Treatment of Abdominal Desmoplastic Small Round Cell Tumor Induces Acute Myeloid Leukemia-M5: A Case Report and Literature Review.

Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive malignancy. Most patients are diagnosed at a late stage with poor prognosis. The treatment usually includes combined intensive chemotherapy, cytoreductive surgery, radiotherapy, and targeted therapy. Due to the low incidence rate and dismal survival, there is currently a lack of case reports on DSRCT with concurrent leukemia. We report a case of a young patient who achieved disease stabilization for 14 months after receiving 6 cycles of chemotherapy and whole abdominal radiation therapy (WART), followed by consolidation treatment with anlotinib. However, the treatment was terminated due to the development of Acute Myeloid Leukemia-M5 (AML-M5). Multimodal therapy may provide a survival benefit for rare tumors that lack standard treatment. However, intensive chemotherapy and extensive radiotherapy carry a risk of inducing secondary malignancies. This is the first reported case of concurrent DSRCT and AML-M5 with short intervals between onset.

Palliative Radiation Therapy in the Treatment of Desmoplastic Small Round Cell Tumors.

An early adolescent male presented with six months of nausea, vomiting, and constipation. A chest computed tomography (CT) scan revealed multiple pulmonary nodules of varying sizes and a 3.1 cm pleural-based mass-like density in the right lower pulmonary lobe suspicious for metastatic disease. A CT scan of the abdomen and pelvis revealed diffuse metastatic disease involving the lungs, liver, and peritoneum. An ultrasound (US)-guided core needle biopsy of the liver was performed, and the morphology and immunohistochemistry were consistent with a poorly differentiated carcinoma. Further workup was performed, and the patient was diagnosed with a desmoplastic small round cell tumor (DSRCT). The patient underwent eight cycles of chemotherapy, but his tumor metastasized to distant sites. He then underwent two courses of palliative radiation therapy to the pelvis. His cancer continued to progress, and he eventually succumbed to his disease. This case report evaluates the evidence, data, radiation dosages, and techniques for palliative radiation therapy for DSRCTs.

Adipose Tissue Distribution and Body Mass Index (BMI) Correlation With Daily Image-Guided Radiotherapy (IGRT) Shifts of Abdominal Radiation Therapy Patients.

Purpose There are several studies suggesting a correlation between image-guided radiotherapy (IGRT) setup errors and body mass index (BMI). However, abdominal fat content has visceral and subcutaneous components, which may affect setup errors differently. This study aims to analyze a potential workflow for characterizing adipose content and distribution in the region of the target that would allow a quickly calculated metric of abdominal fat content to stratify these patients. Methods IGRT shift data was retrospectively tabulated from daily fan-beam CT-on-rails pre-treatment alignment for 50 abdominal radiation therapy (RT) patients, and systematic and random errors in the daily setup were characterized by tabulating average and standard deviations of shift data for each patient and looking at differences for different distributions of adipose content. Visceral and subcutaneous fat content were defined by visceral fat area (VFA) and subcutaneous fat area (SFA) using a region-growing algorithm to contour adipose tissue on CT simulation scans. All contours were created for a single slice at the treatment isocenter, on which the VFA and SFA were calculated. A log-rank test was used to test trends in shifts over quartiles of adiposity. Results VFA ranged from 1.9-342.8c m2, and SFA from 11.8-756.0 cm2. The standard definition (SD) of random error (σ) in the lateral axis for Q1 vs. Q4 VFA was 0.10cm vs. 0.29cm, 0.12cm vs. 0.28cm for SFA, and 0.12cm vs. 0.31cm for BMI. The percentage of longitudinal shifts greater than 10mm for Q1 vs. Q4 VFA was 0% vs. 9%, 2% vs. 19% for SFA, and 0% vs. 20% for BMI. Statistically significant trends in shifts vs. the BMI quartile were seen for both pitch and the longitudinal direction, as well as for pitch corrections vs. the VFA quartile. Conclusion Within this dataset, abdominal cancer patients showed statistically significant trends in shift probability vs. BMI and VFA. Also, patients in the upper quartiles of all adiposity metrics showed an increased SD of σ in the lateral direction and increased shifts over 10 mm in the longitudinal direction. However, despite these relationships, neither VFA nor SFA offered discernible advantages in their relationship to shift uncertainty relative to BMI.

Cardiovascular Risk in Childhood Cancer Survivors.

Cancer is a prominent cause of death worldwide in the pediatric population. Since childhood cancer is not possible to prevent, it is essential to focus on a prompt and correct diagnosis followed by effective, evidence-based therapy with individualized supportive care. Given the enhancement of childhood cancer management over the past decades, survival rate has significantly improved, thus leading to the progression of several late effects, including metabolic derangements. These metabolic imbalances are associated with the underlying disease and the cancer treatments. As a result, the metabolic state may contribute to a high risk of cardiovascular morbidity and premature mortality among childhood cancer survivors. This review aims to summarize the potential pathophysiological mechanisms linked to the risk of diabetes and metabolic syndrome and screening recommendations. Further investigations are needed to clarify the underlying mechanisms of such metabolic abnormalities and to improve long-term cardiometabolic survival among these patients.

Utility of adjuvant whole abdominal radiation therapy in ovarian clear cell cancer (OCCC): a pragmatic cohort study of women with classic immuno-phenotypic signature.

BACKGROUND: To evaluate the initial experience and clinical utility of first-line adjuvant intensity-modulated whole abdominal radiation therapy (WART) in women with ovarian clear cell cancer (OCCC) referred to an academic center. METHODS: Progression-free and overall survival was analyzed in a pragmatic observational cohort study of histologically pure OCCC patients over-expressing HNF-1ß treated between 2013 and end-December 2018. An in-house intensity-modulated WART program was developed from a published pre-clinical model. Radiation dose-volume data was curated to American Association of Physics in Medicine (AAPM) Task Group 263 recommendations. A dedicated database prospectively recorded presenting characteristics and outcomes in a standardized fashion. RESULTS: Five women with FIGO (2018) stage IA to IIIA2 OCCC were treated with first-line WART. Median age was 58 years (range 47-68 years). At diagnosis CA-125 was elevated in 4 cases (median 56 kU/L: range 18.4-370 kU/L) before primary de-bulking surgery. Severe premorbid endometriosis was documented in 3 patients. At a median follow-up of 77 months (range 16-83 mo.), all patients remain alive and progression-free on clinical, biochemical (CA-125), and 18Fluoro-deoxyglucose (FDG) PET/CT re-evaluation. Late radiation toxicity was significant (G3) in 1 case who required a limited bowel resection and chronic nutritional support at 9 months post-WART; 2 further patients had asymptomatic (G2) osteoporotic fragility fractures of axial skeleton at 12 months post-radiation treated with anti-resorptive agents (denosumab). CONCLUSIONS: The clinical utility of intensity-modulated WART in OCCC over-expressing HNF-1ß was suggested in this small observational cohort study. The hypothesis that HNF-1ß is a portent of platinum-resistance and an important predictive biomarker in OCCC needs further confirmation. Curating multi-institutional cohort studies utilizing WART by means of "Big Data" may improve OCCC care standards in the future.

BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury.

BACKGROUND: Radiation-induced gastrointestinal syndrome (RIGS) results from the acute loss of intestinal stem cells (ISC), impaired epithelial regeneration, and subsequent loss of the mucosal barrier, resulting in electrolyte imbalance, diarrhea, weight loss, sepsis, and mortality. The high radiosensitivity of the intestinal epithelium limits effective radiotherapy against abdominal malignancies and limits the survival of victims of nuclear accidents or terrorism. Currently, there is no approved therapy to mitigate radiation toxicity in the intestine. Here we demonstrate that BCN057, an anti-neoplastic small molecular agent, induces ISC proliferation and promotes intestinal epithelial repair against radiation injury. METHODS: BCN057 (90 mg/kg body weight, subcutaneously) was injected into C57Bl6 male mice (JAX) at 24 h following abdominal irradiation (AIR) and was continued for 8 days post-irradiation. BCN057-mediated rescue of Lgr5-positive ISC was validated in Lgr5-EGFP-Cre-ERT2 mice exposed to AIR. The regenerative response of Lgr5-positive ISC was examined by lineage tracing assay using Lgr5-EGFP-ires-CreERT2-TdT mice with tamoxifen administration to activate Cre recombinase and thereby marking the ISC and their respective progeny. Ex vivo three-dimensional organoid cultures were developed from surgical specimens of human colon or from mice jejunum and were used to examine the radio-mitigating role of BCN057 on ISC ex vivo. Organoid growth was determined by quantifying the budding crypt/total crypt ratio. Statistical analysis was performed using Log-rank (Mantel-Cox) test and paired two-tail t test. RESULTS: Treatment with BCN057 24 h after a lethal dose of AIR rescues ISC, promotes regeneration of the intestinal epithelium, and thereby mitigates RIGS. Irradiated mice without BCN057 treatment suffered from RIGS, resulting in 100% mortality within 15 days post-radiation. Intestinal organoids developed from mice jejunum or human colon demonstrated a regenerative response with BCN057 treatment and mitigated radiation toxicity. However, BCN057 did not deliver radio-protection to mouse or human colon tumor tissue. CONCLUSION: BCN057 is a potential mitigator against RIGS and may be useful for improving the therapeutic ratio of abdominal radiotherapy. This is the first report demonstrating that a small molecular agent mitigates radiation-induced intestinal injury by inducing ISC self-renewal and proliferation.

Effect of Whole-abdominal Irradiation on Penetration Depth of Doxorubicin in Normal Tissue After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in a Post-mortem Swine Model.

BACKGROUND: This study was performed to evaluate the impact of whole-abdominal irradiation on local penetration of doxorubicin into the peritoneum and the abdominal organs in a post-mortem swine model. MATERIALS AND METHODS: Doxorubicin was aerosolized into the abdominal cavity of swine at a pressure of 12 mmHg CO2 at room temperature (25°). One swine was subjected to pressurized intraperitoneal aerosol chemotherapy (PIPAC) using Micropump© without irradiation; the second one received 2 Gy and the third one 7 Gy whole-abdominal irradiation, 15 min prior to PIPAC application. Samples of the peritoneal surface were extracted at different positions from within the abdominal cavity. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. RESULTS: The depth of penetration of doxorubicin was found to be wide-ranging, between 17 µm on the surface of the stomach and 348 µm in the small intestine. The penetration depth into the small intestine was 348 µm, 312 µm and 265 µm for PIPAC alone, PIPAC with 2 Gy irradiation and PIPAC with 7 Gy irradiation, respectively (p<0.05). The penetration into the liver was 64 µm, 55 µm and 40 µm, respectively (p=0.05). CONCLUSION: Irradiation was not found to increase the depth of doxorubicin penetration into normal tissue in the post-mortem swine model. A reduction of doxorubicin penetration was observed after application of higher irradiation doses. Further studies are warranted to determine if irradiation can be used safely as chemopotentiating agent for patients with peritoneal metastases treated with PIPAC.

Distribution pattern and penetration depth of doxorubicin after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a postmortem swine model.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach delivering intraperitoneal chemotherapy by means of a pressurized aerosol. This study was conducted to evaluate the distribution pattern of doxorubicin in the abdominal cavity after PIPAC in a postmortem swine model. METHODS: Doxorubicin was aerosolized through a Micropump© (MIP) into the peritoneal cavity of two swines at a pressure of 12 mm Hg CO2 and 32 °C. To measure the distribution of the drug, 9 different positions within the abdominal cavity were sampled. In-tissue doxorubicin penetration was evaluated using fluorescence microscopy on frozen thin sections. RESULTS: A maximum of drug penetration was observed in the area around the MIP. The penetration in the small intestine reached a depth of 349 ± 65 µm. Penetration depth in the right upper abdomen and left upper abdomen were 349 ± 65 and 140 µm ± 26 µm, respectively. Distant areas to the MIP showed variable penetration rates between 50 and 150 µm. CONCLUSIONS: Doxorubicin reached all areas within the peritoneum. Highest penetration rates were measured in the area around the Micropump. Further studies are warranted to evaluate and optimize the distribution and penetration of cytotoxic agent into the tissue after PIPAC.

Survival and toxicity following sequential multimodality treatment including whole abdominopelvic radiotherapy for patients with desmoplastic small round cell tumor.

BACKGROUND AND PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy. We report survival rates and toxicity associated with sequential multimodality treatment including whole abdominopelvic radiation therapy (WART). MATERIAL AND METHODS: Medical records of 32 patients with DSRCT treated at our institution were reviewed. Patients underwent chemotherapy, cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC), followed by WART with intensity-modulated radiation or volumetric-modulated arc therapy. RESULTS: Median overall survival (OS) was 60months. After 18months of follow-up, 20 patients (62.5%) had disease recurrence and median disease-free survival (DFS) was 10months. Median time to extrahepatic abdominal failure was 19.4months. Factors affecting time to local progression included liver metastases at diagnosis, and an interval of greater than 5.6months between diagnosis and HIPEC or greater than 2.1months between HIPEC and WART. None of these factors altered OS. Grade 3 or higher toxicities occurred in 84% of patients. CONCLUSIONS: WART following chemotherapy, surgical cytoreduction and HIPEC is an aggressive treatment for DSRCT patients and can result in severe side effects. Our median OS of 5years is favorable compared to prior studies, despite a median DFS of only 10months, which may be due to improved salvage therapies.

Efeito da suplementação oral de l-glutamina na parede colônica de ratos submetidos à irradiação abdominal

PURPOSE: To evaluate the structural alterations of the irradiated colonic wall in rats, verifying if L-glutamine supplementation is able to prevent them. METHODS: We used 30 male adult Wistar rats, divided into three groups: I - control, II - irradiated, and III - irradiated with L-glutamine supplementation during the 14 days of the study. Control group was maintained in laboratory standard conditions while groups II and three were submitted to abdominal radiation with an only dose of 1000 cGy in the 8th day of experimentation. All the animals were submitted to laparotomy in the 15th day for resection of the colonic segment for stereological analysis. RESULTS: Group II presented total volume of colonic wall significantly smaller than control group without altering the partial volumes of each layer. Compared to groups II and III, group III exhibited maintenance of total volume of colonic wall, nearing control group. Compared to control group, animals of group III exhibited maintenance of epithelial partial volume without altering significantly epithelial surface. CONCLUSION: It is suggested that L-glutamine supplementation can be of benefit in the irradiated colonic wall in rats.

OBJETIVO: Avaliar as alterações estruturais na parede do cólon irradiado, em ratos, verificando se a suplementação de L-glutamina pode prevení-las. MÉTODOS: Foram empregados 30 ratos Wistar, machos, adultos, divididos em três grupos: I - controle, II- irradiado e III - irradiado, com suplementação de L-glutamina durante os 14 dias do estudo. O Grupo Controle foi mantido em condições-padrão de laboratório, enquanto os grupos II e III foram submetidos à irradiação abdominal, com dose única de 1000 cGy, no 8°. dia da experimentação. Todos os animais foram operados no 15°. dia, para ressecção de segmento colônico para análise estereológica. RESULTADOS: O grupo II apresentou volume total da parede colônica significativamente menor que o Grupo Controle, sem alterar os volumes parciais de cada camada histológica. No grupo III, houve manutenção do volume total da parede do cólon, próxima ao Grupo Controle, com aumento significativo da camada mucosa, quando comparada aos grupos I e II. Na camada mucosa do grupo III, houve a manutenção do volume parcial do epitélio, comparado ao Grupo Controle, sem melhora significativa da superfície epitelial. CONCLUSÃO: Sugere-se que a suplementação de L-glutamina seja benéfica na parede do cólon irradiado, em ratos.