Search

Background: The pancreas is an exo-endocrine organ that undergoes rapid autolysis soon after death, which limits its utility in academics and research. The timeline of autolytic changes of pancreatic islets and its immunoreactivity is limited in the literature. Decay score has been used to grade the autolytic changes in organs like the brain, lung and liver. However, reports are not available in the pancreas/ pancreatic islets. Knowledge regarding the decay score may be used as a torchbearer for the immunoreactivity of human pancreatic islets in autopsy cases. The present study is aimed to provide an optimal cut-off time based on the decay score before which pancreatic specimens should be collected for the purpose of immunohistochemical studies of pancreatic islets. Materials and methods: Serial sections of twenty adult human pancreas obtained from the autopsy were subjected to H&E and immunohistochemical staining. Autolytic changes of pancreatic islets were graded by using decay score in H&E sections, which was compared with the results of the immunohistochemical reactivity of pancreatic islets in IHC sections. Results and Conclusions: Pancreatic islets immunoreactivity was found to be well preserved in the samples collected early within 9 h with a decay score of less than 1.4. There was an inverse relation of decay score and immunoreactivity of pancreatic islets. The decay score of less than 1.4 has better-preserved immunoreactivity than having more than 1.4. This knowledge will help researchers working in the field of the endocrine pancreas.

Kimi Soumya Padhi, Govinda Balmuchu, Partha Sarathi Acharya, Sudipta Ranjan Singh, Tony Joseph Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, IndiaCorrespondence: Govinda BalmuchuDepartment of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Bhubaneswar, Sijua, Patrapada, Bhubaneswar, Odisha, 751019, IndiaTel +919871293683Email govindabalmuchu@gmail.comPurpose: To determine the challenges, effectiveness, level of reception and acceptance of E-learning by students (learners) and faculty (educators) in a medical college during the lockdown period of the COVID-19 pandemic.Methods: An online questionnaire-based cross-sectional study was conducted among learners and educators at AIIMS, Bhubaneswar, Odisha, India, in the month of August 2020. A total of 203 learners and 24 educators participated in the study. The link of the Google form containing the questionnaire was sent to the students and teachers, and the responses obtained were analyzed with SPSS software (version 20).Results: Two hundred three MBBS students and twenty-four faculty members participated in the study. In our study, 34.5% (n=70) learners and 62.5% (n=15) educators preferred supplementation of E-learning with conventional mode of pedagogy in the future. There was a significant correlation between the convenience and the effectiveness of E-learning. Both learners and educators considered E-learning to be moderately effective. The major problems faced by the educators while conducting online sessions were network issues, difficulty in conducting practicals, lack of controlled environment, and lack of attentiveness by the learners. More than half of the students were satisfied with the E-learning provided by the institute. Educators found E-learning to be moderately convenient, whereas they felt conventional classroom teaching is highly convenient.Conclusion: Educators and learners were quick to adapt to the online mode of learning but the shift was mired with initial challenges. There is a requirement of capacity building in terms of skill development and digital infrastructure building to ensure seamless and effective E-learning.Keywords: COVID-19, lockdown, medical education, conventional pedagogy effectiveness

Background/aim Dedifferentiated liposarcoma (DDLPS) is associated with a poor survival rate even with multi-modality treatment. In the present study, we evaluated the efficacy of recombinant methioninase (rMETase) combined with tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R against a doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) mouse model. Materials and methods A recurrent high-grade DDLPS from the right retroperitoneum of a patient was grown orthotopically in the retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomly divided into the following groups: Control, no treatment; doxorubicin monotherapy; rMETase monotherapy; S. typhimurium A1-R monotherapy; S. typhimurium A1-R and rMETase combination therapy. Tumor length and width were measured before and after treatment. Results On day 14 after treatment, all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control except for doxorubicin monotherapy. rMETase combined with S. typhimurium A1-R was significantly more effective and regressed tumor volume compared to either rMETase or S. typhimurium A1-R alone. The relative body weight did not significantly differ between days 0 and 14 for individual groups. Conclusion The combination of rMETase and S. typhimurium A1-R has important clinical potential for this recalcitrant sarcoma.

BACKGROUND/AIM In the present study, the breast cancer patient-derived orthotopic xenograft (PDOX) model was used to identify an effective drug for a highly aggressive triple negative breast cancer (TNBC). MATERIALS AND METHODS The TNBC tumor from a patient was implanted in the right 4th inguinal mammary fat pad of nude mice to establish a PDOX model. Three weeks later, 19 mice were randomized into the untreated-control group (n=10) and the eribulin treatment group (n=9, eribulin, 0.3 mg/kg, i.p., day 1). RESULTS On day 8, eribulin significantly inhibited tumor volume compared to the control group (p

Background/aim Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. Materials and methods The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. Results The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). Conclusion Eribulin has clinical potential for triple-negative MPBC patients.

Background/Aim: Pazopanib (PAZ) can inhibit tumor progression, but whether PAZ inhibits lymph node metastasis and lymphangiogenesis in colorectal cancer is still unknown. The aim of the present study was to determine the efficacy of PAZ on tumor growth, lymph node metastasis and lymphangiogenesis in an orthotopic nude mouse model in colorectal cancer. Materials and Methods: CT-26-green fluorescence protein (GFP)-expressing mouse colon cancer cells were injected into nude mice to establish a subcutaneous colorectal cancer model and were treated with saline and PAZ. Additionals subcutaneous tumors were harvested and cut into 5 mm(3 )fragments, then tumor fragments were implanted orthotopically in the cecum to establish an orthotopic colorectal-cancer nude mouse model. Orthotopic mice were randomized into two groups for the treatment with saline and PAZ, respectively. Tumor width, length and mouse body weight was measured twice a week. The Fluor Vivo imaging system was used to image the GFP. Hematoxylin & eosin staining and immunohistochemical staining was used for histological analysis. Results: PAZ inhibited the growth of subcutaneous colorectal cancer, as wells as orthotopic transplanted colorectal cancer tumors. PAZ suppressed lymph node metastasis and lymphangiogenesis in the orthotopic colon cancer model. No significant changes were observed in the body weight between the control and the mice treated with PAZ. Conclusion: PAZ can inhibit the growth of colorectal cancer and inhibit lymph node metastasis and lymphangiogenesis in orthotopic colon cancer nude mouse models.

The aim of this study was to determine the efficacy of oral recombinant methioninase (o-rMETase) on a model of colon cancer growing on the peritoneal surface using a patients-derived orthotopic xenograft (PDOX) nude mouse model. Forty PDOX mouse models with colon cancer growing on the peritoneum were divided into 4 groups of 10 mice each by measuring the tumor size and fluorescence intensity: untreated control; 5-fluorouracil (5-FU) (50 mg/kg, once a week for two weeks, ip) and oxaliplatinum (OXA) (6 mg/kg, once a week for two weeks, ip); o-rMETase (100 units/day, oral 14 consecutive days); combination 5-FU + OXA and o-rMETase. All treatments inhibited tumor growth compared to the untreated control. The combination of 5-FU + OXA plus o-rMETase was significantly more efficacious than the control and each drug alone and was the only treatment that caused tumor regression. The present study is the first demonstrating the efficacy of o-rMETase combination therapy on a PDOX model of peritoneal colon cancer, suggesting potential clinical development of o-rMETase in a recalcitrant cancer.

Background/aim The aim of the present study was to determine the efficacy of trabectedin combined with FOLFIRI (irinotecan, leucovorin and 5-fluorouracil) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (iPDOX) mouse model. Materials and methods A CRC tumor from a patient previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Mice were randomized into four groups: Group 1, untreated control; group 2, FOLFIRI; group 3, trabectedin alone; group 4, trabectedin plus FOLFIRI. Tumor width, length, and mouse body weight was measured twice every week. Results All three treatment groups showed inhibited tumor growth compared to the untreated control group. Only the combination of FOLFIRI and trabectedin arrested tumor growth. No significant changes was observed in body weight in any group. Conclusion These findings suggest that the combination of trabectedin plus FOLFIRI has clinical potential for patients with CRC.

Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of restricting MET with oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, azacitidine (AZA) on a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: control; doxorubicin (DOX) alone; AZA alone; o-rMETase alone; o-rMETase-AZA combination. Tumor size and body weight were measured during the 14 days of treatment. We found that tumor growth was arrested only by the o-rMETase–AZA combination treatment, as tumors with this treatment exhibited tumor necrosis with degenerative change. This study suggests that o-rMETase-AZA combination has clinical potential for patients with chemoresistant osteosarcoma.

Background & objectives: Islet of Langerhans, the endocrine pancreas plays a significant role in glucose metabolism. Obesity and insulin resistance are the major factors responsible for beta cell dysfunction. Asian Indian population has increased susceptibility to diabetes in spite of having lower BMI. The morphology of islets plays a significant role in beta cell function. The present study was designed for better understanding the morphology, composition and distribution of islets in different parts of the pancreas and its impact on beta cell proportion. Methods: We observed islet morphology and beta cell area proportion by Large-scale computer-assisted analysis in 20 adult human pancreases in non-diabetic Indian population. Immunohistochemical staining with anti-synaptophysin and anti-insulin antibody was used to detect islet and beta cells respectively. Whole slide images were analyzed using ImageJ software. Results: Endocrine proportion were heterogeneously increasing from head to tail with maximum islet and beta cell distribution in the tail region. Larger islets were predominately confined to the tail region. The islets in Indian population were relatively smaller in size, but they have more beta cells (20%) when compared to American population. Interpretation & conclusions: The beta cells of larger islets are functionally more active than the smaller islets via paracrine effect. Thus, reduction in the number of larger islets may be one of the probable reasons for increased susceptibility of Indians to diabetes even at lower BMI. Knowledge about the regional distribution of islets will help the surgeons to preserve the islet rich regions during surgery.

Pancreatic cancer is one of the leading causes of cancer death, mainly due to the absence of early diagnostic tool and effective therapeutic agents. To identify an effective therapeutic agent for pancreatic ductal adenocarcinoma cells (PDAC), we used 10 Gene Expression Omnibus (GEO) data sets and L1000CDS2 pharmacogenetic search tool and obtained chemical "perturvants" that were predicted to reverse the abnormal gene expression changes in PDAC. Among 20 initial candidates, we measured IC50 for six compounds and identified BX-795, PDK1/TBK1 inhibitor, as a therapeutic candidate. We found that BX-795 inhibits primary PDAC cell proliferation more effectively than normal cells. Following molecular analysis revealed that BX-795 down-regulates mTOR-GSK3β pathway and trigger apoptosis. Moreover, we found that BX-795 suppresses primary PDAC cell migration via downregulation of Snail and Slug. Finally, efficacy test in patient-derived xenograft model of PDAC showed BX-795 can inhibit in vivo tumor growth as efficient as gemcitabine and a combination with trametinib further suppresses tumor growth. Collectively, these results demonstrate the BX-795 as an effective therapeutic candidate for PDAC treatment.

We previously showed that the Arf1-mediated lipolysis pathway sustains stem cells and cancer stem cells (CSCs); its ablation resulted in necrosis of stem cells and CSCs, which further triggers a systemic antitumor immune response. Here we show that knocking down Arf1 in intestinal stem cells (ISCs) causes metabolic stress, which promotes the expression and translocation of ISC-produced damage-associated molecular patterns (DAMPs; Pretaporter [Prtp] and calreticulin [Calr]). DAMPs regulate macroglobulin complement-related (Mcr) expression and secretion. The secreted Mcr influences the expression and localization of enterocyte (EC)-produced Draper (Drpr) and LRP1 receptors (pattern recognition receptors [PRRs]) to activate autophagy in ECs for ATP production. The secreted ATP possibly feeds back to kill ISCs by activating inflammasome-like pyroptosis. We identify an evolutionarily conserved pathway that sustains stem cells and CSCs, and its ablation results in an immunogenic cascade that promotes death of stem cells and CSCs as well as antitumor immunity.

Introduction Healthcare workers (HCWs) are vulnerable to getting infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Preventing HCWs from getting infected is a priority to maintain healthcare services. The therapeutic and preventive role of ivermectin in coronavirus disease 2019 (COVID-19) is being investigated. Based on promising results of in vitro studies of oral ivermectin, this study was conducted with the aim to demonstrate the prophylactic role of oral ivermectin in preventing SARS-CoV-2 infection among HCWs at the All India Institute of Medical Sciences (AIIMS) Bhubaneswar. Methods A prospective cohort study was conducted at AIIMS Bhubaneswar, which has been providing both COVID and non-COVID care since March 2020. All employees and students of the institute who provided written informed consent participated in the study. The uptake of two doses of oral ivermectin (300 μg/kg/dose at a gap of 72 hours) was considered as exposure. The primary outcome of the study was COVID-19 infection in the following month of ivermectin consumption, diagnosed as per Government of India testing criteria (real-time reverse transcriptase polymerase chain reaction [RT-PCR]) guidelines. The log-binomial model was used to estimate adjusted relative risk (ARR), and the Kaplan-Meier failure plot was used to estimate the probability of COVID-19 infection with follow-up time. Results Of 3892 employees, 3532 (90.8%) participated in the study. The ivermectin uptake was 62.5% and 5.3% for two doses and single dose, respectively. Participants who took ivermectin prophylaxis had a lower risk of getting symptoms suggestive of SARS-CoV-2 infection (6% vs 15%). HCWs who had taken two doses of oral ivermectin had a significantly lower risk of contracting COVID-19 infection during the following month (ARR 0.17; 95% CI, 0.12-0.23). Females had a lower risk of contracting COVID-19 than males (ARR 0.70; 95% CI, 0.52-0.93). The absolute risk reduction of SARS-CoV-2 infection was 9.7%. Only 1.8% of the participants reported adverse events, which were mild and self-limiting. Conclusion Two doses of oral ivermectin (300 μg/kg/dose given 72 hours apart) as chemoprophylaxis among HCWs reduced the risk of COVID-19 infection by 83% in the following month. Safe, effective, and low-cost chemoprophylaxis has relevance in the containment of pandemic alongside vaccine.

Sudden deaths as a result of undiagnosed primary intra-cranial lesions are the rarest of rare. A brought deadcase of 32-year-old female with past history of headache without any clinical diagnosis was found to be thecase of “transitional meningioma with focal rhabdoid differentiation which is histo-pathologically classifiedas WHO Grade 1 intra cranial lesion1. A complete autopsy including gross findings, internal findings withhistopathology and immuno-histochemistry can help us to diagnose the missed pathology to conclude thecause of death. It will also give the idea about autopsy-based statistics of these rare intra-cranial lesionswhich would help us to focus the cases with the history of headache to diagnose early with interventions andinvestigation including MRI or CT scan during life.

Background Osteosarcoma is a recalcitrant disease treated with surgery and intensive chemotherapy as standard. The 5-year survival rate of patients with relapsed and lung metastatic osteosarcoma is as low as 20%. Materials and methods A 16-year-old patient developed left distal femoral high-grade osteosarcoma and underwent cisplatinum-based neoadjuvant chemotherapy and surgery. From the resected tumor, a patient-derived orthotopic xenograft (PDOX) model was established in the femur of nude mice. PDOX models were randomized into the following groups: untreated control, or treatment with doxorubicin (3 mg/kg, i.p., weekly for 14 days), sunitinib (40 mg/kg, oral gavage, daily for 14 days), pazopanib (100 mg/kg, oral gavage, daily for 14 days), temozolomide(25 mg/kg, oral gavage, daily for 14 days), and eribulin (1.5 mg/kg, i.p., daily for 14 days). Tumor volume and body weight were monitored twice a week. Results The osteosarcoma PDOX was resistant to doxorubicin, sunitinib, and pazopanib. In contrast, eribulin and temozolomide arrested tumor growth. Conclusion This study demonstrated the utility of the PDOX model in allowing effective from non-effective drugs to be distinguished in a model in which the tumor was growing on the organ corresponding to that of the patient.

Background/aim Osteosarcoma is a recalcitrant neoplasm which occurs predominantly in adolescents and young adults. Recently, using a patient-derived orthotopic xenograft (PDOX) model of malignant soft-tissue sarcoma (STS), we showed that oral recombinant methioninase (o-rMETase), in combination with caffeine, was more efficacious than o-rMETase alone in inhibiting STS tumor growth. In the present report, we determined the efficacy of o-rMETase combined with oral caffeine on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model. Materials and methods Osteosarcoma PDOX models were randomly divided into seven treatment groups (6 mice in each group): untreated control; CDDP alone; o-rMETase alone; o-rMETase with caffeine; CDDP plus o-rMETase; CDDP plus caffeine; and CDDP plus o-rMETase with caffeine. Tumor size and body weight were measured throughout the treatment. Results Tumors regressed after treatment with CDDP plus o-rMETase with caffeine. Tumors treated with CDDP plus o-rMETase with caffeine also had the most necrosis. Conclusion The combination of o-rMETase and caffeine together with first-line chemotherapy was efficacious for drug-resistant osteosarcoma and has clinical potential in the treatment of this highly-resistant neoplasm.

Chemotherapy-resistant osteosarcoma is a recalcitrant disease. It is a frequent cause of death to the patients who are usually adolescent or young adults. The goal of the present study was to determine the efficacy of the combination of olaratumab (OLA), doxorubicin (DOX), and cisplatinum (CDDP) on osteosarcoma, which is resistant to first-line therapy, in a patient-derived orthotopic xenograft (PDOX) model. The osteosarcoma PDOX model was randomized into six treatment groups of six mice: control; CDDP alone; DOX and CDDP; OLA + DOX; OLA + CDDP; and OLA + DOX and CDDP. Tumor size and body weight were measured during 14 days of treatment. Tumor growth was regressed only by the treatment with a combination of OLA + DOX and CDDP. Tumors treated with this three-drug combination had the most tumor necrosis and the lowest Ki-67 index. The present study demonstrates the power of the PDOX model to identify novel effective treatment strategy for chemotherapy-resistant osteosarcoma.

BACKGROUND/AIM Liver metastasis in colorectal-cancer is a recalcitrant disease. To develop precision individualized therapy of this disease, we developed a patient-derived orthotopic xenograft (PDOX) model of colorectal-cancer liver metastasis. In the present report, we evaluated the efficacy of oral recombinant methioninase (o-rMETase) in combination with 5-fluorouracil (5-FU) and oxaliplatinum (OXA) on the colorectal-cancer liver metastasis PDOX mouse model. MATERIALS AND METHODS Colorectal-cancer liver metastasis PDOX models were randomized into three groups of seven mice. Group 1, untreated control with phosphate buffered saline (PBS); Group 2, treated with 5-FU + OXA; and Group 3, treated with 5-FU + OXA + o-rMETase. RESULTS The colorectal-cancer liver metastasis PDOX model was resistant to 5-FU + OXA (p=0.83 at day 15 of treatment, Group 2). In contrast, the colorectal-cancer liver metastasis PDOX model was arrested by o-rMETase combined with 5-FU + OXA (p

Background/aim Osteosarcoma is a rare but recalcitrant type of bone cancer. To discover an effective therapy for osteosarcoma, we used a patient-derived orthotopic xenograft (PDOX) mouse model. A PDOX mouse model has been established for all major cancer types. Strong synergistic efficacy of sorafenib (SFN) and everolimus (EVL) has been demonstrated in several cancers. In the present study, we examined the efficacy of a SFN and EVL combination on a doxorubicin (DOX)-resistant osteosarcoma PDOX. Materials and methods The osteosarcoma PDOX models were randomly divided into five treatment groups, each containing six mice: Control; DOX; SFN; EVL; and a combination of SFN and EVL. Mice were treated for 14 days. To observe the efficacy of these treatments, tumor size and body weight were measured, and histological sections were analyzed. Results Tumor growth regression was observed only in the mice treated with the combination of SFN-EVL. Histological analysis revealed necrosis with degenerative changes in tumors treated with a combination of SFN-EVL. Conclusion A SFN-EVL combination could be a novel effective treatment option for osteosarcoma.

Hair-follicle-associated pluripotent (HAP) stem cells reside in the upper part of the bulge area of the the hair follicle. HAP stem cells are nestin-positive and keratin 15-negative and have the capacity to differentiate into various types of cells in vitro. HAP stem cells are also involved in nerve and spinal cord regeneration in mouse models. Recently, it was shown that the DNA-damage response in non-HAP hair follicle stem cells induces proteolysis of type-XVII collagen (COL17A1/BP180), which is involved in hair-follicle stem-cell maintenance. COL17A1 proteolysis stimulated hair-follicle stem-cell aging, characterized by the loss of stemness signatures and hair-follicle miniaturization associated with androgenic alopecia. In the present study, we demonstrate that HAP stem cells co-express nestin and COL17A1 in vitro and in vivo. The expression of HAP stem cell markers (nestin and SSEA1) increased after HAP stem-cell colonies were formed, then decreased after differentiation to epidermal keratinocytes. In contrast COL17A1 increased after differentiation to epidermal keratinocytes. These results suggest that COL17A1 is important in differentiation of HAP stem cells.

BACKGROUND/AIM Patient-derived orthotopic xenograft (PDOX) models have patient-like clinical features and may be imaged, in case of some cancers, by passaging of the tumors through transgenic nude mice expressing red-fluorescent protein (RFP) where they stably acquire RFP expressing stroma. The aim of the present study was to quantify red fluorescent area and intensity in colon-cancer peritoneal metastases in PDOX models in non-transgenic nude mice after passage in RFP transgenic nude mice by non-invasive external fluorescence imaging. MATERIALS AND METHODS Tumor fragments originating from a colon cancer patient with peritoneal metastases were implanted in transgenic RFP nude mice. Resultant tumors were harvested, and fragments were implanted in the same strain a second time. Passaged tumors stably acquired RFP-expressing stroma from their transgenic hosts. The tumor with RFP-expressing stromal cells were harvested and implanted orthotopically in non-transgenic nude mice. At eight weeks post-implantation, non-invasive external RFP images were obtained. RFP area and intensity were measured and correlated with tumor weight and volume. RESULTS Metastatic patient colon cancer can be stably and brightly labeled by passage in transgenic RFP-expressing nude mice such that tumor growth could be non-invasively imaged. Tumor growing could be non-invasively imaged when passaged to non-transgenic nude mice. A strong correlation between fluorescence intensity and area values with tumor weight and volume were established by external fluorescence imaging. CONCLUSION This new tumor model of metastatic colon cancer can be used to evaluate novel therapeutics in real time for this recalcitrant disease.

Olaratumab (OLA), a monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRα), has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), with limited efficacy. The goal of the present study was to determine the efficacy of OLA in combination with DOX and ifosfamide (IFO) on STS. Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish USTS patient-derived orthotopic xenograft (PDOX) model. USTS PDOX tumors were treated with OLA alone, DOX alone, DOX combined with IFO, OLA combined with DOX or IFO, and OLA combined with DOX and IFO. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested by OLA combined with DOX and IFO. Tumors treated with OLA combined with DOX and IFO had the most necrosis. The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, DOX and IFO for soft-tissue sarcomas.

Follicular dendritic cell sarcoma (FDCS) is a very rare and highly recalcitrant disease. A patient's doxorubicin-resistant FDCS was previously established orthotopically on the right high thigh into the biceps femoris of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present manuscript was to identify an effective drug for this recalcitrant tumor. Here, we evaluated the efficacy of temozolomide (TMZ), trabectedin (TRAB) and pazopanib (PAZ) on the FDCS PDOX model. PDOX mouse models were randomized into five groups of eight to nine mice, respectively. Group 1, untreated control with PBS, i.p.; Group 2, treated with doxorubicin (DOX), 2.4 mg/kg, i.p., weekly for 3 weeks; Group 3, treated with PAZ, 50 mg/kg, oral gavage, daily for 3 weeks; Group 4, treated with TMZ, 25 mg/kg, oral gavage, daily for 3 weeks; Group 5, treated with TRAB, 0.15 mg/kg, i.v., weekly for 3 weeks. Body weight and tumor volume were assessed 2 times per week. TMZ arrested the FDCS PDOX model compared to the control group (p 0.05). PAZ and TRAB did not have significant efficacy compared to the control group (p = 0.99, p = 0.69 respectively). The PDOX tumor was resistant to DOX (p= 0.99). as was the patient. The present study demonstrates that TMZ is effective for a PDOX model of FDCS established from a patient who failed DOX treatment, further demonstrating the power of PDOX to identify effective therapy including for tumors that failed first line therapy.

Recurrent osteosarcoma is a chemotherapy-resistant disease. Individualized precision therapy is needed for this disease. Toward this goal, we have developed the patient-derived othotopic xenograft (PDOX) mouse model of all major cancer types including osteosarcoma. Synergistic efficacy of trabectedin (TRAB) and irinotecan (IRT) has been reported in Ewing's sarcoma, soft-tissue sarcoma, and ovarian cancer. However, the efficacy of this combination on osteosarcoma is not known. The goal of present study was to determine the efficacy of the TRAB and IRT combination on cisplatinum (CDDP)-resistant osteosarcoma PDOX. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: Untreated control; CDDP alone; TRAB alone; IRT alone; and TRAB and the IRT combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was regressed only by the TRAB-IRT combination. Tumors treated with the TRAB-IRT combination had the most tumor necrosis with degenerative change. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the TRAB and IRT combination for chemotherapy-resistant osteosarcoma.

Cervical cancer is a recalcitrant disease. To help overcome this problem, we previously established a patient-derived orthotopic xenograft (PDOX) model of cervical cancer. In the previous study, we found the tumor to be resistant to nab-paclitaxal (nab-PTX). We also previously developed the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R). The aim of the present study was to investigate the efficacy of S. typhimurium A1-R to overcome nab-PTX resistance in the cervical cancer PDOX model. Cervical-cancer tumor fragments were implanted orthotopically into the neck of the uterus of nude mice. The cervical-cancer PDOX models were randomized into the following four groups after the tumor volume reached 60 mm3: G1: untreated group; G2: nab-PTX (i.v., 10 mg/kg, biweekly, 3 weeks); G3: Salmonella typhimurium A1-R (i.v., 5 × 107 CFU/body, weekly, 3 weeks); G4: nab-PTX combined with Salmonella typhimurium A1-R (nab-PTX, 10 mg/kg, i.v., biweekly, 3 weeks; S. typhimurium A1-R, 5 × 107 CFU/body, i.v., weekly, 3 weeks). Each group comprised eight mice. All mice were sacrificed on day 22. Tumor volume was measured on day 0 and day 22. Body weight was measured twice a week. Nab-PTX and Salmonella typhimurium A1-R did not show significant efficacy as monotherapy compared to the control group (P = 0.564 and P = 0.120, respectively). In contrast, nab-PTX combined with Salmonella typhimurium A1-R significantly suppressed tumor growth compared to the untreated control group and nab-PTX group (P

Olaratumab (OLA) is a monoclonal antibody against platelet-derived growth factor receptor alpha. OLA has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), but with limited efficacy. The goal of present study was to determine the efficacy of OLA combined with gemcitabine (GEM) and docetaxel (DOC) on a chemotherapy-resistant STS patient-derived orthotopic xenograft (PDOX). Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The USTS PDOX was treated with GEM alone, GEM combined with DOC, OLA combined with DOX or GEM, and OLA combined with GEM and DOC. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested only by OLA combined with GEM and DOC. Tumors treated with OLA combined with GEM and DOC also had the most necrosis. The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, GEM and DOC for drug-resistant soft-tissue sarcoma.

There are no effective treatments for leiomyosarcoma (LMS) spreading intraabdominally. The aim of this study was to develop precision chemotherapy for recurrent peritoneal LMS metastases in a patient-derived orthotopic xenograft (PDOX) model. The LMS PDOX models were established orthotopically on the dome of the bladder of nude mice. The LMS PDOX models were randomized into 6 groups when the tumor volume reached 80 mm3: G1: untreated control; G2: doxorubicin (DOX) (DOX: i.p., 3 mg/kg, weekly, 3 weeks); G3: DOX combined with olaratumab (OLA) (DOX: i.p., 3 mg/kg, weekly, 3 weeks; OLA: i.p., 40 mg/kg, 3 times/week, 3 weeks); G4: gemcitabine (GEM) combined with docetaxel (DOC) (GEM: i.p., 100 mg/kg, weekly, 3 weeks; DOC: i.p., 20 mg/kg, weekly, 3 weeks); G5: pazopanib (PAZ) (PAZ: p.o., 100 mg/kg, daily, 3 weeks); G6: palbociclib (PAL) (PAL: p.o., 100 mg/kg, daily, 3 weeks). All mice were sacrificed on day 22. Body weight was assessed twice a week. Tumor volume was measured on day 0 and day 22. Although all regimens had a significant efficacy compared to the untreated group (P

Background/aim Undifferentiated pleomorphic sarcoma (UPS) is a common soft tissue sarcoma and highly recalcitrant. We have previously developed patient-derived orthotopic xenograft (PDOX) mouse models of UPS and other major sarcoma types. Unlike PDOX models of other cancer types, it has been difficult to demonstrate metastasis in the sarcoma PDOX models. Materials and methods To visualize metastasis at high resolution in the UPS PDOX model, established tumor fragments were implanted in transgenic nude mice expressing red fluorescent protein (RFP) for one passage. The tumors acquired RFP-expressing stroma from transgenic host. UPS tumor with RFP stromal cells were harvested and implanted orthotopically in non-transgenic nude mice. After six weeks of UPS tumor growth in the PDOX model, the primary tumor was imaged non-invasively and lung, liver, and spleen were resected and imaged ex-vivo in order to visualize the presence of RFP, with a FluorVivo® imaging system and FV1000® confocal laser microscope, respectively. Results The primary tumor was imaged non-invasively. Confocal microscopy visualized the presence of RFP in the lung and liver indicating metastases in these organs. This is the first report of metastasis in a sarcoma PDOX model. Conclusion This study should prove very useful to screen for anti-metastatic drugs for the PDOX donor patients and to understand the metastatic process in sarcoma.

Liposarcoma is the most common type of soft tissue sarcoma. Among the subtypes of liposarcoma, dedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. The aim of the present study is to determine the efficacy of metabolic targeting with recombinant methioninase (rMETase) combined with palbociclib (PAL) against a doxorubicin (DOX)-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model. A resected tumor from a patient with recurrent high-grade DDLPS in the right retroperitoneum was grown orthotopically in the right retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, DOX; G3, PAL; G4, recombinant methioninase (rMETase); G5, PAL combined with rMETase. Tumor length and width were measured both pre- and post-treatment. On day 14 after initiation, all treatments significantly inhibited tumor growth compared to the untreated control except DOX. PAL combined with rMETase was significantly more effective than both DOX, rMETase alone, and PAL alone. Combining PAL and rMETase significantly regressed tumor volume on day 14 after initiation of treatment and was the only treatment to do so. The relative body weight on day 14 compared with day 0 did not significantly differ between each treatment group. The results of the present study indicate the powerful combination of rMETase and PAL should be tested clinically against DDLPS in the near future.

Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS.

Background Healthcare workers (HCWs) are vulnerable to getting infected withSARS-CoV-2. Preventing HCWs from getting infected is a priority to maintain healthcare services. The therapeutic and preventive role of ivermectin in COVID-19 is being investigated. Based on promising results of in vitro studies of oral ivermectin, this study was conducted with the aim to demonstrate the prophylactic role of oral ivermectin in preventing SARS-CoV-2 infectionamong HCWs at All India Institute of Medical Sciences (AIIMS), Bhubaneswar.Methods A prospective cohort study was conducted at AIIMS Bhubaneswar, which provides both COVID and Non-COVID care since March 2020. All employees and students of the institute who provided written informed consent participated in the study.Uptake of two-doses of oral ivermectin (300 μg/kg at a gap of 72 hours) was considered as exposure. The primary outcome of the study was COVID-19 infection in the following month of ivermectin consumption diagnosed by RTPCR as per Government of India testing criteria guidelines.The log-binomial model was used to estimate adjusted relative risk, and the Kaplan-Meier failure plot was used to estimate the probability of COVID-19 infection with follow-up time.Results Of 3892 employees, 3532 (90.8%) participated in the study. The ivermectin uptake was 62.5% and 5.3% for two-doses and single-dose, respectively. Participants who took ivermectin prophylaxis had a lower risk of getting symptoms suggestive of SARS-CoV-2 infection(6% vs 15%). HCWs who had taken two-doses of oral ivermectin have a significantly lower risk of contracting COVID-19 disease during the following month (ARR 0.17; 95% CI, 0.12-0.23). Females had a lower risk of contracting COVID-19 than males (ARR 0.70 95% CI, 0.52-0.93). The absolute risk reduction of SARS-CoV-2 infection was 9.7%. Only 1.8% of the participants reported adverse events, which were mild and self-limiting.Conclusion and relevance Two-doses of oral ivermectin (300 μg/kg given 72 hours apart) as chemoprophylaxis among HCWs reduces the risk of COVID-19 infection by 83% in the following month. Safe, effective, and low-cost chemoprophylaxis have relevance in the containment of pandemic alongside vaccine.

Background Ivermectin is one among several potential drugs explored for its therapeutic and preventive role in SARS-CoV-2 infection. The study was aimed to explore the association between ivermectin prophylaxis and the development of SARS-CoV-2 infection among healthcare workers. Methods A hospital-based matched case-control study was conducted among healthcare workers of AIIMS Bhubaneswar, India, from September to October 2020. Profession, gender, age and date of diagnosis were matched for 186 case-control pairs. Cases and controls were healthcare workers who tested positive and negative, respectively, for COVID-19 by RT-PCR. Exposure was defined as the intake of ivermectin and/or hydroxychloroquine and/or vitamin-C and/or other prophylaxis for COVID-19. Data collection and entry was done in Epicollect5, and analysis was performed using STATA version 13. Conditional logistic regression models were used to describe the associated factors for SARS-CoV-2 infection. Results Ivermectin prophylaxis was taken by 76 controls and 41 cases. Two-dose ivermectin prophylaxis (AOR 0.27, 95% CI, 0.15–0.51) was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month. Those involved in physical activity (AOR 3.06 95% CI, 1.18–7.93) for more than an hour/day were more likely to contract SARS-CoV-2 infection. Type of household, COVID duty, single-dose ivermectin prophylaxis, vitamin-C prophylaxis and hydroxychloroquine prophylaxis were not associated with SARS-CoV-2 infection. Conclusion Two-dose ivermectin prophylaxis at a dose of 300 μg/kg with a gap of 72 hours was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month. Chemoprophylaxis has relevance in the containment of pandemic.

BackgroundIvermectin is one among several potential drugs explored for its therapeutic and preventive role in COVID-19 infection. The study was aimed to explore the association between ivermectin prophylaxis and development of COVID-19 infection among healthcare workers.MethodsA hospital-based matched case-control study was conducted among healthcare workers of AIIMS Bhubaneswar, India, from September to October 2020. Profession, gender, age and date of diagnosis were matched for 186 case-control pairs. Cases and controls were healthcare workers who tested positive and negative, respectively, for COVID-19 by RT-PCR. Exposure was defined as the intake of ivermectin and/or hydroxychloroquine and/or vitamin-C and/or other prophylaxis for COVID-19. Data collection and entry was done in Epicollect5, and analysis was performed using STATA version 13. Conditional logistic regression models were used to describe the associated factors for COVID-19 infection.ResultsIvermectin prophylaxis was taken by 77 controls and 38 cases. Two-dose ivermectin prophylaxis (0.27, 95% CI, 0.15-0.51) was associated with 73% reduction of COVID-19 infection among healthcare workers for the following one month, those who were involved in physical activity (3.06 95% CI, 1.18-7.93) for more than an hour/day were more likely to contract COVID-19 infection. Type of household, COVID duty, single-dose ivermectin prophylaxis, vitamin-C prophylaxis and hydroxychloroquine prophylaxis were not associated with COVID-19 infection.ConclusionTwo-dose ivermectin prophylaxis at a dose of 300 μg/kg with a gap of 72 hours was associated 73% reduction of COVID-19 infection among healthcare workers for the following one-month. Further research is required before its large scale use.