Tension-free thyroidectomy (medial thyroidectomy)-a prospective study: surgical technique and results of 259 operations.

Background: Thyroid surgery is associated with a number of surgical complications including recurrent laryngeal nerve (RLN) injury and hypoparathyroidism. The existing methods share the same principle-the mobilization of the thyroid from the lateral side. The aim of this study was to evaluate the safety of a novel technique of thyroidectomy-tension-free thyroidectomy (TFT) based on the medial approach to the laryngeal nerves and parathyroid glands (PTGs). Methods: The study was conducted between August 2021 and July 2022 in Saint Petersburg State University Hospital. A total of 261 patients with thyroid diseases were enrolled in the study and operated on using the TFT technique. Results: The operations with the use of TFT technique were completed in all but two cases which required the conversion to the standard lateral approach. Of 259 TFT cases unilateral laryngeal paresis was registered in 6 (2.3%) cases or in 1.7% of the number of RLNs at risk. In all but one case the vocal fold function recovered in less than 6 months of the follow-up. Among 87 patients who underwent total thyroidectomy transient postoperative hypoparathyroidism was found in 10 cases (11.5%), rate of persistent hypoparathyroidism was 0%. One case of postoperative bleeding was recorded (0.4%). Conclusions: The TFT technique demonstrated high safety and several advantages over the traditional method of performing operations on the thyroid gland.

Targeting MCL-1 protein to treat cancer: opportunities and challenges.

Evading apoptosis has been linked to tumor development and chemoresistance. One mechanism for this evasion is the overexpression of prosurvival B-cell lymphoma-2 (BCL-2) family proteins, which gives cancer cells a survival advantage. Mcl-1, a member of the BCL-2 family, is among the most frequently amplified genes in cancer. Targeting myeloid cell leukemia-1 (MCL-1) protein is a successful strategy to induce apoptosis and overcome tumor resistance to chemotherapy and targeted therapy. Various strategies to inhibit the antiapoptotic activity of MCL-1 protein, including transcription, translation, and the degradation of MCL-1 protein, have been tested. Neutralizing MCL-1's function by targeting its interactions with other proteins via BCL-2 interacting mediator (BIM)S2A has been shown to be an equally effective approach. Encouraged by the design of venetoclax and its efficacy in chronic lymphocytic leukemia, scientists have developed other BCL-2 homology (BH3) mimetics-particularly MCL-1 inhibitors (MCL-1i)-that are currently in clinical trials for various cancers. While extensive reviews of MCL-1i are available, critical analyses focusing on the challenges of MCL-1i and their optimization are lacking. In this review, we discuss the current knowledge regarding clinically relevant MCL-1i and focus on predictive biomarkers of response, mechanisms of resistance, major issues associated with use of MCL-1i, and the future use of and maximization of the benefits from these agents.

Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia.

Introduction: Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species. Methods: To investigate the in vitro effects of CB-839 on CLL cells, we tested CB-839 alone and in combination with ibrutinib, venetoclax, or AZD-5991 on the HG-3 and MEC-1 CLL cell lines and on primary CLL lymphocytes. Results: We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed. Discussion: Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.

Tension-free thyroidectomy (TFT): initial report.

The safety of thyroid surgery in terms of recurrent laryngeal nerve palsy and hypoparathyroidism has increased over the last decade. In this study, we present a new method of tension-free thyroidectomy (TFT), which could be used to further decrease the complication rate after a thyroidectomy. The procedure is based on the medial approach to the recurrent laryngeal nerve and the parathyroid glands after the division of the isthmus and successive complete dissection of Berry's ligament. In total, 92 patients (127 nerves at risk) underwent "tension-free thyroidectomy" (TFT) between August and November 2021. All the procedures were performed by a single surgeon at Saint Petersburg State University Hospital. There were 74 females and 18 male patients (ratio 4.1:1) with a mean age of 46.9 (range from 17 to 74). A lobectomy was carried out in 57 (62%) patients and a total thyroidectomy in 35 (38%). In 27 cases, patients additionally underwent central and/or lateral neck dissection. Indications for surgery were papillary carcinoma (N = 34), medullary cancer (N = 2), follicular neoplasia (N = 43), Grave's disease (N = 9), multinodular toxic goiter (N = 3), and multinodular nontoxic goiter (N = 1). Mean thyroid volume was 24.6 ml (ranged 12-70 ml). Intraoperative neuromonitoring was used in all the cases (5 mA). Translaryngeal ultrasound (TLUS) or direct laryngoscopy were routinely used prior and after surgery to evaluate vocal cords mobility. Calcium and parathormone levels were measured in patients after thyroidectomy on the first, 14th and 30th postoperative days. No recurrent laryngeal nerve palsy was observed. One patient exhibited hypoparathyroidism which was resolved in 2 weeks using substitution therapy with calcium and alfacalcidol. The mean operating time for lobectomy was 54 ± 14 min (range: 30-95 min) and for total thyroidectomy 99 ± 28 min (range: 55-158 min). There was no conversion to the conventional lateral-to-medial approach. TFT can be considered a safe and feasible operation. Comparative (randomized studies) with conventional dissection technique should be performed to investigate the hypothesis that this approach can provide a lower complication rate.

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results.

Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.

GATA1 mutation analysis and molecular landscape characterization in acute myeloid leukemia with trisomy 21 in pediatric patients.

INTRODUCTION: Accurate detection of GATA1 mutation is highly significant in patients with acute myeloid leukemia (AML) and trisomy 21 as it allows optimization of clinical protocol. This study was aimed at (a) enhanced search for GATA1 mutations; and (b) characterization of molecular landscapes for such conditions. METHODS: The DNA samples from 44 patients with newly diagnosed de novo AML with trisomy 21 were examined by fragment analysis and Sanger sequencing of the GATA1 exon 2, complemented by targeted high-throughput sequencing (HTS). RESULTS: Acquired GATA1 mutations were identified in 43 cases (98%). Additional mutations in the genes of JAK/STAT signaling, cohesin complex, and RAS pathway activation were revealed by HTS in 48%, 36%, and 16% of the cases, respectively. CONCLUSIONS: The GATA1 mutations were reliably determined by fragment analysis and/or Sanger sequencing in a single PCR amplicon manner. For patients with extremely low blast counts and/or rare variants, the rapid screening with simple molecular approaches must be complemented with HTS. The JAK/STAT and RAS pathway-activating mutations may represent an extra option of targeted therapy with kinase inhibitors.

Acute myeloid leukemia with t(10;11)(p11-12;q23.3): Results of Russian Pediatric AML registration study.

INTRODUCTION: Translocations involving the KMT2A gene (also known as MLL) are frequently diagnosed in pediatric acute leukemia cases with either lymphoblastic or myeloid origin. KMT2A is translocated to multiple partner genes, including MLLT10/AF10 localizing at chromosomal band 10p12. KMT2A-MLLT10 is one of the common chimeric genes diagnosed in acute leukemia with KMT2A rearrangement (8%), especially in acute myeloid leukemia (AML; 18%). MLLT10 is localized in very close proximity to two other KMT2A partner genes at 10p11-12-NEBL and ABI1, so they could not be distinguished by conventional cytogenetics. METHODS: In this work, we present a cohort of 28 patients enrolled into Russian Pediatric AML registration study carrying rearrangements between chromosomal regions 11q23.3 and 10p11-12. G-banding, FISH, reverse transcription PCR, and long-distance inverse PCR were used to characterize the KMT2A gene rearrangements in these patients. RESULTS: We demonstrate that 25 patients harbor the KMT2A-MLLT10 rearrangement, while three patients show the rare KMT2A rearrangements (2× KMT2A-NEBL; 1× KMT2A-ABI1). CONCLUSIONS: Therefore, the combination of cytogenetic and molecular genetic methods is of high importance in diagnosing cases with t(10;11)(p11-12;q23.3).