Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

[Effects of three methods for correction of low-degree against-the-rule corneal astigmatism during cataract surgery].

Objective: To compare the clinical effects of and visual quality after correction of low-degree against-the-rule (ATR) corneal astigmatism by implantation of an astigmatism-corrected intraocular lens (IOL), femtosecond laser release and manual release in cataract surgery. Methods: It was a prospective cohort study. A total of 120 patients (120 eyes) with cataract combined with low-degree ATR corneal astigmatism diagnosed in Chongqing Aier Mega Eye Hospital from December 2017 to October 2020 were included and divided into 3 groups, each with 40 patients, according to their own selections of astigmatism correction methods during cataract surgery. In the astigmatism-corrected IOL group, phacoemulsification for cataract extraction combined with toric IOL implantation was performed. In the femtosecond laser release group, astigmatic keratotomy using a femtosecond laser was combined. In the manual release group, a limbal relaxing incision was made. Uncorrected distance visual acuity (UDVA) and corneal astigmatism were measured before surgery. At 3 months and 1 year after surgery, UDVA and best-corrected distance visual acuity were examined, as well as whole eye residual astigmatism by ARK-1, corneal astigmatism by the IOLMaster 500, whole eye high order aberration (HOA) and modulation transfer function (MTF) by the iTrace visual function analyzer. Analysis of variance was used for the comparison of data in a normal distribution. Repeated measures were used for the comparison within groups. The rank sum test was used for the comparison of data that were not normally distributed. Results: Of the 120 patients, 100 patients (100 eyes), including 44 males and 56 females, with an age of (66.48±6.20) years, completed the follow-up. Among the three groups, the differences were not statistically significant in terms of gender distribution, age, preoperative corneal astigmatism, UDVA and spherical equivalent of the IOL (all P>0.05). At 3 months and 1 year after surgery, the UDVA was significantly better than that before surgery in each group (Z=5.18, 5.04, 4.98, 4.99, 4.90, 4.89; all P<0.001). At the two time points, the differences in the whole eye residual astigmatism among the three groups were statistically significant (H=30.69, 31.23; both P<0.001). At 3 months, the whole eye residual astigmatism in the astigmatism-corrected IOL group was lower than that in the other two groups. At 1 year, the residual astigmatism in the astigmatism-corrected IOL group [0.25(0.00, 0.50) D] was also lower compared to that in the femtosecond laser release group [0.50(0.50, 0.75) D] and the manual release group [0.75(0.50, 0.75) D] (Z=-3.71, -5.18, -3.94, -5.15; all P<0.001). The differences in the HOA at 3 months and 1 year among the three groups were statistically significant (H=36.30, 34.38; both P<0.001). The HOA in the astigmatism-corrected IOL group was significantly higher than that in the other two groups at the two time points (Z=5.01, 4.73, 5.31, 5.27; all P<0.001). At 3 months and 1 year, the differences in the MTF value among the three groups were also statistically significant (H=30.02, 29.92; both P<0.001), and the MTF value in the femtosecond laser release group was significantly higher than that in the other two groups (Z=4.61, 4.67, 4.66, 4.69; all P<0.001). Conclusions: All the three astigmatism correction methods used at the time of cataract surgery can effectively correct low-degree ATR corneal astigmatism. The residual astigmatism in the whole eye after astigmatism-corrected IOL implantation is small and stable, while the HOA after release using the femtosecond laser is low with good visual quality.

GENIPAC: A Genomic Information Portal for Head and Neck Cancer Cell Systems.

Head and neck cancer (HNC)-derived cell lines represent fundamental models for studying the biological mechanisms underlying cancer development and precision therapies. However, mining the genomic information of HNC cells from available databases requires knowledge on bioinformatics and computational skill sets. Here, we developed a user-friendly web resource for exploring, visualizing, and analyzing genomics information of commonly used HNC cell lines. We populated the current version of GENIPAC with 44 HNC cell lines from 3 studies: ORL Series, OPC-22, and H Series. Specifically, the mRNA expressions for all the 3 studies were derived with RNA-seq. The copy number alterations analysis of ORL Series was performed on the Genome Wide Human Cytoscan HD array, while copy number alterations for OPC-22 were derived from whole exome sequencing. Mutations from ORL Series and H Series were derived from RNA-seq information, while OPC-22 was based on whole exome sequencing. All genomic information was preprocessed with customized scripts and underwent data validation and correction through data set validator tools provided by cBioPortal. The clinical and genomic information of 44 HNC cell lines are easily assessable in GENIPAC. The functional utility of GENIPAC was demonstrated with some of the genomic alterations that are commonly reported in HNC, such as TP53, EGFR, CCND1, and PIK3CA. We showed that these genomic alterations as reported in The Cancer Genome Atlas database were recapitulated in the HNC cell lines in GENIPAC. Importantly, genomic alterations within pathways could be simultaneously visualized. We developed GENIPAC to create access to genomic information on HNC cell lines. This cancer omics initiative will help the research community to accelerate better understanding of HNC and the development of new precision therapeutic options for HNC treatment. GENIPAC is freely available at http://genipac.cancerresearch.my/ .

Anaplastic lymphoma kinase (ALK) mutations in patients with adenocarcinoma of the lung.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death. Approximately 2-16% of NSCLC patients with wild-type epidermal growth factor receptor (EGFR) harbour anaplastic lymphoma kinase (ALK) mutations. Both EGFR and ALK mutations occur most commonly in Asian patients with NSCLC. As targeted therapy is available for NSCLC patients with these mutations, it is important to establish reliable assays and testing strategies to identify those most likely to benefit from this therapy. MATERIALS AND METHODS: Patients diagnosed with adenocarcinoma of the lung between 2010 and 2014 were tested for EGFR mutations. Of these, 92 cases were identified as EGFR wild type and suitable candidates for ALK testing utilising immunohistochemistry and the rabbit monoclonal antibody D5F3. The reliability of the IHC was confirmed by validating the results against those achieved by fluorescence in situ hybridisation (FISH) to detect ALK gene rearrangements. RESULTS: Twelve (13%) cases were positive for ALK expression using immunohistochemistry. Of the 18 evaluable cases tested by FISH, there was 100% agreement with respect to ALK rearrangement/ALK expression between the assays, with 11 cases ALK negative and 7 cases ALK positive by both assays. ALK tumour expression was significantly more common in female compared to male patients (29.6% vs. 6.2%, P < 0.001), detected exclusively in patients that had never smoked (P < 0.001) and more frequently in metastases (22.7%) than in primary tumours (10%) (P = 0.047). CONCLUSIONS: Detection of ALK expression by IHC is reliable and the most practical way of identifying NSCLC patients likely to benefit from crizotinib treatment.

Preterm human amnion epithelial cells have limited reparative potential.

The collection and use of stem cells from the fetal membranes as cell therapy for a variety of lung diseases, including preterm lung disease, have been previously proposed. To date, only cells from term amnion have been assessed. In the setting of a future therapy for the preterm neonate, it would be ideal if autologous cells could be given. However, the reparative and anti-inflammatory actions of stem cells isolated from preterm amnions have not been evaluated. In this study, with a view to developing an autologous cell therapy for preterm lung injury, we compared the differentiation potential and efficacy of term versus preterm human amnion epithelial cells (hAECs) to protect against inflammation and fibrosis in a bleomycin mouse model of lung injury. We found that, unlike term hAECs, preterm hAECs did not differentiate into a lung lineage following culture in small airway growth media. Preterm hAECs also exerted significantly less protective effects than term hAEC following acute lung injury. Specifically, preterm hAEC did not improve Ashcroft scoring or collagen deposition in the lung despite a reduction in activated myofibroblasts. Term hAECs expressed double the levels of HLA-G compared to preterm hAECs. These findings indicate that while hAECs can be isolated from term and preterm amnions in similar numbers, they bear distinctive characteristics, which may impact upon their clinical use.

Arthroscopic subacromial decompression for stage-II impingement.

PURPOSE: To evaluate outcomes of arthroscopic subacromial decompression for stage-II impingement. METHODS: Records of 42 consecutive patients with stage-II impingement treated by arthroscopic subacromial decompression from January 2000 to February 2002 were reviewed. Clinical outcomes were measured using the UCLA shoulder rating scale, and radiological outcomes using anteroposterior and supraspinatus outlet shoulder radiographs. RESULTS: The mean follow-up period was 14.6 (range, 12-30) months. Using the UCLA scale, 14 (33%) patients had an excellent result, 21 (50%) had a good result, 4 (10%) had a fair result, and 3 (7%) had a poor result. Mean component scores for the UCLA scale were: 8.0 for pain, 8.8 for function, 4.5 for forward flexion, and 4.5 for strength. The mean extent of resection was 2.9 mm in the anteroposterior and 2.0 mm in the supraspinatus outlet radiographs. There was no correlation between the extent of acromial resection and the UCLA shoulder rating scores. CONCLUSION: Short-term results of arthroscopic subacromial decompression for stage-II impingement are favourable.

Cartilage injury and repair: assessment with magnetic resonance imaging.

Articular cartilage damage plays a major role in joint degeneration and dysfunction. Accurate assessment of the morphology and degree of cartilage wear is important in diagnosis, prognosis and management, particularly as many of these patients are young or participate in high-performance sports. Magnetic resonance imaging is able to directly evaluate such injuries, due to its high spatial resolution and excellent soft-tissue contrast resolution. This pictoral essay aims to demonstrate normal and damaged articular cartilage on MR imaging, as well as surgically-repaired cartilage.

Intrinsic histological abnormalities of aortic root and ascending aorta in tetralogy of Fallot: evidence of causative mechanism for aortic dilatation and aortopathy.

BACKGROUND: Dilatation of the aortic root is a known feature in tetralogy of Fallot (TOF) patients with pulmonary stenosis (PS) or pulmonary atresia (PA). We hypothesized that intrinsic histological abnormalities of the aortic wall present since infancy are an important causative factor leading to aortic root dilatation. METHODS AND RESULTS: We examined the aortic histology of 17 cases with TOF and PS/PA from our cardiac morphology archive and compared them with a control group of normal aortas. Measured circumference of the aortic root at the sinotubular junction and at the ascending aorta was indexed to the left ventricle. Aortic walls were studied by light microscopy with the use of various stains. Seventeen TOF cases (7 with PS, 10 with PA) including 7 infants, 2 children, and 8 adults were compared with 11 hearts with normal aorta. Aortic root circumference to left ventricular index and ascending aortic circumference to left ventricular index were 1.24+/-0.25 and 1.37+/-0.24, respectively, in the TOF group versus 0.89+/-0.10 and 0.88+/-0.11, respectively, in the control group (P<0.001). Histological changes of grade 2 or 3 were present in 29% (medionecrosis), 82% (fibrosis), 35% (cystic medial necrosis), and 59% (elastic fragmentation) in the ascending aorta of the TOF group. Histology grading scores were significantly higher in the TOF group (median score, 7; range, 1 to 12) compared with normal controls (median score, 2; range, 0 to 6) and correlated with the ascending aortic circumference to left ventricular index (r=0.525, P=0.03). CONCLUSIONS: There are marked histological abnormalities in the aortic root and ascending aortic wall of patients with TOF present from infancy, suggesting a causative mechanism for subsequent aortic root dilatation.

Rising trend of anterior cruciate ligament injuries in females in a regional hospital.

INTRODUCTION: We see a rising trend in the number of anterior cruciate ligament (ACL) injuries in females over the past 4 years (1999 to 2002). This article seeks to identify and examine the rising trend in the number of ACL injuries in females in our institution over this period. MATERIALS AND METHODS: Two hundred and fifty-nine patients with ACL reconstructions were identified and their casenotes were retrieved from the medical records office. Of these, 13 were females. RESULTS: The number of ACL reconstructions has increased from 9 cases to 144 cases a year from 1999 to 2002. Over this period, 13 female cases (3 in 2001 and 10 in 2002) with an age range of 13 to 38 years were performed in our institution. Their injuries were mainly sustained from a bad landing or during pivoting on 1 leg. There were 8 patients (61.5 %) with prior conditioning and experience and 5 without (38.5 %). The mean number of years of prior training was 4.4 years. Of these 8, 4 were netball players. All were competitive players either at the school or club level and they were all playing as goal attackers. CONCLUSION: Linear regression analysis shows a significant increase in the number of ACL reconstructions performed for females in our institution over this time period. Netball was a common sport in our series. This suggests a likely relationship between netball and ACL injuries. All the patients were playing as goal attackers. The area of court covered and frequency of jump-stop and sudden deceleration activities could be a cause.

Septic arthritis after arthroscopic anterior cruciate ligament reconstruction.

INTRODUCTION: A retrospective review of postoperative infected anterior cruciate ligament (ACL) reconstruction was done on 472 consecutive cases in one institution. The purpose was to assess the incidence, diagnosis, treatment and outcome factors. MATERIALS AND METHODS: Out of 472 arthroscopic-assisted ACL reconstructions performed between 1999 and 2002, 7 (1%) postoperative deep intra-articular infections were detected. Seven males with a mean age of 23 years (range, 19 to 30 years) formed the study group; 3 had undergone prior knee surgery. RESULTS: Four patients had acute infection (<2 weeks), 3 had subacute infection (2 weeks to 2 months) and none had late infection (>2 months). All were admitted within 24 hours of onset of symptoms and underwent immediate arthroscopic lavage, incision and drainage of abscess, debridement with graft retention and intravenous (8 to 31 days) followed by oral (4 to 6 weeks) antibiotics. Staphylococcus aureus was present in 4 patients, Peptostreptococcus in 3, Klebsiella in 1, and Enterobacter in 1. The patients underwent an average of 1.4 arthroscopic procedures (range, 1 to 3 procedures), with an average hospital stay of 17.3 days per patient. All were evaluated at an average of 11.7 months (range, 5 to 26 months). In all cases, the infection resolved with stable knees and with all grafts and implants retained. Although rare, early diagnosis and prompt treatment of infection can result in successful eradication without sacrificing the graft.

Anthropometry of anterior cruciate ligament in Singaporean Chinese.

Accurate reproduction of the anatomy of the anterior cruciate ligament during reconstructive surgery is paramount for obtaining good functional results. Graft size and length are important components of the reconstruction and the references we have used are Western figures. We feel that these Western figures do not apply to our local population. We performed an anthropometric study to test the hypothesis that the anterior cruciate ligament in the Singaporean Chinese is smaller than that quoted in Western literature. The study revealed that the anterior cruciate ligament in Singaporean Chinese is shorter and narrower. More importantly, the anterior cruciate ligament orientation in our study population is more vertical. This suggests that placement of the femoral tunnel in anterior cruciate ligament reconstruction has to be in a more vertical position to reproduce the physiometry of the anterior cruciate ligament.

The relationship between presurgical hyoid bone position and 1-year postsurgical change in mandibular position following mandibular advancement surgery.

The presurgical hyoid bone position and its relationship to changes in the position of the mandible 1 year following mandibular advancement surgery was studied. Thirty-eight adult patients with mandibular deficiency underwent surgical correction with a bilateral sagittal split ramus osteotomy procedure and rigid fixation. Lateral cephalometric radiographs taken presurgically, 1 week postsurgically, and approximately 1 year postsurgically were hand traced and digitized. Horizontal and vertical measurements, made from the landmarks hyoidale and pogonion to a vertical reference line perpendicular to sellanasion line + 7 degrees and passing through basion point, were used to determine the position of the hyoid bone and the mandible, respectively. The presurgical hyoid bone position and the amount of postsurgical change in position of the mandible were compared using the Pearson's correlation coefficient (r). Results of this study indicate that no statistically significant correlation exists between the presurgical hyoid bone position and the degree of mandibular change 1 year following mandibular advancement surgery (P < .05).

Surgical treatment of metastatic long bone disease.

A retrospective study of the results of operative treatment of 60 long bones secondaries in 46 patients was carried out. The mean period of follow-up was 10 months. The most common primary in this study was carcinoma of the breast (28.2%), followed by carcinoma of the lung (21.7%) and unknown primary (10.9%). Three groups of patients were studied--pathological fracture group, prophylactic fixation group and a mixed group. In the pathological fracture group, 70% of patients achieved good to excellent pain relief and 60.9% was able to walk with or without walking aids. In the prophylactic group, all the patients achieved good to excellent pain relief and 60% were able to ambulate with or without walking aids. In the mixed group, all the patients achieved good to excellent pain relief and 66.6% of the patients were able to walk with aids. The operative mortality in both the pathological fracture group and prophylactic fixation group was 10% and 33.3% in the mixed group. Multiple internal fixation performed at one operative session was associated with high operative mortality (50%).

Dictyostelium myosin light chain kinase. Purification and characterization.

A Dictyostelium myosin light chain kinase has been purified approximately 15,000-fold to near homogeneity. The purified kinase is a single polypeptide of approximately 34 kDa that phosphorylates only the 18-kDa Dictyostelium myosin regulatory light chain and itself among substrates tested. The enzyme was purified largely by ammonium sulfate fractionation and hydrophobic (butyl) interaction chromatography. Analysis using polyclonal antibodies raised against the purified 34-kDa protein confirms that this protein is responsible for myosin light chain kinase activity. Protein microsequence of the 34-kDa protein reveals conserved protein kinase sequences. The purified Dictyostelium myosin light chain kinase exhibits a Km for Dictyostelium myosin of 4 microM and a Vmax of 8 nmol/min/mg. Unlike other characterized myosin light chain kinases, this enzyme is not regulated by calcium/calmodulin. Western blot analysis demonstrates that the purified kinase is not a proteolytic fragment that has lost calcium/calmodulin regulation. The Dictyostelium myosin light chain kinase activity is not directly regulated by cyclic nucleotides. However, this kinase undergoes an intramolecular autophosphorylation that activates the enzyme.