Low-energy amplitude-modulated electromagnetic field exposure: Feasibility study in patients with hepatocellular carcinoma.

BACKGROUND: Patients with advanced hepatocellular carcinoma (HCC) and poor liver function lack effective systemic therapies. Low-energy electromagnetic fields (EMFs) can influence cell biological processes via non-thermal effects and may represent a new treatment option. METHODS: This single-site feasibility trial enrolled patients with advanced HCC, Child-Pugh A and B, Eastern Cooperative Oncology Group 0-2. Patients underwent 90-min amplitude-modulated EMF exposure procedures every 2-4 weeks, using the AutEMdev (Autem Therapeutics). Patients could also receive standard care. The primary endpoints were safety and the identification of hemodynamic variability patterns. Exploratory endpoints included health-related quality of life (HRQoL), overall survival (OS). and objective response rate (ORR) using RECIST v1.1. RESULTS: Sixty-six patients with advanced HCC received 539 AutEMdev procedures (median follow-up, 30 months). No serious adverse events occurred during procedures. Self-limiting grade 1 somnolence occurred in 78.7% of patients. Hemodynamic variability during EMF exposure was associated with specific amplitude-modulation frequencies. HRQoL was maintained or improved among patients remaining on treatment. Median OS was 11.3 months (95% confidence interval [CI]: 6.0, 16.6) overall (16.0 months [95% CI: 4.4, 27.6] and 12.0 months [6.4, 17.6] for combination therapy and monotherapy, respectively). ORR was 24.3% (32% and 17% for combination therapy and monotherapy, respectively). CONCLUSION: AutEMdev EMF exposure has an excellent safety profile in patients with advanced HCC. Hemodynamic alterations at personalized frequencies may represent a surrogate of anti-tumor efficacy. NCT01686412.

Whole body diffusion for metastatic disease assessment in neuroendocrine carcinomas: comparison with OctreoScan® in two cases.

Neuroendocrine tumor (NET) patients must be adequately staged in order to improve a multidisciplinary approach and optimal management for metastatic disease. Currently available imaging studies include somatostatin receptor scintigraphy, like OctreoScan®, computed tomography (CT), scans and magnetic resonance imaging (MRI), which analyze vascular concentration and intravenous contrast enhancement for anatomic tumor localization. However, these techniques require high degree of expertise for interpretation and are limited by their availability, cost, reproducibility, and follow-up imaging comparisons. NETs significantly reduce water diffusion as compared to normal tissue. Diffusion-weighted imaging (DWI) in MRI has an advantageous contrast difference: the tumor is represented with high signal over a black normal surrounding background. The whole-body diffusion (WBD) technique has been suggested to be a useful test for detecting metastasis from various anatomic sites. In this article we report the use of DWI in MRI and WBD in two cases of metastatic pulmonary NET staging in comparison with OctreoScan® in order to illustrate the potential advantage of DWI and WBD in staging NETs.

What can we learn from more than 1,000 Brazilian patients at risk of hereditary cancer?

Background: Identifying individuals at a higher risk of developing cancer is a major concern for healthcare providers. Cancer predisposition syndromes are the underlying cause of cancer aggregation and young-onset tumors in many families. Germline genetic testing is underused due to lack of access, but Brazilian germline data associated with cancer predisposition syndromes are needed. Methods: Medical records of patients referred for genetic counseling at the Oncogenetics Department at the Hospital Sírio-Libanês (Brasília, DF, Brazil) from July 2017 to January 2021 were reviewed. The clinical features and germline findings were described. Detection rates of germline pathogenic/likely pathogenic variant (P/LPV) carriers were compared between international and Brazilian guidelines for genetic testing. Results: A total of 1,091 individuals from 985 families were included in this study. Most patients (93.5%) had a family history of cancer, including 64% with a family member under 50 with cancer. Sixty-six percent of patients (720/1091) had a personal history of cancer. Young-onset cancers (<50 years old) represented 62% of the patients affected by cancer and 17% had multiple primary cancers. The cohort included patients with 30 different cancer types. Breast cancer was the most prevalent type of cancer (52.6%). Germline testing included multigene panel (89.3%) and family variant testing (8.9%). Approximately 27% (236/879) of the tested patients harbored germline P/LPVs in cancer susceptibility genes. BRCA2, BRCA1, and TP53 were the most frequently reported genes, corresponding to 18.6%, 14.4%, and 13.5% of the positive results, respectively. Genetic testing criteria from international guidelines were more effective in identifying carriers than the Brazilian National Agency of Supplementary Health (ANS) criteria (92% vs. 72%, p<0.001). Forty-six percent of the cancer-unaffected patients who harbored a germline P/LPV (45/98) would not be eligible for genetic testing according to ANS because they did not have a family variant previously identified in a cancer-affected relative. Conclusion: The high detection rate of P/LPVs in the present study is possibly related to the genetic testing approach with multigene panels and cohort's characteristics, represented mainly by individuals with a personal or family history of young-onset cancer. Testing asymptomatic individuals with suspicious family history may also have contributed to a higher detection rate. A significant number of carriers would not have been identified using ANS criteria for genetic testing.

Ex vivo Retrieval of Mature Oocytes for Fertility Preservation in a Patient with Bilateral Borderline Ovarian Tumor.

We report a case of ultrasound-guided ex vivo oocyte retrieval for fertility preservation in a woman with bilateral borderline ovarian tumor, for whom conventional transvaginal oocyte retrieval was deemed unsafe because of the increased risk of malignant cell spillage. Ovarian stimulation with gonadotropins was performed. Surgery was scheduled according to the ovarian response to exogenous gonadotropic stimulation; oophorectomized specimens were obtained by laparoscopy, and oocyte retrieval was performed ∼ 37 hours after the ovulatory trigger. The sum of 20 ovarian follicles were aspirated, and 16 oocytes were obtained. We performed vitrification of 12 metaphase II oocytes and 3 oocytes matured in vitro. Our result emphasizes the viability of ex vivo mature oocyte retrieval after controlled ovarian stimulation for those with high risk of malignant dissemination by conventional approach.

Relatamos um caso de obtenção ex vivo de óvulos, guiada por ultrassonografia, para preservação da fertilidade em uma mulher com tumor ovariano borderline bilateral, para quem a recuperação transvaginal convencional foi considerada insegura, devido ao aumento do risco de disseminação de células malignas. Foi realizada estimulação ovariana com gonadotrofinas. A cirurgia foi agendada de acordo com a resposta ovariana à estimulação gonadotrófica exógena; após ooforectomia por laparoscopia, ∼ 37 horas após a maturação folicular, procedeu-se à recuperação extracorpórea de oócitos. Um total de 20 folículos ovarianos foi aspirado e 16 complexos cumulus foram obtidos, resultando na vitrificação de 12 oócitos maduros e de 3 oócitos imaturos amadurecidos in vitro. Nosso resultado enfatiza a viabilidade da recuperação ex vivo de oócitos maduros após estimulação ovariana controlada para mulheres com alto risco de disseminação maligna pela captação oocitária realizada convencionalmente pela via transvaginal.

Differences in Pathology and Mutation Status Among Colorectal Cancer Patients Younger Than, Older Than, and of Screening Age.

BACKGROUND: Screening protocols for colorectal cancer are broadly recommended and effective in reducing mortality. However, populations from different age groups can harbor distinct pathologic and molecular profiles that can also be influenced by screening and polyp resection, especially in older ages. PATIENTS AND METHODS: We retrospectively analyzed tumors from stage IV colorectal cancer patients from a central pathology laboratory in Brazil that is a reference for mutational profiling countrywide. Patients were classified into age groups as follows: prescreening age (PrSA; < 45 years old), screening age (SA; 45-75 years old), and postscreening age (PoSA; > 75 years old). Every tumor was centrally reviewed by the pathologist. Groups were compared regarding clinicopathologic features, and the presence of RAS (renin-angiotensin system) and BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations. RESULTS: We included 1635 patients (215 PrSA, 1213 SA, 207 PoSA). There was no difference among groups regarding sidedness (P = .65) and KRAS (Kirsten rat sarcoma viral oncogene) mutations (P = .57). Stage IV disease at diagnosis (P = .04), the presence of a signet-ring cell component (P < .001), and poorly differentiated tumors (P = .02) were most common in young patients, while BRAF and NRAS (neuroblastoma RAS viral (v-ras) oncogene homolog) mutations were significantly more common among PoSA patients (P = .002 and .03, respectively). When divided by age decade, KRAS mutations seem to have a stable frequency among all ages, while the BRAF mutation rate increased with increasing age. CONCLUSION: BRAF mutations are more frequent among PoSA patients, and this seems to be a continuous trend. PrSA and PoSA patients seem to present a distinct profile from SA, including differences in molecular and pathologic aspects. These findings could impact the frequency of screening tests among different age groups.

Combination of Irinotecan, Oxaliplatin and 5-Fluorouracil as a Rechallenge Regimen for Heavily Pretreated Metastatic Colorectal Cancer Patients.

PURPOSE: Our objective was to evaluate the benefit of re-exposing patients with refractory metastatic colorectal cancer (mCRC) to a combination of oxaliplatin, irinotecan and 5-fluorouracil treatment. METHODS: We retrospectively analysed patients with mCRC who received a combination of oxaliplatin, irinotecan and fluorouracil as a rechallenge regimen after progressing on the same drugs. Both FOLFOXIRI and FOLFIRINOX were used. Toxicity was evaluated for each treatment cycle, and survival analysis was performed using the Kaplan-Meier method. RESULTS: A total of 21 patients who were treated between January 2011 and December 2013 were selected for this study. Most of the patients (95.2%) had an ECOG status of 0-1. The median age at diagnosis was 52.1 years (range 36-77 years), and 14 (66.6%) patients had wild-type KRAS. Thirteen patients received FOLFIRINOX, and eight received FOLFOXIRI. Most patients had previously received at least three regimens, with 80% receiving anti-VEGF and 66% anti-EGFR antibodies. The response rate was 38%, and 24% patients had stable disease. The median time to disease progression was 4.0 months (range 1.0-9.1 months), and the median overall survival duration was 8.6 months (range 6.3-11.5 months). Most patients required dose adjustment and treatment delays. One patient experienced grade 5 neutropenic sepsis. CONCLUSIONS: Both FOLFIRINOX and FOLFOXIRI are active and potentially feasible rechallenge treatment options for heavily pretreated patients with good performance status. With dose reduction and close monitoring for toxicity, the risk of serious adverse events can be minimised.

Guidelines for the management of neuroendocrine tumours by the Brazilian gastrointestinal tumour group.

Neuroendocrine tumours are a heterogeneous group of diseases with a significant variety of diagnostic tests and treatment modalities. Guidelines were developed by North American and European groups to recommend their best management. However, local particularities and relativisms found worldwide led us to create Brazilian guidelines. Our consensus considered the best feasible strategies in an environment involving more limited resources. We believe that our recommendations may be extended to other countries with similar economic standards.

Myocardial infarction increases reactivity to phenylephrine in isolated aortic rings of ovariectomized rats.

Clinical studies demonstrated that the incidence of cardiovascular disease is low in premenopausal women, rises in postmenopausal women, and is reduced to premenopausal levels in postmenopausal women who receive estrogen therapy. The interaction between gender and myocardial infarction indicates that the survival advantage of women is modified by the occurrence of myocardial infarction. Therefore, the effect of myocardial infarction on mortality is greater in women than men. The aim of our study was to investigate the influence of the ovariectomy on the reactivity to phenylephrine in aortic rings of female rats post-myocardial infarction. Animals were divided in four groups: Control (Cont), Ovariectomized (Ovx), Infarcted (Inf) and Ovariectomized and Infarcted (Ovx-Inf). Aortic rings were studied 60 days after ovariectomy and infarction surgery. The infarct area was similar among groups. The maximal response to phenylephrine was increased in the Ovx-Inf group compared to all the other groups (Cont = 2.411+/-0.131 (N = 11); Ovx = 2.863+/-0.121(N = 15); Inf = 2.794+/-0.102 (N = 13); Ovx-Inf = 3.40+/-0.201* (N = 12) g; *P < 0.05). In the absence of endothelium and L-NAME perfusion, the maximal response to phenylephrine was similarly increased in all groups. Relaxation to acetylcholine was also similar. The indirect evaluation of NO bioavailability analyzed by the area under the curve demonstrated a reduction on NO on the Ovx-Inf group that could contributes to increased response to phenylephrine. In conclusion our results showed that ovariectomy associated to a myocardial infarction leads to an increment of aorta reactivity to phenylephrine associated to a reduction of basal NO bioavailability in spite of a normal endothelium-dependent relaxation induced by acetylcholine.

Ex vivo retrieval of mature oocytes for fertility preservation in a patient with bilateral borderline ovarian tumor / Recuperação ex vivo de oócitos maduros para preservação da fertilidade em paciente com tumor ovariano borderline bilateral

Abstract We report a case of ultrasound-guided ex vivo oocyte retrieval for fertility preservation in a woman with bilateral borderline ovarian tumor, for whom conventional transvaginal oocyte retrieval was deemed unsafe because of the increased risk of malignant cell spillage. Ovarian stimulation with gonadotropins was performed. Surgery was scheduled according to the ovarian response to exogenous gonadotropic stimulation; oophorectomized specimens were obtained by laparoscopy, and oocyte retrieval was performed ~ 37 hours after the ovulatory trigger. The sum of 20 ovarian follicles were aspirated, and 16 oocytes were obtained.We performed vitrification of 12 metaphase II oocytes and 3 oocytes matured in vitro. Our result emphasizes the viability of ex vivo mature oocyte retrieval after controlled ovarian stimulation for those with high risk of malignant dissemination by conventional approach.

Resumo Relatamos um caso de obtenção ex vivo de óvulos, guiada por ultrassonografia, para preservação da fertilidade em uma mulher com tumor ovariano borderline bilateral, para quem a recuperação transvaginal convencional foi considerada insegura, devido ao aumento do risco de disseminação de célulasmalignas. Foi realizada estimulação ovariana com gonadotrofinas. A cirurgia foi agendada de acordo com a resposta ovariana à estimulação gonadotrófica exógena; após ooforectomia por laparoscopia, ~ 37 horas após a maturação folicular, procedeu-se à recuperação extracorpórea de oócitos. Umtotal de 20 folículos ovarianos foi aspirado e 16 complexos cumulus foramobtidos, resultando na vitrificação de 12 oócitos maduros e de 3 oócitos imaturos amadurecidos in vitro. Nosso resultado enfatiza a viabilidade da recuperação ex vivo de oócitos maduros após estimulação ovariana controlada para mulheres com alto risco de disseminação maligna pela captação oocitária realizada convencionalmente pela via transvaginal.

Octreotide - A Review of its Use in Treating Neuroendocrine Tumours.

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose incidence has dramatically increased in recent years. Octreotide is a somatostatin analogue used in the treatment of NETs, and its use in clinical trials has been associated with substantially increased survival. Although traditionally used for the relief of symptoms that result from release of peptides and neuroamines, there has been a growing body of evidence that suggest octreotide has antiproliferative effects. A phase III clinical study has demonstrated that the long-acting formulation (LAR), octreotide LAR, lengthens time to tumour progression in patients with well-differentiated metastatic midgut NETs, and that octreotide LAR is a treatment option for patients with metastatic midgut NETs, regardless of functional status. Furthermore, octreotide LAR has demonstrated clinical efficacy in different types of NETs. These data, along with emerging data on somatostatin analogs, may change the way doctors approach this patient population and reinforce the use of these drugs as a treatment option for patients with non-functioning tumours.

68Ga-DOTATATE PET/CT, 99mTc-HYNIC-octreotide SPECT/CT, and whole-body MR imaging in detection of neuroendocrine tumors: a prospective trial.

UNLABELLED: There are different metabolic imaging methods, various tracers, and emerging anatomic modalities to stage neuroendocrine tumor (NET). We aimed to compare NET lesion detectability among (99m)Tc-hydrazinonicotinamide (HYNIC)-octreotide (somatostatin receptor scintigraphy [SSRS]) SPECT/CT, (68)Ga-DOTATATE PET/CT, and whole-body diffusion-weighted MR imaging (WB DWI). METHODS: Nineteen consecutive patients (34-77 y old; mean, 54.3 ± 10.4 y old; 10 men and 9 women) underwent SSRS SPECT/CT, (68)Ga-DOTATATE PET/CT, and WB DWI. Images were acquired with a maximum interval of 3 mo between them and were analyzed with masking by separate teams. Planar whole-body imaging and SPECT/CT were performed from thorax to pelvis using a double-head 16-slice SPECT/CT scanner 4 h after injection of 111-185 MBq of (99m)Tc-HYNIC-octreotide. (68)Ga-DOTATATE PET/CT was performed from head to feet using a 16-slice PET/CT scanner 45 min after injection of 185 MBq of tracer. WB DWI was performed in the coronal plane using a 1.5-T scanner and a body coil. The standard method of reference for evaluation of image performance was undertaken: consensus among investigators at the end of the study, clinical and imaging follow-up, and biopsy of suggestive lesions. RESULTS: McNemar testing was applied to evaluate the detectability of lesions using (68)Ga-DOTATATE PET/CT in comparison to SSRS SPECT/CT and WB DWI: a significant difference in detectability was noted for pancreas (P = 0.0455 and P = 0.0455, respectively), gastrointestinal tract (P = 0.0455 and P = 0.0455), and bones (P = 0.0082 and P = 0.0082). Two unknown primary lesions were identified solely by (68)Ga-DOTATATE PET/CT. (68)Ga-DOTATATE PET/CT, SSRS SPECT/CT, and WB DWI demonstrated, respectively, sensitivities of 0.96, 0.60, and 0.72; specificities of 0.97, 0.99, and 1.00; positive predictive values of 0.94, 0.96, and 1.00; negative predictive values of 0.98, 0.83, and 0.88; and accuracies of 0.97, 0.86, and 0.91. CONCLUSION: (68)Ga PET/CT seems to be more sensitive for detection of well-differentiated NET lesions, especially for bone and unknown primary lesions. NET can be staged with (68)Ga-DOTATATE PET/CT. WB DWI is an efficient new method with high accuracy and without ionizing radiation exposure. SSRS SPECT/CT should be used only when (68)Ga-DOTATATE PET/CT and WB DWI are not available.

Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate.

Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.