Safety and efficacy of post-haematopoietic cell transplantation maintenance therapy with blinatumomab for relapsed/refractory CD19-positive B-cell acute lymphoblastic leukaemia: protocol for a phase I-II, multicentre, non-blinded, non-controlled trial (JPLSG SCT-ALL-BLIN21).

INTRODUCTION: Relapsed and refractory B-cell acute lymphoblastic leukaemia (R/R-B-ALL) is linked to a significant relapse rate after allogeneic haematopoietic cell transplantation (allo-HCT) in children, adolescents and young adults (CAYA). No standard treatment has been established to prevent relapse after allo-HCT for R/R-B-ALL, which is an unmet medical need. The administration of blinatumomab after allo-HCT is expected to enhance the antileukaemic effect on residual CD19-positive blasts by donor-derived CD3-positive T-cells. METHODS AND ANALYSIS: The goal of this multicentre, open-label, uncontrolled, phase I-II clinical trial is to assess the safety and effectiveness of post-transplant maintenance therapy with blinatumomab for CAYA patients (25 years old or younger) with CD19-positive R/R-B-ALL who have received allo-HCT beyond first complete remission (CR) and have CR with haematological recovery between 30 and 100 days after allo-HCT. Eighty-five paediatric institutions in Japan are participating in this study. Forty-one patients will enrol within 2.25-year enrolment period and follow-up period is 1 year. The primary endpoints are the treatment completion rate for phase I study and the 1-year graft-versus-host disease-free/relapse-free survival rate for phase II study, respectively. ETHICS AND DISSEMINATION: This research was approved by the Central Review Board at National Hospital Organization Nagoya Medical Center (Nagoya, Japan) on 21 January 2022 and was registered at the Japan Registry of Clinical Trials (jRCT) on 3 March 2022. Written informed consent is obtained from all patients and/or their guardians. The results of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: jRCTs041210154.

Management of Malignant Colon Polyps.

CASE SUMMARY: A 54-year-old otherwise healthy woman presented for screening colonoscopy, during which 4 pedunculated 5- to 12-mm polyps distributed throughout the colon were found (Fig. 1). The 12-mm sigmoid polyp was removed with hot snare polypectomy in a nonpiecemeal fashion. Pathology demonstrated 3 tubular adenomas and a poorly differentiated invasive carcinoma in a sigmoid polyp without tumor budding, invading 0.8 mm into the submucosa, with lymphovascular invasion and with a deep margin of 0.6 mm. The next week, she underwent repeat flexible sigmoidoscopy with tattooing of the polypectomy site. She had a normal staging CT chest/abdomen/pelvis as well as CEA level and later underwent uneventful laparoscopic sigmoid resection, which included the area of endoscopic tattoo. Final pathology confirmed the presence of the tattooed area and polypectomy scar and showed no residual primary tumor and 2/18 positive lymph nodes (Fig, 2). She was referred to medical oncology for adjuvant chemotherapy.

SARS-CoV-2 Infection During Induction Chemotherapy in a Child With High-risk T-Cell Acute Lymphoblastic Leukemia.

The clinical course of SARS-CoV-2 infection (COVID-19) in children with hematologic malignancies is unclear. We describe the diagnosis, treatment and outcome of a 4-year-old boy with high-risk acute lymphoblastic leukemia and COVID-19. Regardless of immunosuppressive induction chemotherapy his symptoms remained moderate. He received only supportive treatment. Seroconversion occurred in a similar period as in immunocompetent adults. Despite prolonged myelosuppression he did neither acquire secondary infections nor did the treatment delay caused by the infection have a measurable negative impact on the residual disease of acute lymphoblastic leukemia. Intriguingly, residual leukemia even decreased even though he did not receive any antileukemic therapy.

Evolution in the management of chronic lymphocytic leukemia in Japan: should MRD negativity be the goal?

Advances in the molecular biology of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and development of molecularly targeted therapies have resulted in treatment innovations. Therapeutic approaches for previously untreated CLL/SLL patients are changing from chemoimmunotherapy (CIT) to molecularly targeted drugs. The aim of therapy for CLL patients has been to control the disease; however, FCR (fludarabine, cyclophosphamide, rituximab) has improved outcomes and reduced the high incidence of undetectable minimum/measurable residual disease (MRD) in previously untreated CLL patients with no 17p deletion/TP53 disruption and mutated immunoglobulin heavy chain gene (IGHV). Patients achieving undetectable MRD in the bone marrow are expected to be cured. BTK inhibitors and BCL-2 inhibitors are effective for CLL/SLL patients. However, atrial fibrillation and bleeding are associated with the BTK inhibitor, ibrutinib, while tumor lysis syndrome is an adverse event (AE) of the BCL-2 inhibitor, venetoclax. Although these novel targeted drugs are very useful, they are also expensive. Emergence of resistant clones of CLL cells must also be addressed. Therefore, treatments of indefinite duration until progression have been replaced by fixed-duration treatments. This review introduces advances in the treatment of previously untreated CLL/SLL patients in Europe and the United States.

Latest treatment strategies aiming for a cure in transplant-eligible multiple myeloma patients: how I cure younger MM patients with lower cost.

This article presents a practical overview of the treatment of younger, newly diagnosed multiple myeloma patients, focusing on novel treatment strategies. With the introduction of effective new agents, multiple myeloma is one of the most active and changing fields in clinical oncology. In addition, monitoring technology has become reliable and practical. Achieving and sustaining minimal residual disease negativity (MRD- ), such as multiparameter flow cytometry (MFC) < 10-5, is one of the goals of therapy. MRD- is significantly associated with prolonged progression-free survival, whereas MRD persistence (MRD +) is an independent factor for poor progression-free survival. Evidence from several recent studies evaluating modern therapy has further supported the positive correlation between depth of response and outcomes. Multiple myeloma can become a chronic illness with sustained MRD- in a significant number of patients. Our ultimate hope is to leverage tumoricidal-immunomodulatory sequential therapies and to cure a subset of our patients.

Use of the KTP laser in totally endoscopic cholesteatoma surgery.

OBJECTIVE: This paper reviews our experience of potassium titanyl phosphate (KTP) laser in transcanal totally endoscopic cholesteatoma surgery. METHODS: A prospective cohort study was conducted in a tertiary referral centre, involving a consecutive series of children with cholesteatoma who underwent totally endoscopic cholesteatoma surgery with a KTP laser. RESULTS: The patients' mean age was 10.5 years (range, 1.8-18 years). A KTP laser was used in 70 of the 83 cases (84 per cent). The laser was not used in 13 'clean' cases, in which disease was removed more easily. Residual disease was detected in five cases (6 per cent), of which the KTP laser had been used in four (5 per cent). No complications were associated with KTP laser use. CONCLUSION: The combination of KTP laser use with endoscopic visualisation is effective for minimising the risk of residual disease using a minimally invasive surgical approach. The thin, semi-flexible fibre carrier of the KTP laser is ideally suited to work alongside the endoscope within the narrow confines of the ear canal.

Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.

Immunotherapy for acute myeloid leukemia: from allogeneic stem cell transplant to novel therapeutics.

Immunotherapy in the form of allogeneic stem cell transplantation (SCT) plays an instrumental role in the treatment of acute myeloid leukemia (AML), with non-transplant modalities of immunotherapy including checkpoint blockade now being actively explored. Here, we provide an overview of the graft versus leukemia (GVL) effect in AML as a window into understanding the prospects of AML immunotherapy. We explore the roles of various cell types in orchestrating anti-leukemic immunity, as well as those contributing to the unique immune suppressive state of myeloid diseases. We discuss specific approaches to engage the immune system, while noting the challenges of the AML antigen landscape and the barriers to immune modulation. We review the potential for immunomodulatory agents in combination with cellular therapies, donor lymphocyte infusion, and following SCT. Finally, to address the challenge of minimal residual disease (MRD) following chemotherapy, we propose combination epigenetic and immunotherapy for the eradication of MRD.

Is endoscopic inspection necessary to detect residual disease in acoustic neuroma surgery?

MAIN GOALS: To analyze how and when the endoscope is used in vestibular schwannoma surgery and identify the benefits of using endoscopy in this type of surgery. BACKGROUND: It is currently unclear if there is any benefit from using an endoscope in vestibular schwannoma surgery so this retrospective analysis set out to study this. METHODS: All the patients who underwent vestibular schwannoma surgery at our clinic were included for all the vestibular schwannoma approaches taken. We studied when endoscopy was used during surgery and the goal of using endoscopy. Several pre- and postoperative factors were assessed such as complications, facial function, and hearing function in the case of techniques that allow hearing preservation. RESULTS: From January 2015 to September 2018, 280 patients underwent lateral skull base surgery. Of these, 112 were included in this study. The endoscope was used in all 112 patients, and in eight cases it was possible to identify residual disease using the endoscope to check the surgical field, and then to remove the disease under endoscopic view. Moreover, in two other cases, the endoscope was used to resolve a vasculoneural conflict between the anterior inferior cerebellar artery (AICA) loop and facial nerve in one case, and for deafferentation of the superior and inferior vestibular nerves in the second case. No major intraoperative complications occurred in our series. There was no statistically significant difference in postoperative facial nerve function between patients in whom the endoscope was used as a diagnostic tool and patients in whom it was used as an operative tool (p = 0.3152). CONCLUSIONS: The endoscope may be useful, especially in surgical techniques where there is poor control of the internal auditory canal (IAC). An endoscopic support technique is strongly recommended to avoid residual disease, particularly in retrosigmoid and retrolabyrinthine approaches. Moreover, the recent introduction of the transcanal transpromontorial approach allows the endoscope to be used during all the procedures in patients affected by a vestibular schwannoma limited to the IAC or to support surgical procedures during an enlarged microscopic approach.

Location of infantile hemangioma is a predictor of volumetric sequelae after involution.

Although infantile hemangiomas (IH) spontaneously involute, some leave more volumetric sequelae than others. Identifying predictors of such sequelae would provide a management reference for IH lesions and help achieve favorable outcomes. Our objective is to explore the correlation between volumetric residue remaining after IH involution and its location and to identify other potential outcome predictors. All IH patients examined at our hospital from 2008 to 2011 were reviewed, and both the degree of volumetric residue after involution and the quantified degree of sequelae were obtained by comparing follow-up photographs with photographs of lesions at their maximum size. We discovered that for children with a defined age at the initial visit, lesions of the perifacial area achieved significantly more volumetric regression than lesions of the central facial (P < 0.0001) and chest areas (P = 0.0002). Perifacial lesions had a significantly higher aesthetic score than those on the central facial area (P < 0.0001), chest (P < 0.0001) and trunk/extremities (P = 0.0226) when the age at initial visit and lesion type were consistent. Our study reveals that lesion location and age at initial visit are contributing factors to volumetric sequelae and the aesthetics of the lesion after involution. The results of this study provide a reference to guide treatment decisions with the aim of achieving a favorable outcome.

TWENTY-YEAR EXPERIENCE WITH LARGE LOOP EXCISION OF THE TRANSFORMATION ZONE AT SESTRE MILOSRDNICE UNIVERSITY HOSPITAL CENTRE.

The 20-year experience with large loop excision of the transformation zone (LLETZ) at Gynecologic Oncology Unit, Department of Gynecology and Obstetrics, Sestre milosrdnice University Hospital Centre from Zagreb is presented. This retrospective observational study included 1407 women with cervical dysplasia treated by LLETZ technique during the 1995-2016 period. LLETZ was most commonly performed in the 25-35 age group (51%), followed by the 36-45 age group (22%), and least frequently in the >65 age group (2%). Histopathologic results lower than high-grade squamous intraepithelial lesion were found in 23% and high grade squamous intraepithelial lesion or worse findings in 77% of patients. Positive margin as a sign of possible residual dysplasia was found in 25% of cones, 80% of which included endocervical positive margin. Cervical canal biopsy result was positive in 18% of cases. Accurate colposcopy and its findings can help avoid overtreatment, the rate of which was higher than expected in our retrospective study. Long-term follow up is an imperative for proper assessment of the procedure success. This method is the best choice for complete disease removal without unnecessary overtreatment, but it requires continuous education and training of the whole team.

The consensus on the monitoring, treatment, and prevention of leukemia relapse after allogeneic hematopoietic stem cell transplantation in China.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative therapy for patients with leukemia. However, relapse remains the leading cause of death after transplantation. In recent years, substantial progress has been made by Chinese physicians in the field of establishment of novel transplant modality, patient selection, minimal residual disease (MRD) monitoring, and immunological therapies, such as modified donor lymphocyte infusion (DLI) and chimeric antigen receptor T (CART) cells, as well as MRD-directed intervention for relapse. Most of these unique systems are distinct from those in the Western world. In this consensus, we reviewed the efficacy of post-HSCT relapse management practice from available Chinese studies on behalf of the HSCT workgroup of the Chinese Society of Hematology, Chinese Medical Association, and compared these studies withthe consensus or guidelines outside China. We summarized the consensus on routine practices of post-HSCT relapse management in China and focused on the recommendations of MRD monitoring, risk stratification directed strategies, and modified DLI system. This consensus will likely contribute to the standardization of post-HSCT relapse management in China and become an inspiration for further international cooperation to refine global practices.

Radiographically guided shave margins may reduce lumpectomy re-excision rates.

Minimizing margin re-excision optimizes patient care by providing appropriate oncologic resection and reducing costs. This study aims to assess margin positivity rate in two groups: shave margin based on gross specimen (control group, CG) vs shave margin based on intraoperative imaging (radiographic group, RG). A total of 182 patients who underwent lumpectomy for stage O-III breast cancer at a single institution from January 2013 to January 2014 were evaluated. There was statistically significant decrease in margin re-excision rate with intraoperative mammography but not with ultrasound. Surgeons are ideally equipped to use intraoperative imaging to guide margin excision, thus, improving care and reducing costs.

Review of Novel Sentinel Lymph Node Biopsy Techniques in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy.

Breast cancer patients who present with nodal metastasis receive neoadjuvant chemotherapy (NAC) with increasing frequency and can have complete pathologic response after treatment. In this clinical scenario, sentinel node mapping and biopsy are gaining acceptance instead of axillary dissection to avoid morbidity. Biopsy proven positive lymph nodes must be reliably excised and examined after NAC to further decrease the false negativity rate of sentinel lymph node (SLN) surgery. The standard method for axillary staging in breast cancer patients even after NAC is SLN biopsy (SLNB) with a radioisotope, blue dye, or both (dual technique). Currently, preoperative axillary staging with ultrasound and biopsy, along with placement of an image-detectable marker to be removed at the time of definitive surgery is recommended. In this study, we evaluated some methods of SLNB for patients treated with NAC like indocyanine green fluorescence, superparamagnetic iron oxide nanoparticles, indigocarmine blue dye, contrast-enhanced ultrasound using microbubbles, and tattooing. Some methods are also needed to ensure that the initially biopsy proven positive node is removed at the time of surgery to be carefully evaluated for residual disease after chemotherapy like clip placement to the suspected or involved nodes before NAC, and removing the clipped node with the guidance of 125I-labeled radioactive seed or guide wires.

Factors Associated With Positive Margins in Women Undergoing Breast Conservation Surgery.

OBJECTIVE: To identify factors predicting positive margins at lumpectomy prompting intraoperative reexcision in patients with breast cancer treated at a large referral center. PATIENTS AND METHODS: We reviewed all breast cancer lumpectomy cases managed at our institution from January 1, 2012, through December 31, 2013. Associations between rates of positive margin and patient and tumor factors were assessed using χ2 tests and univariate and adjusted multivariate logistic regression, stratified by ductal carcinoma in situ (DCIS) or invasive cancer. RESULTS: We identified 382 patients who underwent lumpectomy for definitive surgical resection of breast cancer, 102 for DCIS and 280 for invasive cancer. Overall, 234 patients (61.3%) required intraoperative reexcision for positive margins. The reexcision rate was higher in patients with DCIS than in those with invasive disease (78.4% [80 of 102] vs 56.4% [158 of 280]; univariate odds ratio, 2.80; 95% CI, 1.66-4.76; P<.001). Positive margin rates did not vary by patient age, surgeon, estrogen receptor, progesterone receptor, or ERBB2 status of the tumor. Among the 280 cases of invasive breast cancer, the only factor independently associated with lower odds of margin positivity was seed localization vs no localization (P=.03). CONCLUSION: Ductal carcinoma in situ was associated with a higher rate of positive margins at lumpectomy than invasive breast cancer on univariate analysis. Within invasive disease, seed localization was associated with lower rates of margin positivity.

Indications for morcellation in gynecologic surgery.

PURPOSE OF REVIEW: Minimally invasive gynecologic procedures, in particular laparoscopic hysterectomy and myomectomy, often require tissue morcellation. RECENT FINDINGS: Whether morcellated or not, myometrial cells can be found in the abdomen and pelvis after either laparoscopic or open myomectomy. Following morcellation, careful inspection for and removal of tissue fragments and copious irrigation and suctioning of fluid can remove residual tissue and cells without the use of containment bags. The dogma of not 'cutting-through' cancer is not correct for many surgical specialties and irrelevant with regards to leiomyosarcoma (LMS) and minimally invasive gynecologic surgery. Eliminating residual disease in the pelvis and abdomen should be the goal of myomectomy or hysterectomy. SUMMARY: Morcellation of excised tissue is necessary for many women with symptomatic fibroids who choose to undergo laparoscopic myomectomy or hysterectomy. LMS is an uncommon disease, with a poor prognosis due to early hematogenous metastasis to lung, bone and liver. Preoperatively, it is often difficult to differentiate from benign fibroids. LMS has a high propensity for local recurrence despite performance of total hysterectomy. Efforts to remove all tissue and cells from the pelvis and abdomen should be the goal of minimally invasive surgery with morcellation.

[Endoscopic tattooing of colorectal neoplasms and laparoscopic surgery: technical aspects and recommendations]. / Éndoskopicheskii tatuazh obrazovanii tolstoi kishki i laparoskopicheskaia khirurgiia. Tekhnicheskie aspekty i rekomendatsii.

Accurate mapping of colorectal neoplasms is needed in many clinical situations. Intraoperative mapping of small lesions previously detected by endoscopy is often challenging, especially during laparoscopic surgery. Tumor location assessed during colonoscopy may be inaccurate because of limitations of the procedure. Small flat neoplasms with signs of invasiveness, which are hard to detect by palpation, hold a special place. The same situation is observed for nonradical endoscopic resection of malignant polyps or early cancer, when visual examination shows that the tumor masses have been completely resected but histological examination reveals the positive lateral or horizontal resection margin. Endoscopic tattooing is an effective, safe, and economically sound method to mark intraluminal colorectal neoplasms, which allows one to perform minimally invasive surgeries without using additional operating room resources.