Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic ...topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer.
In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety.
Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary 0.0202 on the basis of number of deaths). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group.
Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).
Low back pain is the main cause of disability and is associated with intervertebral disc degeneration. Contemporary treatments are limited to palliative therapeutics or aggressive surgical ...interventions; however, current advancements in cell therapy offer to fill this breach. Clinical data suggest that cell transplantation can accomplish pain relief without any observed adverse effects. Despite a large variety of preclinical studies and preliminary clinical investigations, controversy remains on the optimal cell type and transplantation strategies. The translational potential of this article lies in the aim to update on the current state of intervertebral disc cell therapy and to identify current obstacles.
Sagittal misalignment has been associated with negative quality of life (QOL). However, there is no report on whether differences in preoperative sagittal misalignment in patients with lumbar ...degenerative diseases affect postoperative results after lateral lumbar interbody fusion (LLIF). We investigated whether preoperative sagittal alignment influences the correction of alignment after surgery and whether the preoperative sagittal alignment affects the rating of low back pain, leg pain, and leg numbness. The subjects were 81 patients (48 male, 33 females, average age at surgery 70.2 years) who underwent anterior-posterior combined surgery with LLIF and percutaneous pedicle screws from May 2018 to July 2020. Cluster analysis was performed using the preoperative sagittal vertical axis (SVA) value, and patients were classified into two groups (group 1; n = 30, SVA = 129.0 ± 53.4 mm, group 2; n = 51, SVA = 30.8 ± 23.5 mm). Baseline demographics and treatment data were compared between groups. Sagittal and pelvic parameters and pain scores, such as low back pain, leg pain, and leg numbness, were also compared. Operative time, blood loss, and length of hospital stay did not differ significantly between groups. The changes (Δ) in SVA and lumbar lordosis (LL) for all patients from before to after surgery were not significant (ΔSVA; p = 0.218, ΔLL; p = 0.189, respectively). The SVA, LL, and PI - LL changed significantly after the surgery in group 1, but no marked improvement in sagittal imbalance was obtained after LLIF surgery. The improvement in each pain score from before to after the surgery did not differ significantly between groups. LLIF surgery has a limited chance of recovering sagittal imbalance. However, postoperative low back pain, leg pain, and leg numbness may be improved by LLIF surgery, regardless of the preoperative sagittal alignment.
The purpose of this study was to compare the short-term clinical outcomes between extreme lateral interbody fusion (XLIF) and minimally invasive surgery (MIS)-transforaminal interbody fusion (TLIF) ...in patients with degenerative spondylolisthesis with stenosis. One hundred-six patients were enrolled; 44 were treated with MIS-TLIF (direct decompression group; DP), and 62 were treated with XLIF (indirect decompression group; IDP). Perioperative indexes included operation time and intraoperative bleeding. Perioperative indexes preoperative and postoperative numeric rating scale (NRS) scores for low back pain (NRS-BP), leg pain (NRS-LP), and leg numbness (NRS-LN), and the preoperative score on the Japanese version of the painDETECT questionnaire (PDQ-J) were also assessed. The average follow-up period for the collection of NRS scores was 12.6 months. The operation time was significantly shorter in the IDP than in the DP group (109.9 ± 35.4 vs. 153.3 ± 50.9 min; p < 0.001). Intraoperative blood loss was also significantly less in the IDP group than in the DP group (85.4 ± 125.4 vs. 258.3 ± 220.4 mL; p < 0.001). The PDQ-J score and preoperative NRS scores (NRS-BP, NRS-LP, and NRS-LN) did not differ significantly between groups. Less improvement in the NRS-BP (ΔNRS-BP) was observed in the DP group than in the IDP group (p < 0.05). Although pain improved after surgery in both groups, IDP surgery was advantageous in minimizing bleeding and preserving posterior support elements such as the facet joints, lamina, and paraspinal muscles. These findings suggest that this may have contributed to the higher rate of improvement in low back pain compared with DP surgery.
Intervertebral disc (IVD) degeneration is associated with low back pain. In IVDs, a high mechanical load, high osmotic pressure and hypoxic conditions create a hostile microenvironment for resident ...cells. How IVD homeostasis and function are maintained under stress remains to be understood; however, several research groups have reported isolating native endogenous progenitor-like or otherwise proliferative cells from the IVD. The isolation of such cells implies that the IVD might contain a quiescent progenitor-like population that could be activated for IVD repair and regeneration. Increased understanding of endogenous disc progenitor cells will improve our knowledge of IVD homeostasis and, when combined with tissue engineering techniques, might hold promise for future therapeutic applications. In this Review, the characteristics of progenitor cells in different IVD compartments are discussed, as well as the potency of different cell populations within the IVD. The stem cell characteristics of these cells are also compared with those of mesenchymal stromal cells. On the basis of existing evidence, whether and how IVD degeneration and the hostile microenvironment might affect endogenous progenitor cell function are considered, and ways to channel the potential of these cells for IVD repair are suggested.
Lateral lumbar interbody fusion (LLIF) and bilateral percutaneous pedicle fixation are valuable, minimally invasive lateral approaches used to treat symptomatic degenerative disc disease. In the ...current procedure, the patient's position on the operating table is changed after LLIF surgery from the lateral decubitus to the prone position. The ability to perform both approaches with the patient in the same position should reduce operation time. Use of a guide wire is problematic during percutaneous pedicle screw (PPS) insertion using fluoroscopy with the patient in the lateral decubitus position. A new guide wire-less PPS system may solve this problem and reduce operation time. Here, we evaluated the operative data and efficacy for this technique.
This study included 30 patients (aged 70.8 ± 8.5 years; 17 men, 13 women) who underwent a combined operation (indirect decompression) using extreme lateral interbody fusion (XLIF) with only a single level for lumbar spinal canal stenosis and lumbar degenerative spondylolisthesis. Patient demographics and operative data were compared between two groups: patients who remained in the lateral decubitus position for pedicle screw fixation (L group) and those turned to the prone position (P group). Radiographic assessment was performed using pre- and postoperative anteroposterior and lateral lumbar films with measurement of lumbar lordosis, segmental lordosis, and segmental translation.
We analyzed 18 patients in the P group and 12 in the L group. Age, sex, height, body weight, body mass index, estimated blood loss, and length of stay did not differ between groups. The operation time was 34 min shorter for the L group (P group 111.9 ± 25.0 vs. L group 77.5 ± 22.2 min, p < 0.01). Pre- and postoperative lordosis, segmental lordosis, and segmental translation did not differ significantly between groups.
A single position after XLIF surgery is a feasible modification to the standard procedure when used with fluoroscopy and a guide wire-less PPS system. The time saved is the main advantage of inserting the PPS with the patient in the lateral decubitus position without repositioning. Use of the lateral PPS with a guide wire-less technique may help improve operative efficiency and reduce cost.
Background
Since June 2019, cancer genomic profiling (CGP) tests have been reimbursed by the National Health Insurance system in Japan, with restrictions for government-designated hospitals with a ...molecular tumor board composed of multidisciplinary specialists, known as an expert panel (EP). The standardization of EPs is a critical challenge for implementing precision oncology in the clinical setting.
Methods
Data on consecutive cases who underwent the CGP tests at 11 core hospitals between June 2019 and January 2020 were collected. We evaluated the proportions of cases that received genomically matched treatments, including investigational new drugs (INDs) based on CGP results, and/or for which genetic counseling was recommended. Two simulated cases were annotated by each EP. The annotated reports were then centrally assessed.
Results
Each EP mainly discussed the applicability to genomically matched treatments and the necessity of performing genetic counseling. A pre-review of the report by key members in each EP reportedly made the EP conference more interactive and efficient, and thereby saved time. A total of 747 cases underwent CGP tests, 28 cases (3.7%) received genomically matched treatment, and 17 cases (2.3%) were referred for genetic counseling. Annotated reports for the simulated cases varied across the EPs, particularly the number of recommended IND trials, which seemed to be associated with the actual number of participants in IND trials.
Conclusions
This investigation provides reference data for the application of precision oncology in a clinical setting. Further investigations on the standardization of clinical annotations are warranted.
One‐third of all congenital birth defects affect the head and face, and most craniofacial anomalies are considered to arise through defects in the development of cranial neural crest cells. Cranial ...neural crest cells give rise to the majority of craniofacial bones, cartilages and connective tissues. Therefore, understanding the events that control normal cranial neural crest and subsequent craniofacial development is important for elucidating the pathogenetic mechanisms of craniofacial anomalies and for the exploring potential therapeutic avenues for their prevention. Treacher Collins syndrome (TCS) is a congenital disorder characterized by severe craniofacial anomalies. An animal model of TCS, generated through mutation of Tcof1, the mouse (Mus musculus) homologue of the gene primarily mutated in association with TCS in humans, has recently revealed significant insights into the pathogenesis of TCS. Apoptotic elimination of neuroepithelial cells including neural crest cells is the primary cause of craniofacial defects in Tcof1 mutant embryos. However, our understanding of the mechanisms that induce tissue‐specific apoptosis remains incomplete. In this review, we describe recent advances in our understanding of the pathogenesis TCS. Furthermore, we discuss the role of Tcof1 in normal embryonic development, the correlation between genetic and environmental factors on the severity of craniofacial abnormalities, and the prospect for prenatal prevention of craniofacial anomalies.
Tcof1 is the gene primarily mutated in association with Treacher Collins syndrome, severe congenital craniofacial anomalies. Recent findings show that Tcof1 functions as DNA damage response/repair gene and safeguards cranial neural crest cells from oxidative DNA damages.
In Japan, comprehensive genomic profiling (CGP) tests for refractory cancer patients have been approved since June 2019, under the requirement that all cases undergoing CGP tests are annotated by the ...molecular tumor board (MTB) at each government‐designated hospital. To investigate improvement in precision oncology, we evaluated and compared the proportion of cases receiving matched treatments according to CGP results and those recommended to receive genetic counseling at all core hospitals between the first period (11 hospitals, June 2019 to January 2020) and second period (12 hospitals, February 2020 to January 2021). A total of 754 and 2294 cases underwent CGP tests at core hospitals in the first and second periods, respectively; 28 (3.7%) and 176 (7.7%) patients received matched treatments (p < 0.001). Additionally, 25 (3.3%) and 237 (10.3%) cases were recommended to receive genetic counseling in the first and second periods, respectively (p < 0.001). The proportion was associated with the type of CGP test: tumor‐only (N = 2391) vs. tumor‐normal paired (N = 657) analysis (10.0% vs. 3.5%). These results suggest that recommendations regarding available clinical trials in networked MTBs might contribute to increasing the numbers of matched treatments, and that tumor‐normal paired rather than tumor‐only tests can increase the efficiency of patient referrals for genetic counseling.
We investigated the improvement in precision oncology by evaluating and comparing the proportion of patients receiving genomically‐matched therapies and referred to genetic counseling among all designated core hospitals between two study periods (First period: 11 hospitals, June 2019 to January 2020; Second period: 12 hospitals, February 2020 to January 2021). Our results revealed that both the proportion of matched therapies and referrals to genetic counseling improved chronologically, from 3.7% to 7.7% (p 0.001) and 3.3% to 10.3% (p 0.001), respectively.
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