Dose fractionation of CAR-T cells. A systematic review of clinical outcomes.

CAR-T cells are widely recognized for their potential to successfully treat hematologic cancers and provide durable response. However, severe adverse events such as cytokine release syndrome (CRS) and neurotoxicity are concerning. Our goal is to assess CAR-T cell clinical trial publications to address the question of whether administration of CAR-T cells as dose fractions reduces toxicity without adversely affecting efficacy. Systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematologic cancers. Studies published in English were considered. Studies in children (age < 18), solid tumors, bispecific CAR-T cells, and CAR-T cell cocktails were excluded. Data was extracted from the studies that met inclusion and exclusion criteria. Review identified a total of 18 studies that used dose fractionation. Six studies used 2-day dosing schemes and 12 studies used 3-day schemes to administer CAR-T cells. Three studies had both single dose and fractionated dose cohorts. Lower incidence of Grade ≥ 3 CRS and neurotoxicity was seen in fractionated dose cohorts in 2 studies, whereas 1 study reported no difference between single and fractionated dose cohorts. Dose fractionation was mainly recommended for high tumor burden patients. Efficacy of CAR-T cells in fractionated dose was comparable to single dose regimen within the same or historical trial of the same agent in all the studies. The findings suggest that administering dose fractions of CAR-T cells over 2-3 days instead of single dose infusion may mitigate the toxicity of CAR-T cell therapy including CRS and neurotoxicity, especially in patients with high tumor burden. However, controlled studies are likely needed to confirm the benefits of dose fractionation.

Dose-response correlation for CAR-T cells: a systematic review of clinical studies.

The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age <18 years), solid tumors, bispecific CAR-T cells and CAR-T cell cocktails were excluded. As a result, a total of 74 studies met the inclusion criteria. Thirty-nine studies tested multiple dose levels of CAR-T cells with at least >1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50-100 million cells for anti-CD19 CAR-T cells and >100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.

The perplexing postsurgical complication of carotid-jugular fistula: A bitter experience.

BACKGROUND: Vascular injuries occur in approximately 25% of all penetrating neck traumas, with carotid artery injuries being particularly lethal. Penetrating neck injuries are potentially fatal. Vascular injuries occur in approximately 25% of cases, which can lead to the formation of arteriovenous fistulas. CASE DESCRIPTION: The authors present a case of delayed open surgery to repair a carotid-jugular fistula that resulted in an unprecedented complication, as well as a brief review of the condition's diagnosis and treatment options. CONCLUSION: This case report suggests us that, penetrating neck injuries should be thoroughly evaluated for arteriovenous fistulae. To avoid complications, common carotid-jugular fistulas must be treated as soon as possible. Postoperative complications can be effectively managed with prompt action.

Bowel Habits of Healthy Indian Children Less Than Two Years of Age.

Objectives: To define the normal frequency and consistency of stools of healthy Indian children between 0-24 months of age. Material and Methods: Parents of children aged up to 24 months were asked on a three-day recall basis about their child's usual bowel habits and dietary history. Bowel habit was recorded in terms of number of stools the child passes per day, stool consistency, the age at which night bowel movements stopped, and age of regular bowel movements. Feeding type was recorded as exclusive breast feed, mixed milk feeds or on solid feeds. The bowel habits were correlated with the age of the child and type of feeding. Results: Children in first six months of life had stools which were predominantly "pasty" and "runny like cream" with a frequency of one to two per day. On analyzing the combined effect of type of milk feed and age on bowel frequency and consistency children beyond one month of age either on exclusive breast feed or on mixed milk feed had similar frequency and consistency of stools. By one year of age more than 90% of children had attained regular stool pattern and no night time bowel movements. Conclusions: First of its kind study from India which describes the stool pattern of normal health children less than two years of age.

Solitary osteochondroma of the atlas causing spinal cord compression: a case report and literature review.

Solitary osteochondroma (SOC) of the spine is very rare, though OC is the commonest benign tumour of the bone. Only about 1-4% of SOCs occur in the spine. And solitary ostechondroma of spine causing cord compression is even rarer. These tumours slowly enlarge, creating insidious but progressive symptoms of myelopathy or radiculopathy or both. Clinical histories, routine radiographs, CT studies, MRI studies and histopathological studies are the adjuncts for a definitive diagnosis. Surgical intervention can lead to functional and neurologic improvement with very little chance of recurrence. The authors present a case of a C1 posterior arch intraspinal SOC with cord compression who recovered very well after surgery and was doing well without recurrence after 1 year of surgery. The authors are reporting this case with English language medical literature review as it is quite rare among the SOCs of the cervical spine.