Tirabrutinib

Tirabrutinib

Tirabrutinib (brand name Velexbru) is a drug used for the treatment of autoimmune diseases and hematological malignancies.

Tirabrutinib was approved in March 2020 in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma.

In addition, tirabrutinib is in clinical development by Ono Pharmaceutical and Gilead Sciences in the United States, Europe, and Japan for autoimmune disorders, chronic lymphocytic leukemia, B cell lymphoma, Sjogren’s syndrome, pemphigus, and rheumatoid arthritis.

Tirabrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase.

The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).

Methods: Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II.

Results: Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types.

Conclusion: These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL 1).

Yoshioka et al. reported that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient’s level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia 2)


A 64-year-old patient with recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL. The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment. The patient died because of suspected pneumocystis pneumonia and acute exacerbation of interstitial pneumonia 43 days after starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib. This letter pathologically confirms the effect of tirabrutinib on relapsed/refractory PCNSL for the first time in humans.Trial registration: JapicCTI-173646. Registered 14 July 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646 3).


Recovery from coma of a patient having acute progression of primary central nervous system lymphoma using tirabrutinib and methylprednisolone 4).


1)

Narita Y, Nagane M, Mishima K, Terui Y, Arakawa Y, Yonezawa H, Asai K, Fukuhara N, Sugiyama K, Shinojima N, Kitagawa J, Aoi A, Nishikawa R. Phase I/II study of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma. Neuro Oncol. 2021 Jan 30;23(1):122-133. doi: 10.1093/neuonc/noaa145. PMID: 32583848; PMCID: PMC7850159.
2)

Yoshioka H, Okuda T, Nakao T, Fujita M, Takahashi JC. Experience with nasogastric tube administration of tirabrutinib in the treatment of an elderly patient with primary central nervous system lymphoma. Int Cancer Conf J. 2021 Jun 5;10(4):290-293. doi: 10.1007/s13691-021-00491-1. PMID: 34567940; PMCID: PMC8421486.
3)

Okita Y, Kano-Fujiwara R, Nakatsuka SI, Honma K, Kinoshita M. Histological verification of the treatment effect of tirabrutinib for relapsed/refractory primary central nervous system lymphoma. Exp Hematol Oncol. 2021 Apr 26;10(1):29. doi: 10.1186/s40164-021-00222-5. PMID: 33902692; PMCID: PMC8077707.
4)

Satow T, Horiguchi S, Komuro T. Recovery from coma of a patient having acute progression of primary central nervous system lymphoma using tirabrutinib and methylprednisolone. Neurooncol Adv. 2020 Nov 27;2(1):vdaa164. doi: 10.1093/noajnl/vdaa164. PMID: 33409497; PMCID: PMC7770517.

Convexity meningioma surgery

Convexity meningioma surgery

Convexity meningioma surgery indications.

Preoperative embolization of intracranial meningioma.

see Surgical safety checklist.

see Preoperative antibiotic prophylaxis.

see Skin Preparation.

For convexity meningioma, the head is positioned so that the center of the tumor is uppermost, the same position as described for parasagittal tumors or for tumors close to the midline.

The incision and bone flap must be large enough to allow for excision of a good margin of dura around the tumor attachments.

The meningeal arteries are occluded as they are exposed.

These tumors can be removed intact by placing gentle traction on the dural attachment and working circumferentially around the tumor to divide the attachments to the cortex. However, if the surface of the tumor cannot be easily visualized without placing significant retraction on the cortex, internal decompression of the tumor is done and the capsule is reflected into the area of decompression.

In a situation where the tumor arises over the frontal temporal junction and grows into the sylvian fissure, the medial capsule and the dural attachment may extend down onto the lateral floor of the anterior fossa and anterior wall of the middle fossa, and the medial capsule of the tumor can be attached to branches of the middle cerebral artery.

A study showed that meningioma recurrence was unlikely when autologous cranioplasty was done with refashioned hyperostotic bone. This could be done in the same setting with meningioma excision. There was no recurrence at a mean of 5-year follow-up in convexity meningiomas 1).

Right Convexity Meningioma from Surgical Neurology International on Vimeo.

Left Frontal Convexity Meningioma from Surgical Neurology International on Vimeo.

An accurate and real-time model of soft tissue is critical for surgical simulation for which a user interacts haptically and visually with simulated patients. A paper focuses on the real-time deformation model of brain tissue for the interactive surgical simulation, such as neurosurgical simulation.

A new Finite Element Method (FEM) based model with constraints is proposed for the brain tissue in neurosurgical simulation. A new energy function of constraints characterizing the interaction between the virtual instrument and the soft tissue is incorporated into the optimization problem derived from the implicit integration scheme. Distance and permanent deformation constraints are introduced to describe the interaction in the convexity meningioma dissection and hemostasis. The proposed model is particularly suitable for GPU-based computing, making it possible to achieve real-time performance.

Simulation results show that the simulated soft tissue exhibits the behaviors of adhesion and permanent deformation under the constraints. Experiments show that the proposed model is able to converge to the exact solution of the implicit Euler method after 96 iterations. The proposed model was implemented in the development of a neurosurgical simulator, in which surgical procedures such as dissection of convexity meningioma and hemostasis were simulated 2).


1)

Lau BL, Che Othman MI, Fakhri M, San Liew DN, San Lim S, Bujang MA, Hieng Wong AS. Does putting back hyperostotic bone flap in meningioma surgery causes tumor recurrence? An observational prospective study. World Neurosurg. 2019 Mar 26. pii: S1878-8750(19)30863-0. doi: 10.1016/j.wneu.2019.03.183. [Epub ahead of print] PubMed PMID: 30926555.
2)

Hou W, Liu PX, Zheng M. A new model of soft tissue with constraints for interactive surgical simulation. Comput Methods Programs Biomed. 2019 Jul;175:35-43. doi: 10.1016/j.cmpb.2019.03.018. Epub 2019 Apr 1. PubMed PMID: 31104713.

Primary central nervous system ALK-negative anaplastic large cell lymphoma

Primary central nervous system ALK-negative anaplastic large cell lymphoma

see also Primary central nervous system ALK-positive anaplastic large cell lymphoma


Primary central nervous system anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an extremely rare type of primary central nervous system lymphoma (PCNSL).

There are only nine cases reported in the literature to date, most of which have an overall survival time of no more than 8 months. Yuan et al. reported such a rare case that has a good outcome with the longest survival time and performed a literature review 1).


George et al. reported four new cases of primary central nervous system ALCL from the Mayo Clinic and incorporated additional data from five previously published cases. ALK-1 expression was determined in all nine tumors. Patient age was 4-66 years (mean 29 years) with a bimodal distribution: 6 < or = 22 years, 3 > or = 50 years. Six were female. Tumors were mostly supratentorial, five were multifocal, and seven had involvement of dura or leptomeninges. Seven tumors were T cells, two were null cells, and five of nine were ALK-1 immunopositive. Total mortality was six of nine. Three patients, 4-18 years of age (mean 13 years), were alive at 4.8-6.1 years postdiagnosis; these tumors were all ALK-positive. Five patients, 13-66 years of age (mean 43 years), died of tumor 4 days to 11 weeks postdiagnosis; four of five of these tumors were ALK-negative. One 10-year-old child with an ALK-positive tumor died of sepsis, but in remission. The central nervous system ALCL is aggressive. The study suggests that a better outcome may be associated with young age and ALK-1 positivity, prognostic parameters similar to systemic ALCL 2).


A review demonstrated that ALK-negative ALCL exhibits a poor prognosis and is very often fatal. The majority of ALK-negative patients were treated with radiotherapy or supportive care, due to their older age or poor PS. As ALK-negative ALCL tends to occur in older individuals, similar to PCNSL and DLBCL, chemoradiotherapy including HD-MTX should be initiated earlier.

In conclusion, findings indicate that the prognosis of ALCL of the CNS is correlated with ALK positivity and patient age of <40 years. Chemoradiotherapy with MTX is recommended as the standard treatment for ALCL. However, additional multicenter studies including large numbers of cases are required 3).

A 19-year-old male patient was admitted to the hospital complaining of dizzinessCT and MRI imaging showed a heterogeneous enhanced lesion in the left parieto-occipital lobe and the leptomeninges of the occipital lobe and the cerebellum. The lesion was resected and confirmed to be ALK-negative ALCL by pathological examination. Then, the patient received 10 cycles of chemotherapy with high-dose methotrexate (HD-MTX) and whole brain radiotherapy. The patient recovered well and was regularly followed up. He was free of symptoms without recurrence on imaging examination 3 years later. ALCL is a rare type of PCNSL. HD-MTX combined with radiation is an effective therapeutic approach. However, further prospective studies with a large number of patients are needed to identify the biological characteristics of this rare type of PCNSL 4).


1) , 4)

Yuan C, Duan H, Wang Y, Zhang J, Ou J, Wang W, Zhang M. Primary central nervous system ALK-negative anaplastic large cell lymphoma: a case report and literature review. Ann Palliat Med. 2021 Jul 1:apm-21-557. doi: 10.21037/apm-21-557. Epub ahead of print. PMID: 34263607.
2)

George DH, Scheithauer BW, Aker FV, Kurtin PJ, Burger PC, Cameselle-Teijeiro J, McLendon RE, Parisi JE, Paulus W, Roggendorf W, Sotelo C. Primary anaplastic large cell lymphoma of the central nervous system: prognostic effect of ALK-1 expression. Am J Surg Pathol. 2003 Apr;27(4):487-93. doi: 10.1097/00000478-200304000-00008. PMID: 12657933.
3)

Nomura M, Narita Y, Miyakita Y, Ohno M, Fukushima S, Maruyama T, Muragaki Y, Shibui S. Clinical presentation of anaplastic large-cell lymphoma in the central nervous system. Mol Clin Oncol. 2013 Jul;1(4):655-660. doi: 10.3892/mco.2013.110. Epub 2013 Apr 30. PMID: 24649224; PMCID: PMC3915681.
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