Challenges in Robotic Lung Lobectomy through the Anterior Approach.

PURPOSE: Robot-assisted thoracic surgery (RATS) has become popular because of its minimally invasive nature and reduced burden on surgeons. The anterior approach (AA) is beneficial because it utilizes the same field of view and procedures as thoracotomy and video-assisted thoracic surgery, although the disadvantages are less well-known. METHODS: We retrospectively examined 35 consecutive patients who underwent RATS lobectomy via the AA, focusing on clinical factors and postoperative complications. RESULTS: The study included 12 males and 23 females with a median console time of 177 (120-346) min, median blood loss of 0 (0-100) mL, and median stapler usage of 5 (2-10) units. Postoperative complications, classified as Clavien-Dindo grade ≥III, included three cases of grade IIIa (prolonged air leakage) and one case each of grade IIIb and grade IVa (middle lobe torsion and ventricular arrhythmia). The influence of stapling device operation cannot be ruled out in prolonged air leakage and middle lobe torsion. A moderate correlation (correlation coefficient = 0.492, p = 0.003) was observed between console time and the number of staplers used. CONCLUSION: Although no severe incidence of vascular injury was observed with the AA, complications related to the use of stapling devices were noted.

Osimertinib as first-line treatment for recurrent lung cancer patients with EGFR mutation.

Background: Although osimertinib was approved as adjuvant therapy for lung cancer patients with EGFR mutation in various countries, there is still some ongoing debate as osimertinib has been approved based on disease-free survival (DFS) rather than overall survival (OS). We curated a case series in which we documented patterns of recurrence and efficacy and safety of osimertinib after recurrence. Methods: Patients who received osimertinib as first-line treatment for postoperative recurrence between September 2018 and January 2023 were included. Clinicopathological factors, duration of osimertinib treatment (DoT), and adverse events were collected and analyzed. Results: Twenty patients received osimertinib [male, n=6; median age, 75 years (range, 55-85 years)]. The EGFR mutation type was L858R in 11 patients and exon 19 deletion in eight patients. The performance status (PS) was 0 or 1 in all but two patients, who had symptomatic brain metastasis and were therefore PS 3. The first site of postoperative recurrence was locoregional in five patients and distant in 15 patients, including seven with brain metastasis. As of February 2023, 10 patients were still on osimertinib, including three with brain metastasis. Patients with brain metastasis or poor PS had a considerably shorter DoT than their counterparts. Three patients with symptomatic brain metastasis or leptomeningeal metastasis initially responded to osimertinib, but all died of disease progression. Five patients discontinued osimertinib due to serious adverse effects (pneumonitis, drug eruption, and heart failure). Conclusions: Although osimertinib exerts great disease control, even in patients with brain metastasis or poor PS, their presence was associated with a poor prognosis, even with osimertinib treatment. Therefore, adjuvant osimertinib is recommended unless contraindicated.

Giant benign intrathoracic schwannoma: a decade-long progression towards fatality.

BACKGROUND: Intrathoracic neurogenic tumors arise from sympathetic nerve trunks and intercostal nerves; more than 90% are benign. Schwannomas are the most common histological variety, but fatalities due to giant schwannomas are rare. CASE PRESENTATION: We report a case of a 65-year-old woman who presented with chest pain and cough. Computed tomography (CT) revealed a large left chest wall mass of 130-mm in size, and the patient was referred to our department. Tumor biopsy was performed under local anesthesia, and a diagnosis of schwannoma was made. Ten years previously, a 30-mm tumor had been noted in the left third intercostal space by a previous doctor, but follow-up had been interrupted owing to depressive disorder. Although we planned to perform intercostal artery embolization followed by chest wall tumor resection, the patient did not consent to surgery due to uncontrolled depression. After four months, she developed respiratory failure caused by compression due to an enlarged tumor and died. Autopsy also revealed a benign schwannoma with no malignant findings. CONCLUSIONS: Although schwannomas are benign tumors, there are some very rare cases in which they can become huge and life-threatening. Therefore, a benign tumor should not be neglected, and if surgery is not possible at the time of diagnosis, a regular follow up is necessary, in order not to miss the right timing for surgery.

Significance of programmed death-ligand 1 expression in resected lung cancer and its relationship with EGFR mutation.

BACKGROUND: Several studies have reported that the high expression of programmed death-ligand 1 (PD-L1) within tumor cells predicts a poor prognosis. However, the relationship between the PD-L1 expression and lymph node metastasis or driver mutations in lung cancer remains poorly understood. METHODS: A total of 356 consecutive patients who underwent surgical resection for primary lung cancer were included in the study. There were 268 adenocarcinomas including 100 EGFR mutations, 67 squamous cell carcinomas (Sq), and 21 other histologies. The high expression of PD-L1 was defined as a tumor proportion score (TPS) of ≥50. The relationship between the PD-L1 expression and clinicopathological factors and recurrence-free survival (RFS) was analyzed. RESULTS: The PD-L1 expression was high in 75 patients. It was significantly related to smoking history, Sq histology, driver mutation negative, elevated serum carcinoembryonic antigen levels, and lymph node metastasis. Among patients with driver mutations, a high PD-L1 TPS was found in patients with EGFR G719X mutation. A significant difference in RFS was observed in adenocarcinoma patients. A multivariate analysis of adenocarcinoma cases revealed that tumor size and lymph node metastasis were independent prognostic factors for poor RFS, while the PD-L1 expression was not. A logistic regression analysis revealed that the absence of driver mutations, lymph node metastasis, and a history of smoking were significantly associated with the high expression of PD-L1. CONCLUSION: Lymph node metastasis was positively related with the high expression of PD-L1, resulting in poor RFS. A high PD-L1 TPS was observed in patients with the EGFR G719X mutation.

Cyclin-dependent kinase (CDK) 4/6 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide, and EGFR mutation is the most common genetic alteration among Asian patients with lung adenocarcinoma. While osimertinib has been shown to be effective in lung cancer patients with EGFR mutation, the majority of patients eventually develop acquired resistance to treatment. We explored the significance of the cyclin D1 expression in patients with EGFR mutation and the potential efficacy of adding abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, simultaneously with osimertinib in vitro. MATERIALS AND METHODS: Immunohistochemical staining, using an anti-cyclin D1 antibody, of specimens from 83 patients with EGFR mutation (male, n = 27; pStage 0-I, n = 71) who were treated by surgical resection between 2017 and 2020, and the relationship between the cyclin D1 expression and clinicopathological factors was analyzed. Additionally, the combined effect of osimertinib and abemaciclib in lung cancer cell lines were analyzed using a growth inhibition test, and the signaling pathway underlying the combined effect was investigated. RESULTS: Cyclin D1 was negative in 18.1% of patients with EGFR mutation, and cyclin D1 negativity was associated with pStage ≥ II (p = 0.02), lymph node metastasis (p = 0.001), and lymphatic invasion (p = 0.01). The cyclin D1-negative group had significantly shorter recurrence-free survival (p = 0.02), although this difference disappeared when limited to pN0 patients. In EGFR mutated cell lines, the combination of osimertinib and abemaciclib demonstrated synergistic effects, which were thought to be mediated by the inhibition of AKT phosphorylation. CONCLUSION: Combination therapy with CDK4/6 inhibitors and EGFR-TKIs may be a promising approach.

Tracheal injury from dog bite in a child.

BACKGROUND: Dog bites associated with the head and neck area in children are a common problem. Most of the lacerations are found in the upper lip and the nose region, and tracheal injury is rare [1]. Tracheal injury requires prompt and accurate diagnosis and treatment to rescue the patient. Especially in children, securing the airway is often more difficult than in adults because of their short neck and narrow trachea. In this report, we experienced a pediatric case of multiple dog bites with tracheal injuries in the neck. CASE PRESENTATION: We report the case of a 3-year-old girl who presented with multiple dog bites. There were multiple wounds on the head, face, neck, and anterior chest, and air leakage was observed from the cervical wound at the time of transfer. It was difficult to perform oral endotracheal intubation, therefore, we extended the neck wound, probed the trachea with finger, and inserted a tracheal tube directly from the cervical wound in the emergency room. Tracheoplasty and another wound cleansing were performed in the operating room. The patient was discharged on the 18th day after surgery, without further complications. CONCLUSION: Tracheal injury from a dog bite is rare. It is important to prompt and accurate diagnosis and treatment. Children should be especially careful because of their short necks and narrow tracheas.

MET kinase inhibitor reverses resistance to entrectinib induced by hepatocyte growth factor in tumors with NTRK1 or ROS1 rearrangements.

BACKGROUND: Entrectinib is an effective drug for treating solid tumors with NTRK gene rearrangement and non-small cell lung cancer (NSCLC) with ROS1 gene rearrangement. However, its efficacy is limited by tolerance and acquired resistance, the mechanisms of which are not fully understood. The growth factors produced by the tumor microenvironment, including hepatocyte growth factor (HGF) produced by tumor-associated fibroblasts, critically affect the sensitivity to targeted drugs. METHODS: We investigated whether growth factors that can be produced by the microenvironment affect sensitivity of NTRK1-rearranged colon cancer KM12SM cells and ROS1-rearranged NSCLC HCC78 cells to entrectinib both in vitro and in vivo. RESULTS: Among the growth factors assessed, HGF most potently induced entrectinib resistance in KM12SM and HCC78 cells by activating its receptor MET. HGF-induced entrectinib resistance was reversed by the active-HGF-specific macrocyclic peptide HiP-8 and the MET kinase inhibitor capmatinib in vitro. In addition, HGF-producing fibroblasts promoted entrectinib resistance in vitro (culture model) and in vivo (subcutaneous tumor model). The use of capmatinib circumvented entrectinib resistance in a subcutaneous tumor model inoculated with KM12SM and HGF-producing fibroblasts. CONCLUSION: Our findings suggest that growth factors in the tumor microenvironment, such as HGF, may induce resistance to entrectinib in tumors with NTRK1 or ROS1 rearrangements. Our results further suggest that optimally co-administering inhibitors of resistance-inducing growth factors may maximize the therapeutic efficacy of entrectinib.

Inhibition of EGFR and MEK surmounts entrectinib resistance in a brain metastasis model of NTRK1-rearranged tumor cells.

Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology-agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1-G595R. Repotrectinib is a second-generation TRK inhibitor, which is active against NTRK1-G595R. However, its efficacy against entrectinib-resistant tumors has not been fully elucidated. In the present study, we established entrectinib-resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1-rearranged KM12SM cells and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1-G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal-regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors, thereby causing resistance to second-generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.

Mediastinal Malignant Melanoma Markedly Shrinking in Response to Nivolumab.

Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.

Clinical significance of part-solid lung cancer in the eighth edition TNM staging system.

OBJECTIVES: The ground-glass component of part-solid tumour (PST) was eliminated as a clinical T (cT) descriptor in the eighth edition of the tumour, node and metastasis (TNM) staging system. We aimed to validate the new cT descriptor and investigate the prognostic impact of PST in the new staging system. METHODS: Non-small-cell lung cancer (NSCLC) patients (n = 1061) who underwent lung resection and were available for the assessment of thin-section computed tomography images were retrospectively reviewed. Tumours with a solid component (SC) size-to-whole tumour size (STR) ratio of 0, those with 0 < STR < 1 and those with an STR of 1 were defined as pure ground-glass tumours, PSTs and solid tumours (STs), respectively. RESULTS: Tumours with an SC diameter of >30 mm were less frequently observed among PSTs than among STs (4.83% vs 32.6%, P < 0.001). The postoperative 5-year survival of NSCLC patients with ground-glass tumour, PST and ST was 97.6%, 89.0% and 76.3%, respectively. In the survival analysis of patients with an SC diameter ≤30 mm, significant differences were observed among PST and ST (5-year survival, 90.7% vs 74.6%, P < 0.001). The multivariable analysis showed that age <70 years old, female sex, procedures with a lobectomy or more, SC size, pN0 disease and PST were independent predictors of a better survival among all PST and ST patients. CONCLUSIONS: Among patients with cT1 tumours, those with PST showed a significantly better survival than did those with ST. Small-sized PST tumours may not be suitable for the new cT descriptor.

Multi-institutional survey of cancer disparities in disabled patients in the region of northwestern Japan.

BACKGROUND: Potential disparities between cancer patients with and without disabilities remained to be validate in Japan. METHODS: We surveyed retrospective data on hospital cancer registration as well as information on disability certificates obtained through the Hokushin Ganpro database. In total, 93,545 cancer patients in 10 principal hospitals covering the region of northwestern Japan were registered with the Hokushin Ganpro database between 2010 and 2015. The database included the following data: diagnosis date, cancer type, staging, treatment, cancer detection process, and possession of a disability certificate. RESULTS: We found that 2983 patients, which accounted for 3.2% of the total patients, had disabilities. No significant differences in gender, age at diagnosis, cancer stage distribution, and cancer incidence rates were observed between the disabled and non-disabled patients. Even though the proportion of early-stage cancer among disabled patients differed only slightly from that in non-disabled patients, early-stage cancer was more frequently diagnosed in patients with disabilities during their regular hospital visits than in those without disabilities, who had more opportunity for early cancer detection during cancer screening. According to in-house data reflecting treatment period and process from a single hospital, all 16 disabled patients treated with chemotherapy completed the treatment until disease progression or end of predetermined cycles. CONCLUSION: These results indicate that deep disparities between cancer patients with and without disabilities are not apparent and that the disabled patients in the region of northwestern Japan receive appropriate hospital follow-up.

Resection and postoperative radiation therapy for desmoid fibromatosis of the chest wall in a young woman.

BACKGROUND: Surgery is an effective treatment for desmoid fibromatosis, but it may be difficult, depending on the location or local spread of the tumor, and the decision to perform surgery must be made carefully. We herein report a case of desmoid fibromatosis of the chest wall in a young woman suspected of having invasion to the 1st, 2nd and 3rd ribs. CASE PRESENTATION: A 35-year-old woman had been aware of dry cough and right chest pain, so she was referred to our hospital. Chest computed tomography showed a localized pleural tumor mainly at the first rib. Magnetic resonance imaging revealed a 75 × 65 × 27-mm tumor with a smooth surface, with partial contact from the first rib to third rib and partial extension to the 1st intercostal space. The tumor showed growth in the two months after the first visit, so resection was performed. The tumor was completely resected, and adjuvant radiation therapy (50 Gy) was performed for the small margin. The pathological diagnosis was desmoid fibromatosis. The postoperative course has been uneventful, without recurrence at 14 months after surgery. CONCLUSIONS: In chest wall tumors located ventral of the pulmonary apex, we suggest that a combination of the Grunenwald method and Masaoka anterior approach may be a useful option. In cases where margin is not enough, adjuvant radiation therapy should be considered.

Ciliated muconodular papillary tumor of the lung: a case report and literature review.

Ciliated muconodular papillary tumor (CMPT) of the lung is characterized as a peripheral low-grade malignant tumor with ciliated columnar cells and goblet cells with basaloid cell proliferation. Herein, we report on a case of CMPT with a radiologically abnormal shadow which was reminiscent of adenocarcinoma. The patient underwent right S6 + S8a segmentectomy because an intraoperative biopsy suggested CMPT, the malignancy of which was difficult to distinguish; however, the tumor was small and located in the peripheral lung. Many details of this tumor remain unclear, as CMPT is a rare tumor with few reports. CMPT has therefore not yet been classified by the WHO. In this report, we will consider the characteristics of CMPT and treatment based on our case and previous case reports.

Erlotinib and bevacizumab combination therapy for afatinib-refractory leptomeningeal carcinomatosis from EGFR-mutated lung cancer.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors remains the main hurdle in treating EGFR-mutated lung cancer. Besides, when leptomeningeal carcinomatosis occurs during treatment, it often leads to treatment failure. We herein report a case of lung adenocarcinoma involving a patient with an EGFR exon 19 deletion mutation who developed leptomeningeal carcinomatosis after afatinib treatment for post-operative recurrence. He received right lower lobectomy, followed by four cycles of cisplatin and pemetrexed treatment. Follow-up CT/MRI revealed multiple pulmonary metastases and brain metastases at 7 months after surgery, and afatinib (40 mg/day) was administered after stereotactic radiotherapy for brain metastasis. At 28 months after surgery, follow-up MRI revealed asymptomatic leptomeningeal carcinomatosis, which was cytologically proven from the cerebrospinal fluid. Because EGFR T790M was not detected in plasma cell-free DNA or cerebrospinal fluid, erlotinib and bevacizumab combination treatment was administered. He remained asymptomatic and was radiographically clear of LM at 2 months after treatment. In comparison to other EGFR-TKIs, erlotinib shows penetrance into the cerebrospinal fluid. Furthermore, the addition of bevacizumab might enhance the treatment effect, because it is known to relieve brain edema from metastatic brain tumors by normalizing immature vascularity and improving drug penetrance into the cerebrospinal fluid by reducing interstitial fluid pressure.

Elevated red cell distribution width to platelet count ratio predicts poor prognosis in patients with breast cancer.

Red cell distribution width (RDW) to platelet ratio (RPR) is a prognosticator in acute pancreatitis and myocardial infarction; however, the prognostic values of RDW and RPR in breast cancer have not been studied. This retrospective analysis of 299 breast cancer patients investigated the association between RDW and RPR and clinicopathological characteristics and prognosis, compared to platelet distribution width to platelet count ratio (PDW/P) which is a known independent prognostic factor in patients with breast cancer. We found a significant correlation between RPR, and age and HER2 status. An elevated RPR significantly correlated with age and HER2 status. After a median follow-up duration of 48 months, tumour size, nuclear grade, PDW/P, and RPR were recgnized to be significantly associated with lower disease-free survival rates (tumour size: p < 0.01; nuclear grade, PDW/P, and RPR: p < 0.05) in univariate analysis. Tumour size and RPR were significant prognostic factors for lower disease-free survival rates, with hazard ratios of 4.31 (95% confidence interval: 1.76-10.53) (p < 0.01)] and 2.79 [95% confidence interval: 1.01-87.69) (p < 0.05)], respectively, in a multivariate analysis using the Cox proportional hazards model. This is the first study showing that an elevated RPR could independently predict poor prognosis in patients with breast carcinoma. Thus, RPR could be a novel biomarker for prognostic estimation.

Intratumoral heterogeneity of copy number variation in lung cancer harboring L858R via immunohistochemical heterogeneous staining.

BACKGROUND: Although intratumoral heterogeneity is commonly observed in several cancers, few studies have shown its presence in EGFR-mutated lung cancer. We performed immunohistochemistry to analyze the intratumoral heterogeneity in EGFR-mutated (L858R) lung cancer and performed targeted sequencing in specific cases. We discuss the effects of intratumoral heterogeneity and acquired resistance to EGFR-TKI. METHODS: Twenty resected primary lung cancers known to harbor EGFR L858R were analyzed. IHC was performed using an L858R mutant-specific rabbit monoclonal antibody and the samples were scored by staining intensity (0-3) and proportion. For cases with heterogeneous L858R protein expression, the nucleic acids were extracted from each differently stained lesion, and targeted sequencing was performed. Single nucleotide variations (SNVs) and copy number variations (CNVs) were then analyzed. The cell proliferation and apoptosis were also evaluated by the ki-67 labeling index and TUNEL staining. RESULTS: Among 20 cases, 3 showed heterogeneous staining. Genetic analyses for cases with heterogeneous staining revealed an increase in the copy number of EGFR in the IHC-positive part compared to the negative part, and an increase in the copy number of CCNE1 was observed in the IHC-positive part compared to the negative part in one case (case 1). In another case (case 2), an increase in the copy number of EGFR was observed in the IHC-positive part compared to the negative part, and an increase in the copy number of MDM2 was observed in the IHC-positive part compared to the negative part. In three cases, no SNV changes were observed. An increase in the ki-67 labeling index in the L858R-positive part in case 1 and increased apoptosis in the L858R-positive part in case 2 were observed, suggesting the functional significance of CNV changes. CONCLUSION: These cases exhibiting L858R IHC intratumoral heterogeneity suggest a heterogeneous effect on the cell activity due to CNV heterogeneity.

Acquired resistance to an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in an uncommon G719S EGFR mutation.

Background Acquired resistance (AR) to an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a common event, and several underlying mechanisms, including T790 M, MET amplification and PTEN downregulation, have been reported for the common EGFR mutations. EGFR G719X is an uncommon mutation that has been reported to show sensitivity to EGFR-TKIs. However, no established cell lines harboring the EGFR G719X have been reported in the literature. Materials and Methods G719S-GR cells were established from malignant pleural effusion of a patient whose tumor developed AR from gefitinib treatment. G719S-GR cells were then genotyped and tested for drug sensitivities. Multiplex ligation-dependent probe amplification (MLPA) was used to compare the clinical tumor samples with G719S-GR. Results G719S-GR cells were resistant to EGFR-TKIs with an LC50 of around 10 µM. A genomic analysis showed that G719S-GR cells harbor the EGFR G719S mutation as well as the amplification of EGFR locus. The homozygous deletion of CDKN2A and the loss of PTEN and TSC1 were also detected. On comparing the copy number of tumor suppressor genes using MLPA, G719S-GR cells were found to lack one copy of PTEN, which was not observed in a tumor obtained before gefitinib treatment. Loss of PTEN may result in AKT activation. The mTORC1/2 inhibitor Torin-1 was able to inhibit the downstream signaling when combined with osimertinib. Discussion The newly established G719S-GR cell line may be useful for investigating the mechanism underlying the development of AR in the G719X mutation; the loss of PTEN may be one such mechanism.

Cancer-associated retinopathy after surgery for breast cancer: a case report and review of the literature.

We herein report a 50-year-old Japanese woman with breast cancer who complained of blurred vision and central scotoma in her left eye on the 12th day after surgery. Subsequently, the sudden-onset binocular visual disorder progressed, and she was diagnosed with cancer-associated retinopathy (CAR) based on the clinical findings. Although her visual acuity temporarily improved following the start of adjuvant chemotherapy, reductions in her visual acuity progressed once again. After two courses of steroid pulse therapy initiated from the 59th day following the onset of CAR, although her visual field was still constricted, her binocular visual acuity improved from finger movement to 0.8 2 months later. The shorter the period from onset to treatment, the better the prognosis of the visual function. However, a diagnosis is often delayed because the incidence of this disease is very rare. Therefore, it is important to suspect CAR whenever a sudden visual disorder develops in cancer patients. Furthermore, treatment is believed to be effective even if steroid therapy is started up to 2 months from onset.

The Positive Relationship Between γH2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma.

BACKGROUND/AIM: Lung squamous cell carcinoma often arises from precancerous lesions where alterations in tumor suppressor genes and subsequent chromosomal instability are often observed due to carcinogen exposure. These tumors are often immunogenic; as such, immune checkpoint inhibitors are a promising therapeutic option. We hypothesized that the DNA damage response in tumor cells induces an immune response, thereby up-regulating programmed death-ligand 1 (PD-L1) expression on tumor cells, which in turn sensitizes them to anti-PD-1 therapy. PATIENTS AND METHODS: An immunohistochemical analysis was performed in 41 consecutive lung squamous cell carcinoma patients who underwent surgery at our institution between April 2013 and March 2014. RESULTS: The analysis revealed a high PD-L1 expression in 15 patients (37%) (p=0.028). The PD-L1 expression was positively associated with the nuclear γH2AX expression (p=0.02), that was confirmed by immunofluorescent staining. CONCLUSION: Our findings demonstrate that nuclear γH2AX expression is positively associated with the PD-L1 expression in lung squamous cell carcinoma.

The prognostic impact of the platelet distribution width-to-platelet count ratio in patients with breast cancer.

Activated platelets promote tumor cell growth, angiogenesis, and invasion. Platelet activity can be inferred by platelet volume indices (PVIs), which include platelet distribution width (PDW), mean platelet volume (MPV), platelet distribution width-to-platelet count ratio (PDW/P), and mean platelet volume-to-platelet count ratio. Platelets and platelet-related markers, such as the platelet-to-lymphocyte ratio, have been found to be significant prognostic factors in patients with breast cancer. However, the role of PVIs for predicting survival in breast cancer remains unknown; hence, we performed this retrospective analysis of 275 patients with breast cancer. PVIs were compared with clinicopathological variables, and were assessed to identify independent indicators associated with disease-free survival (DFS) using the Cox proportional hazards model. An elevated PDW/P significantly correlated with age and HER2 status. Univariate analysis revealed that elevated PDW, MPV, and PDW/P as well as tumor size, nuclear grade, and lymph node involvement were significantly associated with inferior DFS rates (tumor size: p<0.01; nuclear grade, lymph node involvement, PDW, MPV, and PDW/P: p<0.05). On multivariate analysis, a large tumor size and elevated PDW/P were significant prognostic factors for DFS, with hazard ratios of 3.24 (95% confidence interval [CI]: 1.24-8.47) and 2.99 (95% CI: 1.18-7.57), respectively (p<0.05). Our study is the first to reveal that an elevated PDW/P significantly reduces DFS in patients with breast carcinoma. Measuring the PDW/P is simple, relatively inexpensive, and almost universally available using routine blood counts; this makes it an attractive biomarker for improved risk assessment.