Surgical versus non-surgical management for patients with malignant bowel obstruction (S1316): a pragmatic comparative effectiveness trial.

BACKGROUND: Malignant small bowel obstruction has a poor prognosis and is associated with multiple related symptoms. The optimal treatment approach is often unclear. We aimed to compare surgical versus non-surgical management with the aim to determine the optimal approach for managing malignant bowel obstruction. METHODS: S1316 was a pragmatic comparative effectiveness trial done within the National Cancer Trials Network at 30 hospital and cancer research centres in the USA, Mexico, Peru, and Colombia. Participants had an intra-abdominal or retroperitoneal primary cancer confirmed via pathological report and malignant bowel disease; were aged 18 years or older with a Zubrod performance status 0-2 within 1 week before admission; had a surgical indication; and treatment equipoise. Participants were randomly assigned (1:1) to surgical or non-surgical treatment using a dynamic balancing algorithm, balancing on primary tumour type. Patients who declined consent for random assignment were offered a prospective observational patient choice pathway. The primary outcome was the number of days alive and out of the hospital (good days) at 91 days. Analyses were based on intention-to-treat linear, logistic, and Cox regression models combining data from both pathways and adjusting for potential confounders. Treatment complications were assessed in all analysed patients in the study. This completed study is registered with ClinicalTrials.gov, NCT02270450. FINDINGS: From May 11, 2015, to April 27, 2020, 221 patients were enrolled (143 [65%] were female and 78 [35%] were male). There were 199 evaluable participants: 49 in the randomised pathway (24 surgery and 25 non-surgery) and 150 in the patient choice pathway (58 surgery and 92 non-surgery). No difference was seen between surgery and non-surgery for the primary outcome of good days: mean 42·6 days (SD 32·2) in the randomised surgery group, 43·9 days (29·5) in the randomised non-surgery group, 54·8 days (27·0) in the patient choice surgery group, and 52·7 days (30·7) in the patient choice non-surgery group (adjusted mean difference 2·9 additional good days in surgical versus non-surgical treatment [95% CI -5·5 to 11·3]; p=0·50). During their initial hospital stay, six participants died, five due to cancer progression (four patients from the randomised pathway, two in each treatment group, and one from the patient choice pathway, in the surgery group) and one due to malignant bowel obstruction treatment complications (patient choice pathway, non-surgery). The most common grade 3-4 malignant bowel obstruction treatment complication was anaemia (three [6%] patients in the randomised pathway, all in the surgical group, and five [3%] patients in the patient choice pathway, four in the surgical group and one in the non-surgical group). INTERPRETATION: In our study, whether patients received a surgical or non-surgical treatment approach did not influence good days during the first 91 days after registration. These findings should inform treatment decisions for patients hospitalised with malignant bowel obstruction. FUNDING: Agency for Healthcare Research and Quality and the National Cancer Institute. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Comprehensive genetic analyses of childhood acute leukemia in Iraq using next-generation sequencing.

Background: Molecular analyses in hematological malignancies provide insights about genetic makeup. Probable etiological factors in leukemogenesis could also be disclosed. Since genetic analyses are still primitive in Iraq, a country of repeated wars, we conceived of performing next-generation sequencing (NGS), to disclose the genomic landscape of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) among a cohort of Iraqi children. Methods: Dried blood samples were collected from Iraqi children with ALL (n=55), or AML (n=11), and transferred to Japan where NGS was done. Whole-exome, whole-genome, and targeted gene sequencings were performed. Results: Somatic point mutations and the copy number variations among Iraqi children with acute leukemia were comparable with those in other countries, and cytosine-to-thymine nucleotide alterations were dominant. Strikingly, TCF3-PBX1 was the most recurrent fusion gene (22.4%) in B-cell precursor ALL (B-ALL), and acute promyelocytic leukemia (AML-M3) was subtyped in 5 AML cases. Additionally, a high frequency of RAS signaling pathway mutations was detected in children with B-ALL (38.8%), along with 3 AML cases that carried oncogenic RAS. Conclusions: Apart from disclosing the high frequency of TCF3-PBX1, NGS confirmed our previous finding of recurrent RAS mutations in Iraqi childhood acute leukemia. Our results suggest that the biology of Iraqi childhood acute leukemia is in part characteristic, where the war-aftermath environment or geography might play a role.

Continuous manual agitation significantly improves temperature distribution during closed hyperthermic intraperitoneal chemotherapy: Results of a porcine model.

BACKGROUND: Debate persists regarding the need for shaking during hyperthermic intraperitoneal chemotherapy. Studies assessing the thermal behaviors of the perfusate throughout the abdomen during hyperthermic intraperitoneal chemotherapy are limited. METHODS: A closed hyperthermic intraperitoneal chemotherapy technique was performed in an institutional International Animal Care and Use Committee approved porcine model targeting a 41°C outflow temperature. Continuous temperature monitoring was conducted. Abdominal shaking was performed for 60 second intervals and temperatures were allowed to equilibrate without shaking between intervals. Temperature distributions and changes due to shaking were evaluated. These findings were validated against human subjects' data. RESULTS: The experimental procedure was conducted in 2 different animals and with 6 total shaking intervals assessed. Without shaking, temperatures were highly variable ranging between 38.0 to 42.2°C. Shaking the abdomen reduced the mean range of temperatures across all locations observed from 3.9°C to 0.8°C (P < .01). The locations of the most divergent temperatures varied based on perfusion cannula position. The point of minimum temperature heterogeneity was achieved in 28.3 (19.1-37.5) seconds. After shaking stopped, heterogeneity equal to the baseline measurements was seen on average within 25.7 (13.3-38.0) seconds. The outflow catheter differed from the system mean temperature by 1.4°C and from the coldest-reading probe by 2.8°C and outperformed the inflow catheter for all time points. With shaking these were significantly reduced to 0.4°C (P < .01) and 0.6°C (P < .01). The patient data mirrored that of the pig data. CONCLUSION: Shaking significantly reduces temperature variability within the abdomen during hyperthermic intraperitoneal chemotherapy, and significantly improves the ability of the outflow catheter to estimate internal temperatures.

System Modularity Chip for Analysis of Rare Targets (SMART-Chip): Liquid Biopsy Samples.

Liquid biopsies are becoming popular for managing a variety of diseases due to the minimally invasive nature of their acquisition, thus potentially providing better outcomes for patients. Circulating tumor cells (CTCs) are among the many different biomarkers secured from a liquid biopsy, and a number of efficient platforms for their isolation and enrichment from blood have been reported. However, many of these platforms require manual sample handling, which can generate difficulties when translating CTC assays into the clinic due to potential sample loss, contamination, and the need for highly specialized operators. We report a system modularity chip for the analysis of rare targets (SMART-Chip) composed of three task-specific modules that can fully automate processing of CTCs. The modules were used for affinity selection of the CTCs from peripheral blood with subsequent photorelease, simultaneous counting, and viability determinations of the CTCs and staining/imaging of the CTCs for immunophenotyping. The modules were interconnected to a fluidic motherboard populated with valves, interconnects, pneumatic control channels, and a fluidic network. The SMART-Chip components were made from thermoplastics via microreplication, which lowers the cost of production making it amenable to clinical implementation. The utility of the SMART-Chip was demonstrated by processing blood samples secured from colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) patients. We were able to affinity-select EpCAM expressing CTCs with high purity (0-3 white blood cells/mL of blood), enumerate the selected cells, determine their viability, and immunophenotype the cells. The assay could be completed in <4 h, while manual processing required >8 h.

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Intellectual Equipoise and Challenges: Accruing Patients With Advanced Cancer to a Trial Randomizing to Surgical or Nonsurgical Management (SWOG S1316).

BACKGROUND: Prospective, randomized trials are needed to determine optimal treatment approaches for palliative care problems such as malignant bowel obstruction (MBO). Randomization poses unique issues for such studies, especially with divergent treatment approaches and varying levels of equipoise. We report our experience accruing randomized patients to the Prospective Comparative Effectiveness Trial for Malignant Bowel Obstruction (SWOG S1316) study, comparing surgical and nonsurgical management of MBO. METHODS: Patients with MBO who were surgical candidates and had treatment equipoise were accrued and offered randomization to surgical or nonsurgical management. Patients choosing nonrandomization were offered prospective observation. Trial details are listed on www.clinicaltrials.gov (NCT #02270450). An accrual algorithm was developed to enhance enrollment. RESULTS: Accrual is ongoing with 176 patients enrolled. Most (89%) patients chose nonrandomization, opting for nonsurgical management. Of 25 sites that have accrued to this study, 6 enrolled patients on the randomization arm. Approximately 59% (20/34) of the randomization accrual goal has been achieved. Patient-related factors and clinician bias have been the most prevalent reasons for lack of randomization. An algorithm was developed from clinician experience to aid randomization. Using principles in this tool, repeated physician conversations discussing treatment options and goals of care, and a supportive team-approach has helped increase accrual. CONCLUSIONS: Experience gained from the S1316 study can aid future palliative care trials. Although difficult, it is possible to randomize patients to palliative studies by giving clinicians clear recommendations utilizing an algorithm of conversation, allotment of necessary time to discuss the trial, and encouragement to overcome internal bias.

Follicular dendritic cells display microvesicle-associated LMP1 in reactive germinal centers of EBV+ classic Hodgkin lymphoma.

Expression of the latent membrane protein-1 (LMP1) of Epstein-Barr virus (EBV) was investigated in 153 cases of EBV+ classic Hodgkin lymphoma (cHL); 120 cases were pediatric patients (< 14 years of age) from Iraq, and 33 cases were adult patients from Italy. We describe for the first time the presence of LMP1 protein in EBV-encoded RNA (EBER)-negative follicular dendritic cells (FDCs) of reactive germinal centers (GC) associated with EBV+ cHL. Presence of LMP1+ GCs was independent of geographic region and age of patients. Variable numbers of reactive GCs were present in 22.2% of cases (34 of 153), whereas LMP1 staining of FDCs was present in about a third of cases (10 of 34) with reactive GC. Most cases with LMP1+ GC were mixed-cellularity (MC) subtype, but some nodular sclerosis (NS) was also present. GC cells with LMP1+ FDCs were surrounded by numerous EBV-infected cells which were positive for EBER, LMP1, and CD30. Double immunolocalization analysis revealed that LMP1 was associated with CD63, an exosomal marker, and with CD21. The possibility is discussed that peri-follicular EBV-infected cells release LMP1 protein, perhaps through exosomes, and that the protein is then captured by FDCs and is presented to EBER-negative GC B cells.

Burkitt lymphoma in Iraqi children: A distinctive form of sporadic disease with high incidence of EBV+ cases and more frequent expression of MUM1/IRF4 protein in cases with head and neck presentation.

Epstein-Barr virus (EBV)-related lymphoproliferative disorders are relatively common in Iraqi children. Burkitt lymphoma (BL) accounted for 40% of lymphoma cases. The mean age of 125 BL cases was 5.9 ± 3.1 years, and the male-to-female ratio was 3.6:1. Clinical presentation was abdominal in 66% and head and neck in 34%. Bone marrow involvement was higher (P < 0.001) in children with head and neck disease. Tumor cells had MYC translocation (96%) and were CD20+ /CD10+ /MYC+ /BCL2- . MUM1/IRF4 staining was expressed by a fraction of tumor cells in 19 of 125 cases (15%) and was more frequent (P < 0.007) in head and neck disease (12/42; 29%). EBV-encoded RNA was positive in 100 of 125 (80%) BL cases.

Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.

BACKGROUND: Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population. METHODS: Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled. RESULTS: Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months). CONCLUSIONS: These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.

Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.

Pediatric Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare disease in nonimmunocompromised hosts. In a review of 231 cases of malignant lymphoma (87 Hodgkin lymphoma and 144 non-Hodgkin lymphoma) occurring in Iraqi children, 7 cases (5% of NHLs) were classified as EBV+ DLBCL. Six children presented with nodal disease, and 1 presented with extranodal localization (bone). In all cases, the disease was at an advanced clinical stage (III/IV). Evidence of immunodeficiency (Evans syndrome and selective IgA deficiency) was observed in a single case. Two cases were "monomorphic" with immunoblastic histology, and 5 cases were "polymorphic" with histologic aspects reminiscent of nodular lymphocyte-predominant Hodgkin lymphoma (2 cases) and of CD30+ classical Hodgkin lymphoma (3 cases). In all cases, tumor cells were EBV infected (EBER+/LMP-1+), were medium-large B-cells (CD20+/CD79a+/PAX-5+/BOB-1+/OCT-2+) of non-germinal center (non-GC) origin (CD10-/MUM-1+), and had high proliferative activity (50%-70%). Chromosomal translocations involving BCL2, MYC, and IGH genes were not observed. IGH monoclonality could be demonstrated in 3 of 3 investigated cases. Six cases of EBV-negative DLBCL (4% of NHL) were present in the same series. All had monomorphic histology with centroblastic/immunoblastic morphology; 3 cases were of GC type and 3 of non-GC type. Our findings indicate that in Iraq, DLBCLs are 9% of NHLs. Moreover, 2 different types of the disease do exist; the EBV-positive cases, with strong histologic and immunohistochemical resemblance with EBV+ DLBCL of the elderly, and the EBV-negative cases, which are similar to the pediatric DLBCL usually observed in Western populations.

Epstein-Barr virus (EBV) positive classical Hodgkin lymphoma of Iraqi children: an immunophenotypic and molecular characterization of Hodgkin/Reed-Sternberg cells.

BACKGROUND: Classical Hodgkin lymphoma (cHL) in children is often associated with EBV infection, more commonly in developing countries. PROCEDURE: Here we describe the histological, immunohistochemical, and molecular features of 57 cases of HL affecting Iraqi children under 14 years of age. RESULTS: Histologically, 51 cases were classified as cHL of Mixed Cellularity and Nodular Sclerosis subtypes (MC = 69%; NS = 31%), and 6 cases as Nodular Lymphocyte Predominant HL (NLP-HL). EBV infection of H/RS cells was demonstrated in 44 of 51 cases of cHL (86%), and was more common in MC than in NS (97% vs. 63%; P = 0.0025). The immunophenotypic profile of H/RS cells was similar in MC and NS, and was not influenced by EBV infection; H/RS cells were consistently positive for PAX-5 and to a lesser degree for other B cell markers including CD20/CD79a, OCT-2, and BOB-1. Clonal IGH rearrangements were detected in 14 of 38 cHL (37%), with no significant difference between MC and NS cases, and with no association with the EBV status. Oligoclonal/monoclonal TCRγ rearrangements were present in 28 of 38 cases (74%), suggestive of restricted T cell responses. CONCLUSIONS: Our findings indicate that cHL occurring in Iraqi children is characterized by immunohistochemical and molecular features undistinguishable from those present in cHL occurring elsewhere in the world. Moreover, the high incidence of EBV-infected H/RS cells and frequent occurrence of restricted T cell responses might be indicative of a defective local immune response perhaps related to the very young age of the children.

Preclinical antitumor activity of a nanoparticulate SN38.

The present studies were carried out to examine the efficacy of a nanoparticulate formulation of SN38, the potent topoisomerase I inhibitor and active metabolite of irinotecan. Metabolism of irinotecan to SN38 is inefficient and subject to considerable patient-to-patient variability. One approach to more controlled administration of the anticancer agent is direct administration of the active SN38. A nanoparticulate formulation of SN38 was prepared by a method of precipitation with compressed antisolvent. Nanoparticulate SN38 efficiently inhibited the proliferation of colorectal, ovarian, and mesothelial cancer cell lines in vitro. Concentrations resulting in 50 % inhibition of proliferation were approximately 1000 fold lower for nanoparticulate SN38 compared to irinotecan. In vivo effects were examined using colorectal and ovarian mouse model systems. In a mouse model of peritoneally disseminated ovarian cancer intraperitoneal administration of irinotecan was favorable to intravenous delivery however intraperitoneal delivery of nanoparticulate SN38 was significantly more effective than intraperitoneal irinotecan. In addition, in a mouse colorectal cancer model administration of nanoparticulate SN38 once weekly exhibited greater activity compared to daily or weekly administration of irinotecan. Additional studies demonstrated nanoparticulate SN38 administered as a combination therapy with mitomycin C was more effective than the combination of irinotecan and mitomycin C. Results from the present studies using preclinical colorectal and ovarian cancer model systems demonstrate the efficacy of nanoparticulate SN38 and substantiate continued development.

Combination intraperitoneal chemotherapy is superior to mitomycin C or oxaliplatin for colorectal carcinomatosis in vivo.

BACKGROUND: Hyperthermic intraperitoneal (IP) chemotherapy after cytoreduction improves survival in patients with colorectal carcinomatosis of the peritoneal surface. Most protocols use single agents (mitomycin C or oxaliplatin) provided IP. The purpose of this study was to determine whether combination IP chemotherapy is superior to single-agent therapy in a mouse model. METHODS: Nu/Nu mice were injected IP with HT-29 colorectal cancer cells. Animals were treated with single agents or combinations. Primary end point was overall survival. Agents explored included oxaliplatin, mitomycin C, panitumumab, erlotinib, cetuximab, and irinotecan delivered IP as single agents; mitomycin C, panitumumab, and irinotecan in combination IP; and 5-fluorouracil-leucovorin-irinotecan (FOLFIRI) in combination delivered intravenously. RESULTS: Survival of mice receiving irinotecan or mitomycin C IP was greater than controls. Median survival of mice receiving intravenous FOLFIRI was also greater than control. However, survival of mice receiving IP irinotecan or mitomycin C was far greater than mice receiving intravenous FOLFIRI. For combination therapy, a positive interaction was observed with mitomycin C and irinotecan, whereas survival was greater than either agent individually. No interaction was observed between panitumumab and mitomycin C or irinotecan. However, an overall survival benefit was observed with the combination of irinotecan, mitomycin C, and panitumumab; at 120 days after cell injection, 100% of the triagent therapy group survived. CONCLUSIONS: IP therapy with mitomycin C or irinotecan provided a survival benefit compared with intravenous FOLFIRI. Combination IP therapy with mitomycin C, panitumumab, and irinotecan was superior to all other agents tested alone or in combination. This warrants further combination analysis and supports consideration for a phase I application.

Utility of frozen-section analysis of sentinel lymph node biopsy specimens for melanoma in surgical decision making.

BACKGROUND: Debate exists whether frozen-section analysis of sentinel lymph nodes (SLNs) for melanoma is an accurate method to detect disease that has metastasized to the lymph nodes. The purpose of this study was to evaluate the utility of intraoperative frozen section for SLNs in melanoma. METHODS: We reviewed 133 patients (271 nodes) who underwent SLN biopsy with frozen section for melanoma between April 2003 and September 2007. Frozen-section diagnosis was compared with final diagnosis to determine concordance between intraoperative and postsurgical diagnosis. RESULTS: A total of 11 nodes (8% of patients) were found to have metastatic disease. All patients underwent lymph node dissections at the time of SLN biopsy. No false-positive SLNs were found on frozen section. The false-negative rate for SLN biopsy frozen section was 8% (1 of 133 patients). CONCLUSIONS: Intraoperative frozen section can be an accurate and reliable tool in the right setting for analysis of sentinel nodes in cutaneous melanoma and deserves further study.

Bronchogenic cyst presenting as a symptomatic neck mass in an adult: case report and review of the literature.

We report the unusual clinical manifestation and subsequent management of a symptomatic congenital bronchogenic cyst that connected to the trachea and presented in the neck of an adult. The embryology, clinical presentation, diagnostic evaluation, and management options of this rare aberration are discussed.

High-grade dysplasia within Barrett's esophagus: controversies regarding clinical opinions and approaches.

Barrett's esophagus with high-grade dysplasia is a well-known risk factor for the development of esophageal adenocarcinoma, which has become the predominant form of esophageal cancer in the United States. This review addresses four major fundamental issues that shape our treatment decisions regarding high-grade dysplasia within Barrett's esophagus: (1) the poorly defined natural history of high-grade dysplasia in its progression to adenocarcinoma, (2) the potentially high morbidity and mortality of esophageal resection for high-grade dysplasia, (3) the difficulty in detecting cancer among dysplastic cells during endoscopy, and (4) the controversial role of endoscopic mucosal ablative therapy for high-grade dysplasia. Until there are more accurate surveillance methods, better biochemical or molecular markers in predicting cancerous progression, or more effective minimally invasive methods of treatment, esophagogastrectomy must be considered the standard means of managing patients with Barrett's esophagus and high-grade dysplasia. Regular rigorous systematic surveillance and endoscopic mucosal ablation are alternative treatment options that are available but should be used only under strict conditions. The decision to proceed in a certain direction is quite complex and challenging and ideally requires the feedback of patients who are properly educated about the controversies surrounding this disease.