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Cancer stemness is recognized as a key component of tumor development. Previously coined "cancer stem cells" (CSCs) and believed to be a rare population with rigid hierarchical organization, there is good evidence to suggest that these cells exhibit a plastic cellular state influenced by dynamic CSC-niche interplay. This revelation underscores the need to reevaluate the hallmarks of cancer stemness. Herein, we summarize the techniques used to identify and characterize the state of these cells and discuss their defining and emerging hallmarks, along with their enabling and associated features. We also highlight potential future directions in this field of research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment., (© 2024. The Author(s).)

Sorafenib, a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), has been shown to be a potent ferroptosis inducer in HCC. However, we found that there was a lower level of ferroptosis in sorafenib-resistant HCC samples than in sorafenib-sensitive HCC samples, suggesting that sorafenib resistance in HCC may be a result of ferroptosis suppression. Recent reports have shown that long noncoding RNAs (lncRNAs) are involved in programmed cell death (PCD), including apoptosis and ferroptosis. This study aimed to investigate the roles and underlying molecular mechanisms of lncRNAs in sorafenib-induced ferroptosis in HCC cells. Using lncRNA sequencing, we identified a ferroptosis-related lncRNA, URB1-antisense RNA 1 (AS1), which was highly expressed in sorafenib-resistant HCC samples and predicted poor survival in HCC. Furthermore, URB1-AS1 mitigates sorafenib-induced ferroptosis by inducing ferritin phase separation and reducing the cellular free iron content. Hypoxia inducible factor (HIF)-1α was identified as a key factor promoting URB1-AS1 expression in sorafenib-resistant HCC cells. Notably, we found that specifically inhibiting the expression of URB1-AS1 with N -acetylgalactosamine (GalNAc)-small interfering (si)URB1-AS1 successfully enhanced the sensitivity of HCC cells to sorafenib in an in vivo tumor model. Our study uncovered a critical role for URB1-AS1 in the repression of ferroptosis, suggesting URB1-AS1 targeting may represent a potential approach to overcome sorafenib resistance in HCC.

Targetable drivers governing 5-fluorouracil and cisplatin (5FU + CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Here, we establish 5FU + CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 confers chemoresistance and self-renewal in an RNA editing-dependent manner. WES coupled with RNA-seq identify enrichment of hyper-edited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3'UTR of stearoyl-CoA desaturase (SCD1) increases binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogates chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveil a potential target to circumvent chemoresistance., (© 2023. The Author(s).)

The tumor microenvironment plays a critical role in maintaining the immature phenotype of tumor-initiating cells (TIC) to promote cancer. Hepatocellular carcinoma (HCC) is a unique disease in that it develops in the setting of fibrosis and cirrhosis. This pathologic state commonly shows an enrichment of stromal myofibroblasts, which constitute the bulk of the tumor microenvironment and contribute to disease progression. Follistatin-like 1 (FSTL1) has been widely reported as a proinflammatory mediator in different fibrosis-related and inflammatory diseases. Here we show FSTL1 expression to be closely correlated with activated fibroblasts and to be elevated in regenerative, fibrotic, and disease liver states in various mouse models. Consistently, FSTL1 lineage cells gave rise to myofibroblasts in a CCL 4 -induced hepatic fibrosis mouse model. Clinically, high FSTL1 in fibroblast activation protein-positive (FAP + ) fibroblasts were significantly correlated with more advanced tumors in patients with HCC. Although FSTL1 was expressed in primary fibroblasts derived from patients with HCC, it was barely detectable in HCC cell lines. Functional investigations revealed that treatment of HCC cells and patient-derived 3D organoids with recombinant FSTL1 or with conditioned medium collected from hepatic stellate cells or from cells overexpressing FSTL1 could promote HCC growth and metastasis. FSTL1 bound to TLR4 receptor, resulting in activation of AKT/mTOR/4EBP1 signaling. In a preclinical mouse model, blockade of FSTL1 mitigated HCC malignancy and metastasis, sensitized HCC tumors to sorafenib, prolonged survival, and eradicated the TIC subset. Collectively, these data suggest that FSTL1 may serve as an important novel diagnostic/prognostic biomarker and therapeutic target in HCC. SIGNIFICANCE: This study shows that FSTL1 secreted by activated fibroblasts in the liver microenvironment augments hepatocellular carcinoma malignancy, providing a potential new strategy to improve treatment of this aggressive disease., (©2021 American Association for Cancer Research.)

The enrichment of cancer-associated fibroblast (CAFs) in a tumor microenvironment (TME) cultivates a pro-tumorigenic niche via aberrant paracrine signaling and matrix remodeling. A favorable niche is critical to the maintenance of cancer stem cells (CSCs), a population of cells that are characterized by their enhanced ability to self-renew, metastasis, and develop therapy resistance. Mounting evidence illustrates the interplay between CAF and cancer cells expedites malignant progression. Therefore, targeting the key cellular components and factors in the niche may promote a more efficacious treatment. In this study, we discuss how CAF orchestrates a niche that enhances CSC features and the potential therapeutic implication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Loh and Ma.)

CDK8 and its paralog, CDK19, collectively termed 'Mediator Kinase,' are cyclin-dependent kinases that have been implicated as key rheostats in cellular homeostasis and developmental programming. CDK8 and CDK19 are incorporated, in a mutually exclusive manner, as part of a 4-protein complex called the Mediator kinase module. This module reversibly associates with the Mediator, a 26 subunit protein complex that regulates RNA Polymerase II mediated gene expression. As part of this complex, the Mediator kinases have been implicated in diverse process such as developmental signaling, metabolic homeostasis and in innate immunity. In recent years, dysregulation of Mediator kinase module proteins, including CDK8/19, has been implicated in the development of different human diseases, and in particular cancer. This has led to intense efforts to understand how CDK8/19 regulate diverse biological outputs and develop Mediator kinase inhibitors that can be exploited therapeutically. Herein, we review both context and function of the Mediator kinases at a molecular, cellular and animal level. In so doing, we illuminate emerging concepts underpinning Mediator kinase biology and highlight certain aspects that remain unsolved.

It is common for biomechanics data sets to contain numerous dependent variables recorded over time, for many subjects, groups, and/or conditions. These data often require standard sorting, processing, and analysis operations to be performed in order to answer research questions. Visualization of these data is also crucial. This manuscript presents biomechZoo, an open-source toolbox that provides tools and graphical user interfaces to help users achieve these goals. The aims of this manuscript are to (1) introduce the main features of the toolbox, including a virtual three-dimensional environment to animate motion data (Director), a data plotting suite (Ensembler), and functions for the computation of three-dimensional lower-limb joint angles, moments, and power and (2) compare these computations to those of an existing validated system. To these ends, the steps required to process and analyze a sample data set via the toolbox are outlined. The data set comprises three-dimensional marker, ground reaction force (GRF), joint kinematic, and joint kinetic data of subjects performing straight walking and 90° turning manoeuvres. Joint kinematics and kinetics processed within the toolbox were found to be similar to outputs from a commercial system. The biomechZoo toolbox represents the work of several years and multiple contributors to provide a flexible platform to examine time-series data sets typical in the movement sciences. The toolbox has previously been used to process and analyse walking, running, and ice hockey data sets, and can integrate existing routines, such as the KineMat toolbox, for additional analyses. The toolbox can help researchers and clinicians new to programming or biomechanics to process and analyze their data through a customizable workflow, while advanced users are encouraged to contribute additional functionality to the project. Students may benefit from using biomechZoo as a learning and research tool. It is hoped that the toolbox can play a role in advancing research in the movement sciences. The biomechZoo m-files, sample data, and help repositories are available online (http://www.biomechzoo.com) under the Apache 2.0 License. The toolbox is supported for Matlab (r2014b or newer, The Mathworks Inc., Natick, USA) for Windows (Microsoft Corp., Redmond, USA) and Mac OS (Apple Inc., Cupertino, USA)., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of this study was to evaluate the prognostic significance of primary tumor volume and uterine body invasion assessed by pre-treatment MRI for uterine cervical cancer patient treated with concurrent chemotherapy and radiotherapy., Methods: A retrospective analysis of 106 patients with IB-IIIB cervical carcinoma was performed. Potential prognostic factors were stage, clinical tumor diameter, histology, age, pelvic lymph node, vaginal extension, parametrial invasion, tumor volume and uterine body invasion status. Multivariate analyses were performed to identify the prognostic factor for overall survival (OS) and disease-free survival (DFS)., Results: The 5-year OS, DFS rate were 59.7 and 56.6%. Using multivariate analyses, a large tumor volume (>/=30 ml; P = 0.012) and uterine body invasion (P = 0.020) and positive pelvic lymph node (LN) enlargement (P = 0.040) showed a significantly unfavorable influence on OS. Using these three factors, patients were divided into four subgroups: the OS rates of patients with risk 0 (volume <30 ml, no uterine body invasion, and negative LN), risk 1 (one of these three factors), risk 2 (two of these three factors) and risk 3 (volume >/=30 ml, uterine body invasion, and positive LN) were 96.3, 77.5, 53.0 and 14.8%, respectively (P < 0.0001)., Conclusions: Tumor volume and uterine body invasion determined by MRI were significant prognostic factors for patients with cervical carcinoma. Pelvic lymph node enlargement diagnosed by CT also proved to be a significant prognostic factor in OS. Using these three parameters, we devised a practical and effective model to predict OS.

Purpose: It is difficult to reproduce a brachytherapy measurement because of changes in the rectal shape during inter-fraction. We constructed a multi-purpose brachytherapy phantom (MPBP) and reproduced the same conditions found in actual therapy. We further attempted to apply the measured optimal dose to reduce rectal complications., Methods: A measured dose was administered at rectal reference point R1 using a diode detector in four patients who used a tandem and ovoid in brachytherapy for carcinoma of the cervix. A total number of 20 rectal dose measurements were performed five times per patient. In addition, discrepancies in the set-up of the diode detector were analyzed with each repetitive measurement. After reproducing the same conditions as found in actual therapy using a multi-function applicator (MFA) in the multi-purpose brachytherapy phantom constructed for this study, the dose was measured at reference points in the rectum using a thermoluminescence dosimeter (TLD)., Results: According to the discrepancies measured in the set-up using a diode detector, Patient 1 showed a maximum value of 11.25 +/- 0.95 mm in the Y direction, Patients 2 and 3 exhibited 9.90 +/- 2.40 mm and 20.85 +/- 4.50 mm in the Z direction, respectively. Patient 4 showed 19.15 +/- 3.33 mm in the Z direction. In addition, values of the mean dose according to the position of the diode detector were recorded as 122.82 +/- 7.96-323.78 +/- 11.16 cGy. In the measured results for TLD in an MPBP, relative error for Patients 1 and 4 at the rectal reference point R2 were a maximum of 8.6 and 7.7%, respectively. For Patients 2 and 3 they were 1.7 and 1.2%, respectively. Furthermore, the dose measured at point R1 and R2 exhibited values approximately 1.7-8.6% higher than the dose calculated in advance, excluding point R1 in Patient 2. The discrepancies in the set-up owing to repetitive measurements and alterations in dosage according to these changes were not analyzed. It was evident that the relative error between the calculated and measured value was within 15%, which was allowable according to the recommendations by the American Association of Physicists in Medicine (AAPM)., Conclusions: The multi-purpose brachytherapy phantom constructed for this study successfully reproduced an optimal dose measured under the same conditions found in actual therapy in which the dose was precisely analyzed at a rectal reference point. In addition, these results were considered reliable and applicable for dose optimization before applying therapy using the measured data from the phantom in order to reduce rectal complications.

Background: Traditionally, low dose rate (LDR) brachytherapy has been used as a standard modality in the treatment of patients with carcinoma of the uterine cervix. The purpose of this work was to evaluate the effects of high dose rate (HDR) brachytherapy on patients with adenocarcinoma of the uterine cervix and to compare them with the effects of LDR brachytherapy., Methods: From January 1971 to December 1992, 104 patients suffering from adenocarcinoma of the uterine cervix were treated with radiation therapy in the Department of Radiation Oncology, Yonsei University. LDR brachytherapy was carried out on 34 patients and HDR brachytherapy on 70 patients. In the LDR group, eight patients were in stage IB, six in IIA, 12 in IIB, three in IIIA and five in IIIB. External radiation therapy was delivered with 10 MV X-rays, 2 Gy fraction per day, total dose of whole pelvis 36-52 Gy (median 46 Gy). LDR radium intracavitary irradiation was performed with a Henschke applicator, 37-59 Gy targeted at point A (median 43 Gy). In the HDR group, there were 16 patients in stage IB, six in IIA, 32 in IIB and 16 in IIIB. The total whole pelvis dose of external radiation was 40-50 Gy (median 44 Gy), daily 1.8-2.0 Gy. HDR Co-60 intracavitary irradiation was performed with a remotely controlled after-loading system (RALS), 30-48 Gy (median 39 Gy) targeted at point A, three times per week, 3 Gy per fraction., Results: The 5-year overall survival rate in the LDR group was 72.9, 61.9 and 35.7% in stage I, II and III, respectively and the corresponding figures for HDR were 87.1, 58.3 and 43.8% (p > 0.05). There was no statistical difference between the HDR group and the LDR group in terms of the 5-year overall survival rate from adenocarcinoma of the uterine cervix. There was a late complication rate of 12% in the LDR group and 27% in the HDR group. The incidence of late complications in stages II and III was higher in the HDR group than in the LDR group (31.6 vs 16.7% in stage II, 37.3% vs 12.5% in stage III, p > 0.05). No prognostic factors were evident in the comparison between the two groups., Conclusion: There was no difference in terms of 5-year survival rate in the patients with adenocarcinoma of the uterine cervix between those treated with HDR and those treated with LDR brachytherapy. Even though late complication rates were higher in the HDR group, most of them were classified as grade I. This retrospective study suggests that HDR brachytherapy may be able to replace LDR brachytherapy in the treatment of adenocarcinoma of the uterine cervix.

Repeated trauma to the ear very often results in "cauliflower ear." Many methods have been suggested to prevent an injured ear from demonstrating a cauliflowerlike deformity. The principles of treatment are evacuation of the hematoma, control of the reaccumulation of fluid, and maintenance of the cartilage contour. The authors studied the effect of ionizing radiation on deformed rabbit ears induced by repeated trauma. Twenty ears (10 rabbits) were used in the experiment. The animals were divided into four groups (control, preradiation, low dose, and high dose). Hematoma was produced by pounding the lateral side of the auricle 10 times with a 50-g weight at a height of 15 cm. The thickness of the injured and uninjured sites was measured, and histological analysis was performed for each group. The thickness of the ears of the irradiated groups was significantly less than the control group. The authors think that radiation treatment of repeatedly injured ears could prevent ear deformity, and could possibly be an adjunctive form of management of cauliflower ear in addition to hematoma evacuation and compression therapy.

The purpose of this work is to investigate the consistency of determining N(pp)(gas) and N(pp)(D) by using three independent calibration methods from the AAPM TG 39 and IAEA TRS 381 protocols: 1) calibration with a high-energy electron beam in a phantom; 2) in-phantom calibration in a (60)Co beam; and 3) in-air calibration in a (60)Co beam. The plane-parallel chamber considered was the PTW-Markus and the comparisons were made against a calibrated PTW cylindrical Farmer-type chamber 30001. The phantom material used for the electron beam and (60)Co in-phantom methods was a solid water phantom (RW3). For the electron beam method, the nominal energies were 18 and 21 MeV. An acrylic buildup of 0.5 g/cm(2) thickness was used for the (60)Co in-air method. For each method, N(pp)(gas) and N(pp)(D) were obtained for the plane-parallel chamber as proposed by the AAPM TG 39 and IAEA TRS 381 protocols. The absorbed doses were measured along the central axis at a distance of 100 cm (SSD=100 cm) with 10 x 10 cm(2) field size at the depth of the maximum for each electron beam. The values of N(pp)(gas) by the three independent calibration methods agreed to within +/-0.6%. This meant that any of the methods would give a fairly good value. Similar results were obtained for N(pp)(D). In comparing the results for the electron beam method at energies of 18 and 21 MeV, the latter gave better agreement. The ratios of N(pp)(gas) and N(pp)(D) for the three methods were in agreement within 0.7%. The results for the absorbed dose intercomparison in the AAPM TG 39 and IAEA TRS 381 protocols showed that they agreed to within +/-0.7% which meant that any of the calibration methods and two different protocols would give an accurate result.

Purpose: To determine the proper role of radiation treatment in the management of patients with extrahepatic biliary tract metastasis due to recurrent gastric cancer., Methods and Materials: Twenty patients with malignant biliary obstruction due to recurrent gastric carcinoma after gastrectomy were treated with palliative intent at the Yonsei University College of Medicine from 1986 to 1990. Treatment consisted of external drainage alone in 11 patients (Group I) and external drainage followed by radiation treatment in nine patients (Group II). Five of nine patients in Group II underwent external irradiation in combination with intraluminal brachytherapy using high dose rate Iridium-192 (Ir-192) sources within the expandable intrabiliary prosthesis, a Gianturco stent, inserted transhepatically at the site of obstruction., Results: An excellent local response was observed in five of nine patients in Group II, in whom biliary patency was restored following treatment so that the external drainage catheter could be removed. Prolongation of median survival was observed in Group II (9 months) as compared to Group I (2 months). There were no serious treatment-related complications with this approach., Conclusion: This treatment approach with external radiotherapy +/- intraluminal brachytherapy could achieve effective palliation and improve the quality of life in selected patients with extrahepatic biliary metastasis from gastric carcinoma.

Internal radiation therapy with subsegmental arterial injection of iodine 131(131I)-labeled iodized oil (Lipiodol; Laboratorie, Guerbet, France) was evaluated in 24 patients with nodular hepatocellular carcinoma (HCC) ranging from 2.5 to 8.0 cm in size. 131I Lipiodol (555 to 2220 MBq in 3 to 8 ml) was injected depending on the tumor size. Tumor reduction was seen in 88.9% of tumors smaller than 4.0 cm in diameter, 65.5% of tumors between 4.1 to 6.0 cm, and 25.0% of tumors larger than 5.1 cm. The tumor size reduction corresponded to the gradual drop of serum alpha-fetoprotein (AFP) levels and devascularization on follow-up angiography. Adverse reactions from treatment included fever, mild abdominal pain, nausea, and elevation of transaminases. These were mild and well tolerated by patients. This method provided long-term local control without complications related to the thyroid, lung, gastrointestinal tract, and bone marrow.

Four cases of hepatocellular carcinoma (HCC) were surgically resected following combined radiotherapy (RT) and hyperthermia (HT). Complete necrosis of the tumor without viable tumor cell was found in one case and extensive tumor necrosis was observed in the other three cases; the percentage of necrosis in the specimens were 40%, 70%, and 80%, respectively. Histologic assessment showed mainly coagulative necrosis in the tumor with focal liquefactive necrosis. Cystic dilatation of sinusoids was observed in both tumor and nontumorous normal liver tissue. Other changes in normal liver tissue were unremarkable except for infiltration of inflammatory cells, fatty change, and proliferation of the bile ducts which can usually be seen beyond the area where any space occupying lesions are present. It is concluded that combined radiotherapy and hyperthermia can significantly induce coagulative necrosis of hepatocellular carcinoma with nonsignificant minimal histologic changes in adjacent nontumorous liver tissue.

Sixty patients, treated with postoperative radiation therapy following radical hysterectomy and pelvic lymphadenectomy for stage lb carcinoma of the uterine cervix between Jan. 1980 and Dec. 1984 at Department of Radiation Oncology, Yonsei University College of Medicine, were retrospectively analysed. The minimum follow-up period was 5 years. The indications for postoperative radiotherapy were positive pelvic lymph node (34 pts), a large tumor size more than 3 cm in longest diameter (18 pts), positive surgical margin (10 pts), deep stromal invasion (10 pts), and lymphatic permeation (9 pts). The overall 5-year survival rate was 81.8%. The univariate analysis of prognostic factors disclosed tumor size (less than 3cm, greater than or equal to 3cm) and the status of the surgical margin (positive, negative) as significant factors (tumor size; 88.1% vs 6.3%, surgical margin; 85.5% vs 60%, p less than 0.05). Age (less than or equal to 40, greater than 40 yrs) was marginally significant (90.2% vs 73.1%, p less than 0.1). Multivariate analysis clarified two independent prognostic factors; tumor size (p = 0.010) and surgical margin (p = 0.004). Analysis of the tumor factors with the radiation dose disclosed a better survival rate for patients with a positive surgical margin who were given over 50 Gy than for those who were given below 50 Gy in patients (4/4, 100% vs 2/6, 33.4%; p = 0.06). Significant complications requiring surgical correction were not observed. In conclusion, it is believed that the status of the surgical margin and tumor size both have important prognostic significance, and that a radiation dose over 50 Gy is advisable for patients with a positive surgical margin.

Sixteen cases of male breast cancer seen over a 20-year period were reviewed. The causes of cancer of the male breast are no better understood, but major alterations in hormonal environment could be a significant factor. Some clinical characteristics correspond well with the results of other series. The median age at presentation was 61.7 years. The most frequent initial symptom was a painless mass, and the incidences of nipple discharge, central tumor location, and axillary node involvement were high. Males also had a higher incidence of local advancement which was associated with a longer delay in seeking treatment and small breast tissue. The pathologic type was infiltrating ductal type in all cases except one, and all cases showed favorable nuclear grade. Estrogen receptor analysis was performed from the tumor of 2 patients. Both of them showed a high receptor level. There was no locoregional relapse in 5 patients who received adjuvant radiotherapy in contrast to the 2 relapses in 3 patients who underwent surgery alone. And three of the five patients who received radiotherapy suffered from systemic metastasis which suggested the important role of adjuvant chemotherapy as well as radiotherapy. In light of the encouraging results about adjuvant chemotherapy in the treatment for female breast cancer with axillary lymph node involvement, it would be desirable to extend this policy to male breast cancer.

Forty patients (median age 49.6 years) were treated for primary gastrointestinal lymphoma between 1979 and 1989. There were twenty-three cases of gastric lymphoma and seventeen cases of intestinal lymphoma. Following surgery, seventeen patients received postoperative chemoradiotherapy (ACOP) by the sandwich technique, seven patients received postoperative radiotherapy, and sixteen patients did not receive any other form of adjuvant treatment. Nineteen patients were stage IE and twenty-one were stage IIE. Stage IE disease was more prevalent in the gastric lymphoma group than the intestinal lymphoma group (p less than 0.01). At a median follow-up of 17 months (1-102 + months), 17 of 19 stage IE patients and 15 of 21 stage IIE patients remained alive. The survival rate was 90% in the postoperative chemoradiotherapy group and 83.3% in the postoperative radiotherapy group at five years, and 42.7% in the surgery alone group at four years, which showed statistical significance (p less than 0.01, p less than 0.05, each). Statistically improved survival rates were achieved with a postoperative chemoradiotherapy modality in intestinal lymphoma (p less than 0.01), stage IIE (p less than 0.01), intermediate grade by NCI criteria (p less than 0.01), poorly differentiated lymphocytic lymphoma (p less than 0.05), and diffuse histiocytic lymphoma (p less than 0.01) according to Rappaport classification, compared to those of the surgically treated only group. Three local relapses occurred in the operation alone group, and one in the adjuvant radiotherapy group which occurred simultaneously with distant lymph node recurrence. The pathologic stage of all of these relapsed patients was stage IIE-2. These results suggest that adjuvant chemoradiotherapy in completely resected localized gastrointestinal non-Hodgkin's lymphoma can decrease local and systemic relapse resulting in long-term disease free survival and overall survival compared to operation alone.

Macromolecular synthesis was studied in cultured newt forelimb blastemas. Late bud stage blastemas were explanted into organ culture and thus denervated. When the response of the blastemas to explantation was examined, it was found that a peak in 3H-leucine incorporation occurred at 2 hr of incubation, and a similar peak in 3H-thymidine incorporation occurred at 3-4 hr. After these initial increases, both parameters declined to levels lower than those determined at the time of explantation. The peaks in macromolecular synthesis reported here in vitro are similar to those observed in blastemas in vivo after denervation (Singer, '74). In the second part of the study, the ability of various growth-promoting substances to stimulate DNA synthesis in cultured blastemas was investigated. Increasing concentrations of fetal bovine serum caused increased levels of 3H-thymidine incorporation, with maximal stimulation at 30% serum. Newt brain extract (NBVE) was as effective as additional serum, with optimal stimulation at 100 micrograms total NBE protein per ml culture medium. Fibroblast growth factor (FGF), derived from brain tissue, at a concentration of 10 ng/ml was as effective as both 30% serum and the optimal concentration of NBE. Epidermal growth factor (EGF) produced a maximal effect at 1 ng/ml. Neither nerve growth factor nor the platelet-derived growth factor were stimulatory. Bovine insulin was highly active in stimulating DNA synthesis at concentrations from 1-10 micrograms/ml. The requirement of nerves for blastemal development, as well as the possible roles of the various growth-promoting substances in this process, are discussed.

Among 80 patients with advanced hepatocellular carcinoma, treated by systemic chemotherapy, 19 patients (24%) achieved partial response or stable disease. The median survival time of responders was 20 weeks. Radioiodinated fatty acid esters ([131I]lipiodol) are localized in hepatoma tissue for a considerable time. Taking advantage this phenomenon, there is a potential therapeutic effect of [131I]lipiodol, since the radioactive oil can deliver a therapeutic dose of internal radiation. The response rate of patients who had a small hepatoma (less than 5 cm in diameter) was 80%. Among 25 responders, 12 cases are alive after more than 1 year. A pilot study of hyperthermia, using a heating device capable of delivering radiofrequencies, combined with radiotherapy or chemotherapy, demonstrated that this modality is safe and effective in the treatment of advanced hepatocellular carcinoma. Of the 19 patients treated, 47% showed partial remission or stable disease. The median survival time of 9 responders was 9 months. Among the 9 responders 3 patients survived for over 1 year.

Chemotherapy (with 5-fluorouracil and either mitomycin-C or cis-platinum) combined with radiotherapy was used either for palliation or as preoperative therapy in 67 patients with squamous cell carcinoma of the esophagus. In 25 patients having chemotherapy and 5000-6000 rads, good local palliation was obtained in 11 (49%) without surgery. In the remaining 25 patients, swallowing was restored with a variety of procedures (primarily Celestine tube or gastric bypass). The average survival time was seven months and two patients are still alive at 9 and 12.5 months. Of 42 patients receiving preoperative chemotherapy and radiotherapy, 35 had surgery. Of these, 13 (37%) had complete eradication of their tumors with no histologic evidence of carcinoma in the resected esophagus or associated lymph nodes. In another six (17%), the only evidence of tumor was small microscopic foci of cancer cells in the wall of the esophagus. The 6-, 12-, and 24-month survival rates for patients having surgery after the combined preoperative chemotherapy and radiotherapy were 83 per cent, 52 per cent, and 30 per cent, respectively. These results are far superior to those previously obtained.

Yonsei Cancer Center developed an RF(Radiofrequency) capacitive type heating device, GHT-RF8(Greenytherm) in cooperation with Green Cross Medical Corp., Korea in 1986 for the first time in Korea. Cooperative clinical studies of hyperthermia for the treatment of cancer using GHT-RF8 were conducted by Yonsei Cancer Center in collaboration with the Presbyterian Medical Center, Chonju, Korea. A total of forty patients with various histologically proven malignant tumors, including superficial (N = 13) and deep-seated tumors (N = 27), were treated with this newly developed heating device in conjunction with radiotherapy (N = 38) or chemotherapy (N = 2) at two different institutes between October 1986 and September 1987. These patients were locally far advanced or recurrent cases and considered to be refractory to conventional cancer treatment modalities. Radiotherapy was given in 200cGy per day, five times a week fractionations with a total tumor dose of 50-60Gy in 5-6 weeks. Within an hour after radiotherapy, the RF capacitive type of hyperthermia was given two times a week for a total of 4-10 treatment sessions and an attempt was made to maintain the tumor temperature at 41-45 degrees C for 30-60 minutes. Of forty patients treated, 14 patients with deep-seated tumors showed complete response and 20 patients showed partial response. The overall response rate was 85% (34 out of 40 patients) and only 6 patients showed no response. Complications from this treatment were mainly burns, superficial first degree burn in 2 cases, second degree in 4 cases and subcutaneous fat necrosis was observed in 2 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Between April, 1977, and March, 1981, 86 unselected patients with proved squamous cell carcinoma of the esophagus were treated with a combination of chemotherapy and radiotherapy followed by operation whenever feasible. The preoperative chemotherapeutic agents used initially were 5-fluorouracil, and mitomycin C. After December, 1979, cis-platinum was used instead of mitomycin C. Radiotherapy (3,000 rads) of the tumor was begun at the same time as the chemotherapy. An esophagectomy was performed on suitable candidates 3 to 4 weeks after the chemotherapy and radiotherapy were completed. The mucosal lesion disappeared in 69 of the 86 patients, and dysphagia was relieved at least temporarily in 57 of 62 patients. Recurrent dysphagia resulting from fibrosis at the tumor site caused a secondary stenosis in 11 patients. Excellent palliation was obtained in five patients with bronchoesophageal fistulas who had an initial substernal gastric bypass followed by chemotherapy and radiotherapy. Of the 48 patients who had an esophagectomy, 15 (31%) had no tumor in the resected specimen. Eleven of these 15 patients are still alive with no evidence of disease. All patients with a lesion less than 5.0 cm in length had complete regression of the tumor. We believe that this combination of chemotherapy, radiotherapy, and surgical therapy provides excellent palliation, increases resectability, and has a potential for cure.

A total of 44 patients with previously untreated Stage IV squamous cell carcinomas of the head and neck were treated with a combination of cis-platinum (100 mg/sq m) and 96-hour infusion of 5-fluorouracil (5-FU) (1,000 mg/sq m/day) in two courses or with cis-platinum (100 mg/sq m) and 120-hour infusion of 5-FU (1,000 mg/sq m/day) in three courses. In the 26 patients receiving the two course regimen, the tumor response rate was 88.5%. In five of the 26 patients complete disappearance of the tumor was achieved; partial remission was obtained in 18 of 26 patients. The main side effects were nausea and vomiting (70%), leukopenia (27%), and mild-to-moderate renal toxicity (27%). In the 18 patients who received the three course regimen of 5-FU and cis-platinum, there were 11 (61%) complete responses, 6 (33%) partial responses, and 1 (6%) minimal response. The incidence of complete response was increased with each course given. No added toxicity was observed with surgery or radiotherapy.

A prospective study was carried out to investigate the effectiveness and toxicity of three courses of combination high-dose bolus CDDP and 120-hour continuous infusion 5-FU every three weeks prior to definitive surgery and/or radiation therapy in 35 patients with locally advanced Stage III and IV squamous cell carcinoma of the head and neck. Twenty-two patients (63%) achieved a CR and 11 (31%) a PR after three cycles of chemotherapy, for an objective response rate of 94%. Toxicity was clinically acceptable. Nausea and vomiting occurred in 23 of 35 (66%) without any patients discontinuing therapy for this reason. Leukopenia in 13 (37%) and reversible azotemia in six (17%). Following three courses of chemotherapy, 13 patients had surgical resection and 12 patients had radiation therapy. Ten of these 35 patients had no pathologic evidence of cancer in the surgical specimen or preradiation therapy biopsy. Only two patients of those achieving a complete objective response have relapsed. However, the median follow-up has been short. The authors concluded that three courses of CDDP and 5-FU is a highly effective and safe adjuvant treatment in patients with advanced carcinoma of the head and neck.

Twelve patients with primary lymphomas of the central nervous system were treated in the Department of Radiation Oncology, Yonsei University College of Medicine, between 1976 and 1987. There were seven males and five females ranging from 19 to 63 years of age. They had single (6 cases) or multiple (6 cases) discrete intracerebral nodules. All patients were treated with radiation therapy. Surgical resection was performed in five cases and intrathecal chemotherapy with methotrexate was performed in seven cases after radiotherapy. All patients except one had received whole brain irradiation with a median dose of 4000 cGy. The radiation dose for a primary tumor was 4800-6000 cGy (median 5560 cGy). Initial response to radiation was excellent with a 91.7% complete response rate, but late recurrences were noted and the median survival was 42.3 months. Intracranial recurrences were observed in two patients who received less than 4000 cGy to the whole brain without intrathecal chemotherapy. Although intracranial recurrence was not seen in the patients receiving intrathecal chemotherapy after radiation, a high incidence of necrotizing leukoencephalopathy was noted. High dose irradiation with a minimum of 4000 cGy to the whole brain and more than 5000 cGy to the primary tumor is recommended for the treatment of primary CNS lymphomas. Combined use of chemotherapy should be carefully attempted because of the increased toxicity.

Seventy-five patients with stage III and IV squamous cell cancer of the head and neck, previously untreated, had two courses of chemotherapy with cis-platinum, Oncovin and bleomycin, followed by radical surgery, radiotherapy or both. Response to chemotherapy (complete and partial) was high (80 percent). In 36 patients radical surgery became possible. The overall survival improved statistically in patients who achieved complete or partial response to chemotherapy compared with those who had minimal or no response. Patients with well to moderately well differentiated cancer, or stage III disease, had a statistically better prognosis than patients with poorly differentiated cancer, or stage IV disease.