Efficacy and challenges of anti-PD1 in MSI-H mCRC: a case report on concurrent infections and ir-AIHA.

Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated notable efficacy in treating patients with deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) metastatic colorectal cancer (mCRC). However, its clinical application is fraught with challenges and can lead to significant immune-related adverse events (ir-AEs). In this report, we present a complicated case of an mCRC patient with MSI-H and mutations in ß2M and LRP1B proteins, complicated by concurrent bacteremia and liver fluke infection, who received first-line anti-PD1 therapy. The patient exhibited a positive response to anti-PD1 treatment, even in the presence of concomitant antibiotic and anti-parasitic interventions. Additionally, the patient experienced immunotherapy-related autoimmune hemolytic anemia (ir-AIHA), a rare hematological ir-AE, which was effectively treated later on. Immunotherapy represents a pivotal and highly effective approach to tumor treatment. Baseline assessment of the MMR and MSI status is a crucial step before initiating immunotherapy, and regular ongoing assessments during the treatment course can facilitate early recognition of any secondary complications, enabling prompt intervention and ensuring optimal therapeutic outcomes. Overall, a multidisciplinary diagnostic and therapeutic algorithm can help maximize the therapeutic benefits of immunotherapy.

3D Killer Turn Angle in Transtibial Posterior Cruciate Ligament Reconstruction Is Determined by the Graft Turning Angle both in the Sagittal and Coronal Planes.

OBJECTIVE: During the transtibial posterior cruciate ligament (PCL) reconstruction, surgeons commonly pay more attention to the graft turning angle in the sagittal plane (GASP), but the graft turning angle in the coronal plane (GACP) is always neglected. This study hypothesized that the three-dimensional (3D) killer turn angle was determined by both the GASP and GACP, and aimed to quantitively analyze the effects of the GASP and GACP on the 3D killer turn angle. METHODS: This was an in-vitro computer simulation study of transtibial PCL reconstruction using 3D knee models. Patients with knee injuries who were CT scanned were selected from the CT database (April 2019 to January 2021) at a local hospital for reviewing. A total of 60 3D knees were simulated based on the knees' CT data. The femoral and tibial PCL attachment were located on the 3D knee model using the Rhinoceros software. The tibial tunnels were simulated based on different GASP and GACP. The effects of the GASP and GACP on the 3D killer turn angle were quantitatively analyzed. One-way analysis of variance was used to compare the outcomes in different groups. The regression analysis was performed to identify variables of the GASP and GACP which significantly affected 3D killer turn angle. RESULTS: The 3D killer turn angle showed a significant proportional relationship not only with the GASP (r2 > 0.868, P < 0.001), but also with the GACP (r2 > 0.467, P < 0.001). Every 10° change of the GACP caused 2.8° to 4.4° change of the 3D killer turn angle, whereas every 10° change of the GASP caused 6.4° to 9.2° change of the 3D killer turn angle. CONCLUSIONS: The 3D killer turn angle was significantly affected by both the GASP and GACP. During the transtibial PCL reconstruction, the proximal anterolateral tibial tunnel approach could increase the 3D killer turn angle more obviously compared with the most distal anteromedial tibial tunnel approach. To minimize the killer turn effect, both the GASP and GACP were required to be considered to increase.

Primary mediastinal seminoma with leiomyosarcoma: a rare case report.

Germ cell tumor is the most common malignant tumor of the gonads, sometimes they are found in locations other than the gonads, called Extra-gonadal Germ cell tumours (EGCTs). Primary mediastinal germ cell tumors (PMGCTs) are a kind of rare neoplasm in the anterior mediastinum, including seminoma and non-seminomatous, or appear as a mixture. Primary mediastinal seminoma mixed with sarcoma is an extremely rare clinicopathologic entity. Previous studies have revealed that primary pure mediastinal seminomas are commonly sensitive to chemoradiotherapy and possibly to palliative excision. The treatment options for mixed germ cell tumor composed of seminoma and sarcoma remain unknown. Only one case of primary mediastinal seminoma with rhabdosarcoma has been reported in the literature up to date and the patient benefited from chemotherapy as the neoadjuvant therapy. However, cases of primary mediastinal seminoma with leiomyosarcoma have not been documented. Herein, we report a case of an 18-year-old patient, who presented with dyspnea, orthopnea, and chest pain, the CECT scan of the chest showed a large mass in the anterior mediastinum, which turned out to be seminoma mixed with leiomyosarcoma after partial excision. We investigate the treatment strategy and potential molecular mechanism of this disease. Finally, our study demonstrated that the patient benefited from the treatment of chemotherapy alone, or combined with target therapy after the operation. Meanwhile, the BRAF p.G466V, TP53 mutations, MTOR p.T1977I and exons 2-5 deletion of FLCN may be potential molecular mechanisms and oncogenic drivers of this disease.

The Permissive Safe Angle of the Tibial Tunnel in Transtibial Posterior Cruciate Ligament Reconstruction: A Three-Dimensional Simulation Study.

OBJECTIVE: To determine the permissive safe angle (PSA) of the tibial tunnel in transtibial posterior cruciate ligament (PCL) reconstruction based on a three-dimensional (3D) simulation study. METHODS: This was a computer simulation study of transtibial PCL reconstruction using 3D knee models. CT images of 90 normal knee joints from 2017 to 2020 were collected in this study, and 3D knee models were established based on CT data. The tunnel approaches were subdivided into the anterior 1/3 of the anteromedial tibia (T1), middle 1/2 of the anteromedial tibia (T2), the tibial crest (T3), anterior 1/3 of the anterolateral tibia (T4), middle 1/2 of the anterolateral tibia (T5). Five tibial tunnels (T1-T5) were simulated on the 3D knee models. The PSAs, in different tibial tunnel approaches were measured, and subgroup analyses of sex, age and height were also carried out. RESULTS: The mean PSAs of the tibial tunnels with 5 different approaches (T1-T5) were 58.49° ± 6.82°, 61.14° ± 6.69°, 56.12° ± 7.53°, 52.01° ± 8.89° and 49.90° ± 10.53°, respectively. The differences of the mean PSAs between the anteromedial and anterolateral approaches were significant (P < 0.05). However, there was no significant difference of the mean PSA value between the two anteromedial tibial tunnel approaches (T1-T2) (P > 0.05), as well as between the two anterolateral tibial tunnel approaches (T4-T5). The patient's anthropomorphic characteristics of sex, age, and height were not associated with the PSAs. CONCLUSIONS: The PSA varied with the anteromedial, tibial crest and anterolateral approaches for transtibial PCL reconstruction, and surgeons should limit the PCL drill guide by referring to the specific PSA for different surgical approaches.

What Is the Maximum Tibial Tunnel Angle for Transtibial PCL Reconstruction? A Comparison Based on Virtual Radiographs, CT Images, and 3D Knee Models.

BACKGROUND: To minimize the killer turn caused by the sharp margin of the tibial tunnel exit in transtibial PCL reconstruction, surgeons tend to maximize the angle of the tibial tunnel in relation to the tibial plateau. However, to date, no consensus has been reached regarding the maximum angle for the PCL tibial tunnel. QUESTIONS/PURPOSES: In this study we sought (1) to determine the maximum tibial tunnel angle for the anteromedial and anterolateral approaches in transtibial PCL reconstruction; (2) to compare the differences in the maximum angle based on three measurement methods: virtual radiographs, CT images, and three-dimensional (3D) knee models; and (3) to conduct a correlation analysis to determine whether patient anthropomorphic factors (age, sex, height, and BMI) are associated with the maximum tibial tunnel angle. METHODS: Between January 2018 and December 2020, 625 patients who underwent CT scanning for knee injuries were retrospectively reviewed in our institution. Inclusion criteria were patients 18 to 60 years of age with a Kellgren-Lawrence grade of knee osteoarthritis less than 1 and CT images that clearly showed the PCL tibial attachment. Exclusion criteria were patients with a history of tibial plateau fracture, PCL injuries, tumor, and deformity around the knee. Finally, 104 patients (43 males and 61 females, median age: 38 [range 24 to 56] years, height: 165 ± 9 cm, median BMI: 23 kg/cm2 [range 17 to 31]) were included for analysis. CT data were used to create virtual 3D knee models, and virtual true lateral knee radiographs were obtained by rotating the 3D knee models. Virtual 3D knee models were used as an in vitro standard method to assess the true maximum tibial tunnel angle of anteromedial and anterolateral approaches in transtibial PCL reconstruction. The tibial tunnel's entry was placed 1.5 cm anteromedial and anterolateral to the tibial tubercle for the two approaches. To obtain the maximum angle, a 10-mm- diameter tibial tunnel was simulated by making the tibial tunnel near the posterior tibial cortex. The maximum tibial tunnel angle, tibial tunnel lengths, and perpendicular distances of the tunnel's entry point to the tibial plateau were measured on virtual radiographs, CT images, and virtual 3D knee models. One-way ANOVA was used to compare the differences in the maximum angle among groups, and correlation analysis was performed to identify the relationship of the maximum angle and anthropomorphic factors (age, sex, height, and BMI). RESULTS: The maximum angle of the PCL tibial tunnel relative to the tibial plateau was greater in the anteromedial group than the anterolateral group (58° ± 8° versus 50° ± 8°, mean difference 8° [95% CI 6° to 10°]; p < 0.001). The maximum angle of the PCL tibial tunnel was greater in the virtual radiograph group than the CT image (68° ± 6° versus 49° ± 5°, mean difference 19° [95% CI 17° to 21°]; p < 0.001), the anteromedial approach (68° ± 6° versus 58° ± 8°, mean difference 10° [95% CI 8° to 12°]; p < 0.001), and the anterolateral approach (68° ± 6° versus 50° ± 8°, mean difference 18° [95% CI 16° to 20°]; p < 0.001), but no difference was found between the CT image and the anterolateral groups (49° ± 5° versus 50° ± 8°, mean difference -1° [95% CI -4° to 1°]; p = 0.79). We found no patient anthropomorphic characteristics (age, sex, height, and BMI) that were associated with the maximum angle. CONCLUSION: Surgeons should note that the mean maximum angle of the tibial tunnel relative to the tibial plateau was greater in the anteromedial than anterolateral approach in PCL reconstruction, and the maximum angle might be overestimated on virtual radiographs and underestimated on CT images. CLINICAL RELEVANCE: To perform PCL reconstruction more safely, the findings of this study suggest that the PCL drill system should be set differently for the anteromedial and anterolateral approaches, and the maximum angle measured by intraoperative fluoroscopy should be reduced 10° for the anteromedial approach and 18° for the anterolateral approach. Future clinical or cadaveric studies are needed to validate our findings.

Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Although combination therapy with immune checkpoint inhibitors (ICIs) provides a promising efficacy in multiple cancers, their use is facing challenges for a high incidence of adverse effects. This meta-analysis was conducted to compare the risks of organ-specific immune-related adverse events (IRAEs) associated with ICI monotherapy versus combination therapy among cancer patients. METHODS: Electronic databases were systematically searched to include eligible randomized controlled trials (RCTs). Any-grade and 3-5 grade IRAEs (colitis, pneumonitis, hepatitis, hypothyroidism, hyperthyroidism, and hypophysitis) were extracted for meta-analysis. Two reviewers independently assessed the methodological quality. The RevMan 5.3.5 software was used for meta-analysis. RESULTS: A total of 10 studies involving 8 RCTs with 2716 patients were included in this study. The most common any-grade adverse event was colitis (14.5%), followed by hypothyroidism (13.8%), hepatitis (10.4%), hypophysitis (10.0%), hyperthyroidism (9.3%), and pneumonitis (4.6%). Meta-analysis showed that ICI combination therapy significantly increased the risks of any-grade IRAEs in colitis [relative risk (RR), 3.56; 95% confidence interval (CI), 1.56-8.12; p < 0.05], pneumonitis (RR, 2.31; 95% CI, 1.54-3.45; p < 0.05), hepatitis (RR, 2.54; 95% CI, 1.65-3.91; p < 0.05), hypothyroidism (RR, 2.17; 95% CI, 1.71-2.76; p < 0.05), hyperthyroidism (RR, 3.13; 95% CI, 2.08-4.70; p < 0.05), and hypophysitis (RR, 3.54; 95% CI, 2.07-6.07; p < 0.05) compared with ICI monotherapy, as well as 3-5 grade IRAEs in colitis (RR, 2.50; 95% CI, 1.62-3.86; p < 0.05), pneumonitis (RR, 1.99; 95% CI, 1.00-3.93; p = 0.05), and hepatitis (RR, 2.70; 95% CI, 1.29-5.63; p < 0.05). CONCLUSIONS: This meta-analysis demonstrated that, compared with ICI monotherapy, patients receiving ICI combination therapy significantly increased organ-specific IRAEs in colitis, hypothyroidism, hepatitis, hypophysitis, hyperthyroidism, and pneumonitis. The incidence and severity of organ-specific IRAEs were drug and dose independent.

Transcription factor glioma-associated oncogene homolog 1 is required for transforming growth factor-ß1-induced epithelial-mesenchymal transition of non-small cell lung cancer cells.

Epithelial­mesenchymal transition (EMT) is the process by which epithelial cells depolarize and acquire a mesenchymal phenotype, and is a common early step in the process of metastasis. Patients with lung cancer frequently already have distant metastases when they are diagnosed, highlighting the requirement for early and effective interventions to control metastatic disease. Transforming growth factor­ß1 (TGF­ß1) is able to induce EMT, however the molecular mechanism of this remains unclear. In the current study, TGF­ß1 was reported to induce EMT and promote the migration of non­small cell lung cancer (NSCLC) cells. A notable observation was that EMT induction was accompanied by the upregulation of human glioma­associated oncogene homolog 1 (Gli1) mRNA and protein levels. Furthermore, Gli1 levels were depleted by small interfering RNA, and the Gli1 inhibitor GANT 61 attenuated the TGF­ß1­mediated induction of EMT and cell migration. The results of the current study suggest that Gli1 regulates TGF­ß1­induced EMT, which may provide a novel therapeutic target to inhibit metastasis in patients with NSCLC.