed up for 12 months; 26 (9.9%) patients showed complications, including incomplete lung re-expansion (11 patients) and persistent air leak (6 patients). While early disease recurrence was observed in 3 (1.1%) patients after surgery, late recurrence was reported for 6 (2.3%) individuals. Interestingly, the complication rate was much higher in patients with chronic empyema (15/34, 44.1%) than in subjects with acute empyema (11/228, 4.8%). Decortication by VATS decreases postsurgical complications, and results in decreased disease recurrence. This study demonstrated improved outcomes by decortication by VATS, even in patients with stage III tuberculous empyema.

Abstract 2558: HLA-A2 and HER2 expression levels as clinical prognostic factors in breast cancer patients: implications for peptide cancer vaccine trials

Abstract Introduction: Our group has been investigating HER2-derived peptide vaccines administered in the adjuvant setting to high risk breast cancer patients (pts) to prevent disease recurrence. Our group has previously shown that pts with HER2 low-expressing (LE) tumors are at higher risk of recurrence than over-expressing (OE) tumors in the trastuzumab era. Given peptide-based cancer vaccination require presentation by a specific HLA molecule, our group has also examined and found comparable disease recurrence rates between HLA-A2+ and HLA-A2- patients. Here, we report recurrence data based on HLA-A2 allele/HER2 expression sub-grouping in our unvaccinated, control pts. Methods: After completing standard of care therapy, high-risk, disease-free breast cancer pts with HER2 LE (IHC 1+, 2+) or OE (IHC 3+) tumors are eligible for enrollment in our phase II trial evaluating the HER2-derived peptide vaccines, AE37 (MHC Class II, HLA-non-restricted epitope) and GP2 (MHC Class I, HLA-A2+ restricted epitope). Patients are HLA-typed as A2+ or A2- then randomized to vaccine vs. adjuvant alone. Demographics between groups are compared using chi squared or fisher exact. Results: Thus far, 208 pts have been enrolled to the adjuvant alone control arms of the trial. Five pts were excluded from analysis (1 ineligible and 4 second malignancies) for a total of 203 evaluable pts: 88 HLA-A2+ (48 OE and 40 LE) and 115 HLA-A2- (48 OE and 67 LE). A2+ and A2- OE pts exhibited significant difference in respect to age (52 vs. 47, p=0.013) and tumor size (41.7% vs. 68.1% ≥ 2 cm, p=0.01) respectively. With median follow-up of 39 months, recurrence rates were again compared between A2+ vs. A2- pts (11.4% vs. 11.3%, p=0.50) as well as HER2 subgroups (OE, 6.25% vs. LE, 15.8%, p=0.02). The latter difference was particularly prominent among the A2- pts (A2-/OE, 4.2% vs. 16.4%, p=0.03) but less so in the A2+ pts (A2+/OE, 8.3% vs. A2+/LE, 15%, p=0.26). With no recurrence difference between LE A2 subgroups (LE/A2+, 15% vs. LE/A2-, 16.4%, p=0.54), the OE subgroup comparison was notable for 50% increased disease recurrence in A2+ pts (A2+/OE, 8.3% vs. A2-/OE, 4.2%, p=0.33). Conclusions: While there is no difference in recurrence between A2+ and A2- pts overall or among the HER2 LE subset, there does appear to be a difference in the HER2 OE subset. Compared to A2+/OE pts, the A2-/OE pts exhibit 50% decreased disease recurrence despite significantly younger age and larger tumor size. These findings need to be confirmed but are important given that many peptide vaccines target A2+ pts. Therefore, these results may impact future trial design. Citation Format: Erika J. Schneble, Alfred F. Trappey, Timothy J. Vreeland, John S. Berry, Diane F. Hale, Alan K. Sears, Guy T. Clifton, Sathibalan Ponniah, Elizabeth A. Mittendorf, George E. Peoples. HLA-A2 and HER2 expression levels as clinical prognostic factors in breast cancer patients: implications for peptide cancer vaccine trials. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2558. doi:10.1158/1538-7445.AM2014-2558

Prognostic factors and survival rates for parotid duct carcinoma patients

ObjectiveTo investigate the survival rates of patients diagnosed with parotid duct carcinoma (PDC) and analyze the associated risk factors. MethodsThis study included 38 patients with PDC and the following information was collected for each patient: gender, age, tumor size, TNM classification, neck node metastasis, House–Brackmann grade, neural invasion, use of postoperative radiation therapy and survival data. The Kaplan–Meier method and the Cox model were used to determine prognostic factors for disease-specific survival (DSS) and recurrence-free survival (RFS) rates. ResultsOf the 38 patients, 36 (94.7%) were male. Mean age at initial diagnosis was 59.9 years (range: 43–79). A total of 32 (84.2%) patients had T3/T4 tumors, and 29 (76.3%) patients had a preoperative House–Brackmann grade of Ⅰ/Ⅱ. A correlation analysis showed that tumor stage was significantly associated with House–Brackmann grade (Spearman r = 0.521, p = 0.001). The 5-year DSS and RFS rates were 45% and 30%, respectively. Using Cox-regression analysis, node metastasis and the preoperative House–Brackmann grade were the independent predictors of both RFS and DSS. Postoperative radiation could decrease disease recurrence, but did not improve disease-specific survival. ConclusionParotid duct carcinoma is an aggressive tumor. Node status and preoperative House–Brackmann grade are key prognostic factors.