Incomplete Tumor Regression Research Articles

Abstract 1853: Microparticle-delivered Cxcl9 prolongs Braf inhibitor efficacy in melanoma

Abstract Patients with BRAF-mutant melanoma show significant responses to combined BRAF and MEK inhibition, but most patients relapse within 2 years. A major reservoir for such drug resistance is minimal residual disease (MRD), which is comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis of tumors after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines that may be central players in the process, being strongly upregulated initially and then steeply decreasing as the immune response faded. As a result, we hypothesized that sustaining the chemokine signaling could impair MRD maintenance through increased recruitment of effector T-cells. We show that intratumoral administration of recombinant Cxcl9, either naked or loaded in microparticles, significantly impaired the relapse of MRD in BRAF-inhibited tumors, including several complete pathological responses after the triple combination of microparticle-delivered rCxcl9 with BRAF and MEK-inhibition. Our experiments constitute a proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of frontline treatment methods. Citation Format: Gabriele Romano, Francesca Paradiso, Peng Li, Pooja Shukla3, Lindsay Barger, Olivia El Naggar, John P. Miller, Roger J. Liang, Timothy L. Helms, Jennifer A. Wargo, Francesca Taraballi, James C. Costello, Lawrence N. Kwong. Microparticle-delivered Cxcl9 prolongs Braf inhibitor efficacy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1853.

Первый опыт транссклеральной лазерной термотерапии ретинобластомы

Purpose. To evaluate the efficacy of transscleral thermotherapy (TSTT) in eight patients with retinoblastoma (Rb). Material and methods. In total, 8 patients (9 eyes, 22 tumors) with Rb were treated by TSTT. The average age at the time of treatment was 28 months (from 10 to 45 months). Bilateral Rb was observed in six patients, unilateral – in two. All tumors had preequatorial localization (7 foci – on the mid periphery and 15 – on the far periphery of the fundus). The number of tumors in one eye varied from 1 to 6. The mean tumor thickness was 0.7 mm (from 0.5 to 1.4), the mean basal diameter was 1.5 mm (from 1.0 to 2.9). TSTT was performed transconjunctivally using a diode laser with the following parameters: wavelength – 810 nm, spot diameter – 1000 microns, power from 200 to 500 MW (average – 350 MW), exposure – from 3 to 15 seconds in the scanning mode. Results. Complete tumor regression after TSTT was achieved in 86% of cases (19 tumors). In one case (5%) an incomplete tumor regression was observed and transpupillary thermotherapy was performed. In two cases (9%) continued tumor growth occurred, which required the use of cryotherapy. Overall local tumor control was achieved in all cases (22 tumors). All eyes are preserved, all patients included in the study are alive without distant metastases. No complications from both the anterior and posterior segments, as well as visual signs of scleral damage were not observed in any case. The follow–up period after TSTT ranged from 3 to 11 months (mean – 6 months). Conclusion. First experience of TSTT showed that this method is very promising and can be used to treat small Rb of preequatorial localization in the absence of risk of damage to the iris and equator of the lens, which is the benefit of TSTT compared to transpupillary thermotherapy. Key words: retinoblastoma, transcleral thermotherapy, laser treatment, preequatorial localization, small tumors

Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma.

Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as strongly upregulated initially and steeply decreasing as the immune response faded. Therefore, we hypothesized that sustaining chemokine signaling could impair MRD maintenance through increased recruitment of effector T cells. We found that intratumoral administration of recombinant Cxcl9 (rCxcl9), either naked or loaded in microparticles, significantly impaired MRD relapse in BRAF-inhibited tumors, including several complete pathologic responses after microparticle-delivered rCxcl9 combined with BRAF and MEK inhibition. Our experiments constitute proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of first-line treatment methods.

Preliminary report of patients with meningiomas exposed to Cyproterone Acetate, Nomegestrol Acetate and Chlormadinone Acetate – Monocentric ongoing study on progestin related meningiomas

IntroductionThe relationship between meningioma and progestins has not been elucidated. Meningioma regression after acetate cyproterone (CA) withdrawal has been reported. Our purpose was to evaluate the meningioma evolution after withdrawal of progestins in patients who underwent long-term exposure to CA, nomegestrol acetate (NA), chlormadinone acetate (ChlA). MethodsOur study retrospectively included 69 patients with intracranial meningioma and exposed to one of these 3 progestins between December 2006 and March 2019. In each patient, clinico-radiological (MRI) follow-up was performed every 6 months after diagnosis and treatment withdrawal recommendation. Statistical analyses were applied to compare tumor location and respect of prescription rules between the 3 groups. ResultsThe mean hormonal exposure was 16 years in CA group (n = 46), 16 years in NA group (n = 12) and 9.7 years in ChlA group (n = 11). A higher rate of “out of label” use was observed in the CA group (p = 0.003). Multiple meningiomas were demonstrated in more than 60% of cases in each group. Anterior skull base location was noted in 60.5% of cases in CA group, 25% of cases in NA group and 36.7% of cases in ChlA group (p = 0.05). Incomplete tumor regression was recorded in 11 cases of CA group and in 2 cases of ChlA group. ConclusionIn CA group, our results suggest a strong relationship between this treatment and development of intracranial meningioma. In presence of voluminous asymptomatic meningioma, treatment can be delayed due to the potential regression after withdrawal. On the contrary in NA and ChlA groups, further studies are needed.

The role of three-component selective intra-arterial chemotherapy in the failure of standard organ-preserving treatment in children with intraocular retinoblastoma

Introduction. Retinoblastoma (RB) is a malignant tumor of the retina, the survival rate for the intraocular form reaches 99 %. According to the researchers, the risk factors for the occurrence of refractory or recurrent forms of RB are the size of the tumor at primary diagnosis (more than 15 mm), the child's age at the onset of the disease (up to one year), bilateral RB, and the presence of subretinal and vitreal screenings. If methods of local destruction of the tumor are not applicable for the successful treatment of intraocular refractory or recurrent RB, then they resort to the second line of polychemotherapy as an alternative to enucleation. New versions of local chemotherapy and radiation therapy (gamma knife) are being developed and applied. Nowadays, researchers have a negative attitude towards traditional radiation therapy (EBRT) as a method of organ-preserving treatment due to serious consequences (asymmetry of the facial skeleton and second radio-induced tumors).Aim of the study — to increase the effectiveness of organ-preserving treatment in patients with refractory or recurrent intraocular RB.Materials and methods. In the period from 10.2018 to 12.2019 at the N.N. Blokhin National Medical Research Centre of Oncology it was received three-component selective intra-arterial chemotherapy (SIAC) in 15 patients (15 eyes) aged 11 to 52 months. Eyes initially affected by RB (n = 15), according to the IIRC (Murphree) classification, had the following groups: group B in 1 case, group C in 3, group D in 7, and group E in 4 eyes. It should be noted that all patients initially received intensive combined conservative therapy: in 11 (73 %) of 15 cases — systemic chemotherapy VEC; in 13 (86 %) of 15 — SIAC with melphalan, in all cases, additionally, two-component SIAC was used in combination with melphalan with topotecan. In some cases, local therapy in the form of intravitreal chemotherapy (IVIC) was added to the treatment of 6 (40 %) of 15 patients in the form of melphalan monotherapy and in one case (6 %) a doublet was used in combination with melphalan and topotecan. Also, in some patients, additional local ophthalmic therapy was used: transpupillary thermotherapy (TTT) in 6 out of 15 patients, including in combination with cryotherapy (CT) in 1 patient and in combination with brachytherapy (BT) in one case. At the same time, incomplete tumor regression (refractory form of the disease) was noted in 7 out of 15, and a recurrent course of the disease — in 8 out of 15 patients. Incomplete tumor regression and recurrent RB were the reasons for the appointment of a three-component SIAC using carboplatin, melphalan and topotecan, in combination with IVIC with pronounced endophytic growth of RB, as an alternative to irradiation and enucleation of the eye.Results. The average number of three-component SIAC courses was 1.46 ± 0.63 (rang 1—3). The combination of SIAHT with IVHT was performed in 3 out of 15 patients. All children (n = 15) are alive with a median period of follow-up of23.92 ± 15.68 (10—64) months. One in 15 patients was lost from observation due to their parents’ desire to be treated abroad. It is known that the child is alive, but there is no data on the condition of his eyes. 9 out of 14 patients needed additional treatment after SIAC intensification. To consolidate the resulting effect as a full regression in 2 cases, the final IVIC courses were conducted (n = 2). In connection with the presence of residual tumor and/or intraocular progression and/or appearance of new lesions in 1 of 9 patients were IVIC and TTT, 2 of 9 — IVIC, SIAC, CT, TTT. In 4 out of 9 cases, enucleation was performed, and in 2 out of 4 — the operation was performed after continuing the attempt of organ-preserving treatment: after CT and TTT (n = 1) and IVIC, CT, TTT and BT (n = 1). No child was given ERBT. There were no cases of stroke after SIAC. We managed to save 10 (71.4 %) of 14 eyes with visual acuity: object vision in 4 (40 %) out of 10, eye fixation in 3 (30 %) out of 10, and light perception in 3 (30 %) out of 10 cases. The average follow-up period from the end of three-component SIAC in 14 patients was 13.57 ± 5.27 (6—22) months.Conclusion. Thus, the three-component SIAC is effective and safe for patients with refractory and recurrent retinoblastoma, as evidenced by a high percentage of retained eyes and the presence of visual functions from light perception to object vision.

Circulating Biomarkers for Response Prediction of Rectal Cancer to Neoadjuvant Chemoradiotherapy.

Rectal cancer response to neoadjuvant Chemoradiotherapy (pCRT) is highly variable. In fact, it has been estimated that only about 21 % of patients show pathologic Complete Response (pCR) after therapy, while in most of the patients a partial or incomplete tumour regression is observed. Consequently, patients with a priori chemoradioresistant tumour should not receive the treatment, which is associated with substantial adverse effects and does not guarantee any clinical benefit. For Locally Advanced Rectal Cancer Patients (LARC), a standardized neoadjuvant treatment protocol is applied, the identification and the usefulness of prognostic or predictive biomarkers can improve the antitumoural treatment strategy, modifying the sequence, dose, and combination of radiotherapy, chemotherapy and surgical resection. For these reasons, a growing number of studies are actually focussed on the discovery and investigation of new predictive biomarkers of response to pCRT. In this review, we have selected the most recent literature (2012-2017) regarding the employment of blood-based biomarkers potentially predicting pCR in LARC patients and we have critically discussed them to highlight their real clinical benefit and the current limitations of the proposed methodological approaches.

Nano-pulse stimulation induces potent immune responses, eradicating local breast cancer while reducing distant metastases.

Nano-pulse stimulation (NPS) as a developing technology has been studied for minimally invasive, nonthermal local cancer elimination for more than a decade. Here we show that a single NPS treatment results in complete regression of the poorly immunogenic, metastatic 4T1-Luc mouse mammary carcinoma. Impressively, spontaneous distant organ metastases were largely prevented, even in those animals with incomplete tumor regression. All tumor-free mice were protected from secondary tumor cell challenge, demonstrating a vaccine-like effect. NPS treatment induced antitumor immunity, long-term memory T cells, destruction of tumor microenvironment and reversal of the massive increase of immune suppressor cells in the tumor microenvironment and blood. NPS-treated 4T1 cells exhibited release of damage-associated molecular patterns (DAMPs), including calreticulin, HMGB1 and ATP, and activated dendritic cells. Those findings suggest that NPS is a potent immunogenic cell death inducer that elicits antitumor immunity to prevent distant metastases in addition to local tumor eradication.

635. Mechanisms of Caspase-1 Mediated Schwannoma Regression

Schwannomas are tumors composed of Schwann-lineage cells that form along peripheral nerves. These tumors can cause pain, sensory/motor dysfunction, and death through compression of peripheral nerves, the spinal cord, and/or the brain stem. Management of these tumors-essentially restricted to operative resection and gamma-knife debulking- is limited in scope and efficacy and has significant associated morbidity. Chemotherapeutic treatment strategies have shown incomplete and transient tumor regression. Treatment of Schwannomas remains a major unmet clinical need.Schwannomas are appealing targets for gene therapy as they: 1) grow slowly, 2) have cellular and genetic homogeneity, and 3) can be readily localized using magnetic resonance and/or ultrasound imaging for direct intratumoral vector injection. Gene-therapy is potentially advantageous compared to resection as gene therapy is minimally invasive, kills tumor cells without damaging tumor-associated nerve, and may allow treatment of lesions not amenable to resection. We have previously published that schwannomas can be effectively treated with a gene therapy strategy that uses an adeno-associated virus (AAV) vector to deliver the apoptotic and inflammatory enzyme ICE (IL1-converting enzyme, aka caspase-1) under the Schwann cell specific promoter, myelin Protein 0 (P0). It efficiently debulkes schwannomas and resolves schwannoma associated pain, without any neuronal toxicity.However, the mechanisms by which AAV-P0-ICE selectively kills schwannomas without causing schwann-cell damage and associated neural demyelination are not clear. Understanding these mechanisms would provide the basis for broader utilization of schwannoma gene therapy and insight into how we might increase the efficacy of our current therapy.Through this project we have explored how the role of the P0 promoter and the inflammasome in regulating selective killing of schwannoma cells. Our results indicate that P0 is a highly stringent promoter as it is not expressed in neurons or even in schwannoma cells grown in vitro. P0 is active only in schwann and schannoma cells in vivo, and lack of P0 activity prevents any caspase-1 induced death in other cell types. Second, our data indicates that caspase-1 killing requires concomitant activation of the inflammasome. This pathway was active in 2 different schwannoma cell lines and may be the differentiating factor that prevents caspase-1 to cause axonal demyelination following AAV-P0-ICE injection into peripheral nerve. Finally, our data indicate that adjuvant treatment with factors that stimulate the inflammasome activity increases the efficacy of caspase-1 mediated schwannoma killing. Taken together, these data strongly support the safety of using the P0 promoter for the development of gene therapies for schwannomas and provide new, more efficient, venues for schwannoma capsase-1 mediated gene therapy.

Therapy-induced tumour secretomes promote resistance and tumour progression.

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer1,2. Here we show that targeted therapy with BRAF, ALK, or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed melanoma and lung adenocarcinoma cells. This therapy-induced secretome (TIS) stimulates the outgrowth, dissemination, and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The vemurafenib reactive secretome in melanoma is driven by down-regulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of multiple signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and PI3K/AKT/mTOR pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant melanoma tumours, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.

A Conditional Zebrafish MITF Mutation Reveals MITF Levels Are Critical for Melanoma Promotion vs. Regression In Vivo

The microphthalmia-associated transcription factor (MITF) is the “master melanocyte transcription factor” with a complex role in melanoma. MITF protein levels vary between and within clinical specimens, and amplifications and gain- and loss-of-function mutations have been identified in melanoma. How MITF functions in melanoma development and the effects of targeting MITF in vivo are unknown because MITF levels have not been directly tested in a genetic animal model. Here, we use a temperature-sensitive mitf zebrafish mutant to conditionally control endogenous MITF activity. We show that low levels of endogenous MITF activity are oncogenic with BRAFV600E to promote melanoma that reflects the pathology of the human disease. Remarkably, abrogating MITF activity in BRAFV600Emitf melanoma leads to dramatic tumor regression marked by melanophage infiltration and increased apoptosis. These studies are significant because they show that targeting MITF activity is a potent antitumor mechanism, but also show that caution is required because low levels of wild-type MITF activity are oncogenic.

Chemotherapy first, followed by chemoradiation (CRT) and then surgery, in the management of locally advanced rectal cancer (LARC).

3605 Background: Standard pre-op CRT and post-op chemo for LARC delays the start of optimal systemic therapy by 18-22 weeks. To more promptly address micrometastases that could lead to distant failure, and supported by evidence of excellent primary tumor response to FOLFOX, we began offering FOLFOX as initial treatment for patients (pts) with high-risk LARC. More recently, we have begun offering all planned FOLFOX prior to CRT and surgery. Methods: We obtained an IRB waiver to review records of all clinical stage II/III RC pts treated with initial FOLFOX followed by CRT and total mesorectal excision (TME) at our institution between 2007 and 2012. Of approximately 300 rectal pts treated with CMT, 61 received some or all of their planned FOLFOX as initial therapy. Results: The median age of these 61 pts was 52 years, 54% male. At diagnosis, 84% had T3N1-2 or T4N0-1 tumors and 16% had T3N0 tumors. Of these, 57 received induction FOLFOX (median 7 cycles) then received pre-op CRT, while 4 pts achieved an excellent response to chemotherapy alone, declined CRT, and went directly to TME. Twelve pts did not undergo surgery; 9 had a complete clinical response and elected to be managed non-operatively; 1 refused recommended surgery despite incomplete tumor regression, 1 had surgery deferred due to comorbidities, and 1 developed distant metastatic disease prior to planned surgery. Of the 61 patients, 19 (31%) had either a pathCR (14) or a complete clinical response (5) leading to non-operative management. Of the 49 pts who underwent TME, all had R0 resections and 23 (47%) had tumor response >90%, including 13 (27%) with pathCR. Of the 28 patients who received all 8 cycles of initial FOLFOX, 8 achieved a pathCR (29%) and 3 achieved a complete clinical responses (11%), managed non-operatively. All patients completed therapy as planned. There were no SAEs requiring delay in treatment during either FOLFOX or CMT. Conclusions: FOLFOX before CRT results in substantial tumor regression, a high rate of delivery of all planned therapy, and a substantial rate of pathCRs. Chemo and CMT before planned TME provides a favorable opportunity for consideration of non-operative management.

Abstract 3975: Regression of established tumors requires timely adoptive T cell transfer following whole body irradiation.

Abstract Adoptive immunotherapy with CD8+ T cells has achieved some success in treating established cancer. Response rates are increased by preconditioning the patient with lymphodepleting whole body irradiation (WBI) prior to T cell transfer, including an increased fraction of complete responses. Using a mouse model of autochthonous brain cancer, we previously demonstrated that adoptive transfer of tumor-specific T cells following WBI promotes complete regression of established tumors and long-term survival. However, the mechanisms required to achieve complete responses remain to be defined. Here we investigate kinetic requirements for adoptive T cell transfer to achieve tumor control following WBI. To test the hypothesis that adoptive transfer early after irradiation is required for maximum long-term tumor control, we delayed adoptive transfer of T cells to tumor-bearing mice at varying intervals following irradiation. We show that delay of adoptive transfer did not affect initial T cell priming or the timing of initial appearance of activated T cells at the tumor site. However, we observed a modest decrease in T cell accumulation at the earliest appearance of cells in the brain (5 days post-transfer). Tumors were completely eliminated within 10 days in mice that received T cell transfer one day following WBI, while delayed transfer abrogated this effect. When adoptive transfer was delayed by one week following WBI, incomplete tumor regression was observed at 10 days post-transfer. Although mice in this group lived significantly longer than control animals, they eventually succumbed to lethal tumor recurrence. Our data suggest that lymphodepleting doses of WBI promote a prolonged window for effective T cell priming against the endogenous tumor antigen, but that optimal therapeutic potential requires T cell transfer early after irradiation conditioning. Supported by research grant CA02500 from the National Cancer Institute/National Institutes of Health. Citation Format: Eugene M. Cozza, Lynn R. Budgeon, Neil D. Christensen, Todd D. Schell. Regression of established tumors requires timely adoptive T cell transfer following whole body irradiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3975. doi:10.1158/1538-7445.AM2013-3975

Androgen deprivation induces senescence characteristics in prostate cancer cells in vitro and in vivo

The treatment of non-localized prostate cancer involves androgen deprivation (AD) therapy which results in tumor regression. Apoptosis has been implicated in the tumor response to AD, but constitutes a small fraction of the total tumor at any time. Cellular senescence is a response to sub-lethal stress in which cells are persistently growth arrested and develop distinct morphological and biochemical characteristics. The occurrence of senescence in prostate tumor tissue after AD therapy has not previously been investigated. Phenotypic and molecular characteristics of senescence were examined in models of androgen-sensitive prostate cancer after AD and compared with androgen-intact controls. In vitro in LNCaP cells, AD induced elevated senescence-associated β-galactosidase (SA-β-gal) staining, decreased proliferation, and increased flow cytometric side scatter while minimally affecting cell viability. The increased expression of the senescence-related proteins Glb1, the cyclin-dependent kinase inhibitor p27(Kip1) and chromatin-regulating heterochromatin protein 1γ (HP1γ) were detected in LNCaP cells after AD in vitro by immunoblot and immunofluorescence microscopy. In mice bearing LuCaP xenograft tumors in vivo, surgical castration similarly increased SA-β-gal staining, increased expression of p27(Kip1) and HP1γ, and decreased expression of the proliferation marker KI-67, with minimal induction of apoptosis identified by detection of cleaved caspase 3 and TUNEL. Immunohistochemical analysis of human prostate tumors removed after AD shows similar induction of Glb1, HP1γ and decreased KI-67. We conclude that AD induces characteristics consistent with cellular senescence in androgen-sensitive prostate cancer cells. This finding may explain incomplete tumor regression in response to AD.

Editor's response

There is an unmet need for predictive biomarkers of the clinical benefit of antiangiogenic drugs. The aim of the present study was to prospectively evaluate the value of ¹⁸F-FDG PET/CT performed during and after preoperative chemoradiotherapy with bevacizumab for the prediction of complete pathologic tumor regression and survival in patients with MRI-defined high-risk locally advanced rectal cancer. <b>Methods:</b> Sixty-one patients treated in a nonrandomized phase II study (BRANCH) with concomitant or sequential (4 d before chemoradiotherapy) administration of bevacizumab with preoperative chemoradiotherapy were included. ¹⁸F-FDG PET/CT was performed at baseline, 11 d after the beginning of chemoradiotherapy (early), and before surgery (late). Metabolic changes were compared with pathologic complete tumor regression (TRG1) versus incomplete tumor regression (TRG2–TRG5), progression-free survival, cancer-specific survival, and overall survival. Receiver-operating-characteristic curves were calculated for those ¹⁸F-FDG PET/CT parameters that significantly correlated with TRG1. <b>Results:</b> Early total-lesion glycolysis and its percentage change compared with baseline (ΔTLG-early) could discriminate TRG1 from TRG2–TRG5. Only receiver-operating-characteristic analysis of ΔTLG-early showed an area under the curve greater than 0.7 (0.76), with an optimal cutoff at 59.5% (80% sensitivity, 71.4% specificity), for identifying TRG1. Late metabolic assessment could not discriminate between the 2 groups. After a median follow-up of 98 mo (range, 77–132 mo), metabolic responders (ΔTLG-early ≥ 59.5%) demonstrated a significantly higher 10-y progression-free survival (89.3% vs. 63.6%, <i>P</i> = 0.02) and cancer-specific survival (92.9% vs. 72.6%, <i>P</i> = 0.04) than incomplete metabolic responders. <b>Conclusion:</b> Our results suggest that early metabolic response can act as a surrogate marker of the benefit of antiangiogenic therapy. The findings provide further support for the use of early ¹⁸F-FDG PET/CT evaluation to predict pathologic response and survival in the preoperative treatment of patients with locally advanced rectal cancer. ΔTLG-early showed the best accuracy in predicting tumor regression and may be particularly useful in guiding treatment-modifying decisions during preoperative chemoradiotherapy based on expected response.

Stage-specific sensitivity to p53 restoration during lung cancer progression

Tumourigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts toward pharmaceutical reactivation of defective p53 pathways are underway1–3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas but not in adenomas. We define amplification of MAPK signaling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signaling to mediate tumor regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.

Long-Term Outcome and Prognostic Factors for Adenocarcinoma/Adenosquamous Carcinoma of Cervix After Definitive Radiotherapy

To study the outcomes of patients with adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix primarily treated with radiotherapy (RT), identify the prognostic factors, and evaluate the efficacy of concurrent chemoradiotherapy (CCRT) or salvage surgery. A total of 148 patients with Stage I-IVA AC/ASC of cervix after full-course definitive RT were included. Of the 148 patients, 77% had advanced stage disease. Treatment failure was categorized as either distant or local failure. Local failure was further separated into persistent tumor or local relapse after complete remission. The effectiveness of CCRT with cisplatin and/or paclitaxel was examined, and the surgical salvage rate for local failure was reviewed. The 5-year relapse-free survival rate was 68%, 38%, 49%, 30%, and 0% for those with Stage IB/IIA nonbulky, IB/IIA bulky, IIB, III, and IVA disease, respectively, and appeared inferior to that of those with squamous cell carcinoma of the cervix treated using the same RT protocol. Incomplete tumor regression after RT, a low hemoglobin level, and positive lymph node metastasis were independent poor prognostic factors for relapse-free survival. CCRT with weekly cisplatinum did not improve the outcome for our AC/ASC patients. Salvage surgery rescued 30% of patients with persistent disease. Patients with AC/ASC of the cervix primarily treated with RT had inferior outcomes compared to those with squamous cell carcinoma. Incomplete tumor regression after RT was the most important prognostic factor for local failure. Salvage surgery for patients with persistent tumor should be encouraged for selected patients. Our results did not demonstrate a benefit of CCRT with cisplatin for this disease.

Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival

Hedgehog pathway activity has been demonstrated in malignant glioma. However, its role in tumor growth has not been determined. Here we demonstrate that pharmacological inhibition of the Hedgehog pathway in established orthotopic malignant glioma xenografts confers a survival advantage. Pathway inhibition is measured in transplanted human tumor cells and not in host mouse brain. Correspondingly, survival benefit is observed only in tumors with an operational Hedgehog pathway. These data indicate that Hedgehog signaling regulates the growth of select malignant gliomas. We also demonstrate that Hedgehog pathway component and gene target expression segregate to CD133+ tumor initiating cells. Treated mice eventually succumb to disease, thus targeting the Hedgehog pathway in CD133+ cells produces significant, but incomplete tumor regression. Therefore, our studies suggest that more complete tumor regression may require the inclusion of other therapeutic targets, including CD133− cells.

Histomorphological tumor regression grading of esophageal carcinoma after neoadjuvant radiochemotherapy: which score to use?

Histopathological tumor regression grade (TRG) has been shown to be a prognostic factor in patients with esophageal cancer after neoadjuvant radiochemotherapy (RCT). The system introduced by Mandard to group TRG (Cancer 1994;73:2680-2686) has been used to analyse and discuss its prognostic significance on survival in a single institution retrospective analysis: TRG 1 (complete regression) - TRG 5 (absence of regressive changes). Sixty patients with locally advanced (T3/4 or N1) adenocarcinoma or squamous cell carcinoma received cisplatin-based RCT. Three to four weeks later operation for curative intent was performed. Median follow-up was 17.7 months. Histopathological tumor stages were stage 0 in 17%, stage I in 10%, stage II in 60%, stage III in 12% and stage IVA in 1%. The 5-year overall survival (OS) rate was 35%. In univariate analysis, ypN-status and TRG correlated significantly with OS (P = 0.004, P = 0.0008, respectively). While OS of TRG 1 differed significantly from all other groups, no differences in OS between the other TRG groups were seen. Patients with complete tumor regression after neoadjuvant RCT showed a much better survival than patients with tumors that responded less to induction therapy. Further qualitative subdivision of tumor regression could not identify patient groups with significant differences in prognosis. After comparing our data with the literature, it is reasonable to consider classifying all patients into 'Complete tumor regression' and 'Incomplete tumor regression'.

Regression grading of neoadjuvant non-small-cell lung carcinoma treatment

In the scope of a multi-center-study 35 resection specimens from patients with locally advanced non-small cell lung cancer after neoadjuvant chemotherapy and radiation were processed histologically and graded according to the following regression grading system: grade I: no or only slight, in general spontaneous tumor regression, grade IIa: incomplete tumor regression with more than 10% and grade IIb less than 10% vital tumor tissue as well as grade III: complete tumor regression. In 15 patients with grade II a to III tumor regression roughly concentric foci of various size with a sequence of central tumor necrosis, narrow foam cell rim, vascular granulation tissue and peripheral scar formation were demonstrated as characteristic feature of response to neoadjuvant therapy. In patients with grade IIb to III tumor regression ("responders") median survival time of 27.9 months was significantly longer than in patients with grade I to II a tumor regression ("non-responders") with a median survival time of 12.7 months.

Kleinzelliges Bronchialkarzinom nach Chemotherapie Morphologische Befunde

Resection specimens of 14 patients with small cell bronchial carcinoma after neoadjuvant chemotherapy were processed histologically and graded according to a three-step regression grading system: grade I, no or only slight tumor regression; grade II, incomplete tumor regression; grade III, complete tumor regression without vital tumor tissue. In five patients with either no vital tumor tissue or only small tumor remnants in the resection samples, a typical sequence of central fresh tumor necrosis, foam cell rim, vascular granulation tissue and peripheral scar formation was seen. This morphological finding may be interpreted as a characteristic, but unspecific parameter of good response to preoperative chemotherapy. The presence of vital tumor rims surrounding the capillary bed with intermingled necrotic foci, however, argues in favor of spontaneous tumor regression, which is commonly observed in small cell lung cancer.