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Background: Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting., Methods: Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation., Results: Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2-4.8 and 4.3-9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08-3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups., Conclusions: This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms., (© 2024. The Author(s).)

Background/aim: Cisplatin-induced nephrotoxicity (CIN) is one of the most attention-requiring adverse effects. We have reported that diabetes mellitus significantly increases the incidence of CIN in a short hydration method in real-world lung cancer treatment. However, the effect of prediabetes on CIN development remains unclear. This study investigated whether patients with prediabetes exhibit CIN at a greater rate during real-world cisplatin-including treatments as a subgroup analysis., Patients and Methods: This retrospective observational study enrolled patients with lung cancer receiving cisplatin treatment (≥75 mg/m 2 ) from May 2014 to January 2021 (n=169). Patients were divided into a prediabetes group (baseline HbA1c 5.7-6.4%) and a control group (baseline HbA1c <5.7%). The primary endpoint of this study was the incidence of CIN in all treatment cycles between the two groups. We also assessed variations in serum creatinine (SCr) levels and creatinine clearance (CCr)., Results: CIN occurred in 4.7% of controls and 8.3% of patients with prediabetes in all cycles, with no significant difference (p=0.37). In contrast, variation of SCr levels and CCr was significantly worse in the prediabetes group [median variation level (range) 0.11 mg/dl (-0.11-0.46 mg/dl) and 0.12 mg/dl (-0.02-1.08 mg/d) in controls and prediabetes, p=0.04 for SCr; -12.9 ml/min (-54.1-4.9 ml/min) and -16.3 ml/min (-49.4-3.0 ml/min), p=0.02 for CCr, respectively]. These results were also confirmed during the first cycle of treatment., Conclusion: Patients with prediabetes did not develop problematic CIN, although they exhibited significant increases in SCr and decreases in CCr., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Treatment using docetaxel (DOC) and ramucirumab (RAM) is an effective regimen in second or later line advanced non-small cell lung carcinoma (NSCLC) treatment. However, it induces severe adverse effects, resulting in treatment reduction such as dose reduction and/or discontinuation. This study aimed to reveal the factor(s) associated with treatment reduction in DOC + RAM. We retrospectively evaluated patients with advanced NSCLC (n = 155). Treatment reduction of the second course due to severe adverse effects was conducted in 25.8% of the participants, and relative dose intensity at the second course was 95.7 ± 8.4% for DOC and 91.9 ± 24.8% for RAM. Multivariate logistic regression analyses identified that baseline anemia and prophylactic granulocyte colony-stimulating factor (G-CSF) administration are preventive factors for the reduction (adjusted odds ratio, 0.29; 95% confidence interval, 0.12-0.66; P = 0.004 for baseline anemia, 0.18; 0.08-0.42; P < 0.0001 for prophylactic G-CSF administration). The primary cause of the reduction was febrile neutropenia, and the same factors were identified. Our study revealed that patients with baseline anemia and prophylactic G-CSF administration have less risk for treatment reduction in DOC + RAM for NSCLC treatment., (© 2023. The Author(s).)

Objective: Chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-associated dyspepsia syndrome (CADS) are frequently appearing adverse effects of cisplatin (CDDP)-containing chemotherapy. Antiemetic guidelines suggest that the administration of antacids such as proton pump inhibitors (PPIs) or histamine type-2 receptor antagonists be considered for CADS, although their efficacy for treating these symptoms remains unknown. This study aimed to reveal whether antacids attenuate gastrointestinal symptoms in CDDP-containing chemotherapy., Materials and Methods: In total, 138 patients with lung cancer who received ≥ 75 mg/m 2 CDDP-containing regimens were enrolled in this retrospective study. Patients were divided into an antacid group including patients administered PPIs or vonoprazan during all chemotherapy periods and controls without antacid administration. The primary endpoint was the comparison of anorexia incidence during the first cycle of chemotherapy. Secondary endpoints were CINV evaluation and risk factor analysis for the incidence of anorexia using logistic regression analysis., Results: The incidence of anorexia during the first cycle was 54.4% in the control group and 60.3% in the antacid group, without significant differences (p = 0.60). The incidence of nausea was also similar between the groups (p = 1.00). Multivariate analysis suggested that antacid administration was not associated with anorexia., Conclusion: Baseline antacid administration does not affect gastrointestinal symptoms associated with CDDP-containing treatment in lung cancer.

Chemotherapy-induced myositis is a severe adverse event caused by chemotherapeutic agents such as immune checkpoint inhibitors (ICIs) or cytotoxic agents. We experienced a patient with gefitinib-induced myositis with symptoms of muscle cramps and stiffness in the limbs, and reported the treatment process. A 70-year-old woman received four courses of carboplatin (CBDCA)+pemetrexed (PEM)+gefitinib (intravenous CBDCA area under the curve (AUC) 5 and PEM 500 mg/m 2 , every 3 weeks, and oral gefitinib 250 mg daily), for epidermal growth factor receptor (EGFR) mutation-positive stage IV lung cancer treatment; followed by seven courses of PEM+gefitinib, and continued gefitinib monotherapy thereafter. Myositis occurred 5 months after the initiation of gefitinib monotherapy. She developed strong limb cramps despite regular oral administration of 400 mg acetaminophen three times a day and complained of pain on a numeric rating scale of 10/10. Her creatine kinase (CK) was elevated from the second course of CBDCA+PEM+gefitinib but was stable at grade 1-2 thereafter. However, the muscle symptoms disappeared with CK normalization within a few days of gefitinib discontinuation due to disease progression. The Naranjo Adverse Drug Reaction Scale score was 6, suggesting a probable association. Osimertinib (an EGFR tyrosine kinase inhibitor)-induced myositis has been reported, but similar events were first observed with gefitinib in this case. Consequently, when treating with gefitinib, myositis, including the CK variation, should be monitored and appropriately managed with multidirectional treatment.

Purpose: Osteosarcoma, the most common bone malignancy in children, has a poor prognosis, especially when the tumor metastasizes to the lungs. Therefore, novel therapeutic strategies targeting both proliferation and metastasis of osteosarcoma are required. Podoplanin (PDPN) is expressed by various tumors and is associated with tumor-induced platelet activation via its interaction with C-type lectin-like receptor 2 (CLEC-2) on platelets. We previously found that PDPN contributed to osteosarcoma growth and metastasis through platelet activation; thus, in this study, we developed an anti-PDPN humanized antibody and evaluated its effect on osteosarcoma growth and metastasis., Experimental Design: Nine osteosarcoma cell lines and two osteosarcoma patient-derived cells were collected, and we evaluated the efficacy of the anti-DPN-neutralizing antibody PG4D2 and the humanized anti-PDPN antibody AP201, which had IgG4 framework region. The antitumor and antimetastasis effect of PG4D2 and AP201 were examined in vitro and in vivo. In addition, growth signaling by the interaction between PDPN and CLEC-2 was analyzed using phospho-RTK (receptor tyrosine kinase) array, growth assay, or immunoblot analysis under the supression of RTKs by knockout and inhibitor treatment., Results: We observed that PG4D2 treatment significantly suppressed tumor growth and pulmonary metastasis in osteosarcoma xenograft models highly expressing PDPN. The contribution of PDGFR activation by activated platelet releasates to osteosarcoma cell proliferation was confirmed, and the humanized antibody, AP201, suppressed in vivo osteosarcoma growth and metastasis without significant adverse events., Conclusions: Targeting PDPN with a neutralizing antibody against PDPN-CLEC-2 without antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity is a novel therapeutic strategy for PDPN-positive osteosarcoma., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: Carboplatin (CBDCA) + nanoparticle albumin-bound paclitaxel (nab-PTX) is one of the most effective chemotherapeutic regimens for advanced non-small cell lung cancer (NSCLC) treatment. However, neutropenia and neuropathy are well-known dose-limiting toxicities associated with this regimen, frequently resulting in treatment suspension and dose reduction. In the present study, we aimed to identify risk factors associated with CBDCA + nab-PTX treatment suspension., Methods: Patients with NSCLC who received CBDCA + nab-PTX ± atezolizumab or pembrolizumab regimens were retrospectively evaluated. The risk factor(s) for treatment suspension and primary causes underlying suspension during the first course were assessed; the relative dose intensity (RDI) was compared between patients with and without identified factors., Results: The frequency of treatment suspension was determined as 55%. The causes for suspension were neutropenia (65.2%), infection (24.2%), thrombocytopenia (6.1%), and other conditions. The calculated RDI was 98.5% for CBDCA and 79.3% for nab-PTX. Based on univariate and multivariate analyses, grade 1 or higher liver dysfunction was identified as a risk factor for treatment suspension. We determined primary causes for treatment suspension as neutropenia and/or infection, as they are closely related. Next, we evaluated associated factors and determined age ≥65 years and performance status (PS) 2 as potential factors, in addition to liver dysfunction., Conclusion: We observed that liver dysfunction at baseline is a risk factor for treatment suspension. In addition, age ≥65 years and PS 2 can result in treatment suspension owing to neutropenia and/or infection during CBDCA + nab-PTX treatment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib., Methods: Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3-5 or 8-12 h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects., Results: Median PFS in H2RA group and control group was 8.0 months and 9.0 months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60-1.48, 0.52-1.43; p = 0.82 and 0.60, respectively)., Conclusion: This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib.

The most effective drugs based on the type of cancer are chosen for chemotherapy. Tumor cells can be targeted at the DNA, RNA or protein level, and most of the classical anticancer drugs interact with tumor DNA in a time-dependent manner or a concentration-dependent manner. However, it has been unclear to date whether a combination therapy is carried out by using exact classification. Thus it is necessary to reclassify a great number of anticancer drugs. We propose a new classification system based on pharmacological effects of anticancer drugs. Classification of four anticancer drugs (cisplatin, carboplatin, paclitaxel and gemcitabine) was performed by the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The four anticancer drugs were grouped by IC50 values (inhibitory concentration, 50%) in a time-dependent manner and a concentration-dependent manner. The present approach may be combined to enhance the chemosensitivity, improve the dose of cytotoxic drugs and evaluate the effects of novel anticancer drugs.

Background: The establishment of limited resection procedures for non-small cell lung cancer is expected. Many groups have suggested noninvasive bronchioloalveolar carcinoma (BAC) to be a potential indication for limited resection., Methods: We designed a prospective phase II study evaluating limited resection for noninvasive BAC diagnosed by intraoperative pathologic examination. From 1999 to 2007, limited resection was the procedure in 46 patients (16 men and 30 women; median age, 69 years; range, 49 to 83) who were diagnosed intraoperatively as having noninvasive BAC. The first end point was the predictive value of the intraoperative pathologic examination for noninvasive BAC diagnosis. The second end point was overall survival, disease-free survival, and cancer-specific survival, calculated using the Kaplan-Meier method., Results: We performed wedge resections for 44 patients and segmentectomy for 2 patients. Permanent pathologic examination revealed 3 patients had primary lung adenocarcinomas other than noninvasive BAC. The predictive value of intraoperative pathologic examination for noninvasive BAC diagnosis was 94%. During a median 51-month follow-up, there were only 2 cancer unrelated deaths. The 5-year overall survival rate and the disease-free survival rate were 93%, and the 5-year cancer-specific survival rate was 100%., Conclusions: The results of our prospective phase II study indicate that limited resection, mainly by wedge resection, is a potentially curative surgical procedure and may be an acceptable alternative to lobectomy for patients with noninvasive BAC. Furthermore, an intraoperative pathologic diagnosis of noninvasive BAC is strongly predictive and allows for an intraoperative decision to perform a limited resection in these patients.

We retrospectively studied the surgical treatment for pulmonary metastases from colon and rectal cancer. A total of 24 patients (9 males and 15 females; mean age 61 years) underwent 29 thoracotomies for metastatic colon carcinoma, while 22 patients (16 males and 6 females; mean age 63 years) underwent 29 thoracotomies for metastatic rectal cancer. The median interval between the primary procedure and lung resection for metastases was 26 months in the patients with colon carcinoma and 32 months in the patients with rectal cancer. In the patients with colon carcinoma, 16 underwent wedge resection or segmentectomy (including 4 video-assisted procedures) and 13 (54%) underwent lobectomy or pneumonectomy. In the patients with rectal cancer, 15 underwent wedge or segmentectomy (including 1 video-assisted procedure), 13 (59%) underwent lobectomy or pneumonectomy, and 1 underwent exploratory thoracotomy. All procedures except exploratory thoracotomy were curative operations. There was no mortality. Overall 5-year survival was 56% (n=46). Five-year survival was 65% for patients with colon metastases (n=24) and 45% for patients with rectal metastases (n=22), and there was no significant difference. Recurrent sites were 4 lungs (36%), 4 livers (36%), 1 bone, 1 uterus, and 1 peritoneum in patients with colon carcimoma, and 10 lungs (43%), 5 brains (22%), 3 livers (13%), 1 bone, and 1 vagina in patients with rectal cancer. Pulmonary resection for metastases from colon carcinoma may have better prognosis than that from rectal cancer. However, further investigation may be required to obtain convincing conclusions.

A 72-year-old male referred for surgical treatment underwent chest computed tomography to further investigate a well defined mass with a maximal diameter of 3.2 cm at the left S10. There was no pathological diagnosis established by either bronchoscopic biopsy specimens or computed tomography-guided percutaneous needle biopsy. The lower lobe and mediastinal lymph nodes were excised (complete resection). The 6.5-cm encapsulated grayish mass showed extensive areas of hemorrhage and necrosis on cut surface. Results from histological and immunohistochemical study yielded a definitive diagnosis of malignant schwannoma. Primary malignant schwannomas of the lung are extremely rare and the prognosis is poor in most cases. Our patient is currently well without recurrence more than 2 years after complete resection. Complete surgical resection is the best therapeutic option for primary malignant schwannoma of the lung.

Objective: We hypothesized that the cause of one-lobe intrapulmonary metastasis of primary lung cancer is mainly lymphatic, and investigated by means of the long-term outcome., Methods: From 1988 to 2000, 860 patients underwent complete resection of primary lung cancer patients in our hospital without neoadjuvant therapy. Patients were classified into 4 groups: group A (n 0 pm 0, n = 573), group B (n 0 pm 1, n = 37), group C (n 1 pm 0-1, n = 122), and group D (n 2 pm 0-1, n = 128)., Results: No significant difference was seen between groups in median age, sex ratio, histological cell type, or pathological tumor-size and p-factor. The rates of bi-lobectomy and pneumonectomy were higher in groups C and D than in groups A and B. The 5-year survival rate was 73% for group A, 57% for group B, 43% for group C, and 28% for group D. The 10-year survival rate was 57% for group A, 45% for group B, 20% for group C, and 16% for group D. There was a significant difference (p < 0.0001) between 4 groups in the 5- and 10-year survival rate., Conclusion: The hypothesis that the cause of one-lobe intrapulmonary metastasis may be lymphatic was not incompatible with the long-term results.

A 72-year-old woman developed left pneumothorax 14 months after the first operation of a gingival carcinoma. The chest X-ray films and computed tomographic scans on admission revealed left pneumothorax and 2 lesions with a thin-walled cavity in the upper lung field. They seemed to be pulmonary metastasis from a carcinoma of gingiva and one of them ruptured into the pleural cavity. As airleak continued after tube thoracostomy, wedge resections of 2 lesions were performed through thoracotomy. Postoperative histological examination revealed that both of the lesions were moderately differentiated squamous cell carcinoma and they were the same histological findings as the gingival carcinoma excised previously. Pulmonary metastasis from a carcinoma of gingiva is rare, while it may be thought 1% of metastatic lung tumors. And also pulmonary metastasis is unusual cause of pneumothorax, especially without chemotherapy for it. We reported the very rare case of pneumothorax due to pulmonary metastasis from a carcinoma of gingiva.

From 1986 to 2000, 42 patients (3.7%) underwent resection for intrathoracic recurrence or second primary lung cancer. Survival in 27 patients with recurrent diseases was 60% at 5 years and 35% at 10 years compared with 65% at 5 and 10 years for 15 patients with metachronous lung cancers morphologically. Ten patients had the second operation less than 2 years since the first operation, 19 patients between 2 and 5 years, and 13 patients more than 5 years, while these 5-year survivals were 72%, 53%, 67% respectively. At the first operation lobectomy was performed in 39 patients (93%), wedge resection or segmentectomy in 3. The reoperation was 14 lobectomy or completion pneumonectomy, 24 wedge or segmentectomy (57%), and 4 other procedures, while these 5-year survivals were 35%, 73%, and 100% respectively. The 5-year survival was 78% for 27 patients with stage I disease and 26% for 10 patients with stage III disease at the first operation, compared with 55% for 30 patients with stage I and 53% for 9 patients with stage III at the reoperation. These data suggest that limited resection is recommended for intrathoracic recurrent diseases and metachronous multiple lung cancers whenever possible.

Between 1988 and 2000, 1,040 patients with primary lung cancer underwent pulmonary resection at Nagaoka Red Cross Hospital. Thirty-one (2.9%) patients had synchronous primary lung cancer (group A) and 78 patients (7.5%) had intrapulmonary metastases (group B). The 5-year and 10-year survival rate for group A was 64% and 56% respectively and for group B 37% and 32% respectively. The patients in group A showed a better survival rate in the different lobes (80% at 5 years) than in the same lobe (55%), while those in group B gave reverse results (31% and 42%). In group A, the patients had a better survival rate in the different histology (73% at 5 years) than in the same histology (45%). The 5-year survival was 65% for 20 patients with stage I disease, 75% for 4 patients with stage II disease, 43% for 75 patients with stage III and 25% for 10 patients with stage IV. These data suggest that synchronous primary lung cancer had a better prognosis than primary lung cancer with satellite nodules, but the histological discrimination between multiple lung cancers and intrapulmonary metastases was uncertain.

Twelve patients with stage IIIb non-small cell lung cancer underwent induction therapy and resection from January 1990 to July 1998. They were divided into two groups; group A (n = 5) received two (to four) preresectional cisplatin and videsine chemotherapy, group B (n = 7) received chemoradiotherapy (radiation with concurrent low-dose-daily cisplatin). All patients in both groups had clinically down-stage and had no major side effects preventing surgery. 3 patients underwent radical pneumonectomy and 9 patients had radical lobectomy with no operative mortality. In 9 patients the disease was pathologically downstaged. Overall five-year survival was 27%, while in group A it was 50%. In group B 2-year survival was 18% and the longest survivor had pulmonary recurrence four years after surgery. Our data show better prognosis in group A than in group B. This results suggest that chemotherapy may be superior pre-resectional therapy to chemoradiotherapy.

The effect of chemotherapy as the adjuvant therapy to bulky N2 disease (stage IIIA) non-small-cell lung cancer was examined. From January 1992 to December 1996, 464 patients with non-small-cell lung cancer underwent surgery. Seven patients (1.5%) with N2 disease (stage IIIA) received two cycles of preresectional cisplatin and vindesin chemotherapy, followed by standardized surgical resection (Group A). 46 patients (9.9%) had pathological N2 disease (T1-3, M0) after surgery (Group B). In Group A a complete resection was accomplished in two patients (28.6%), and five patients had incomplete resection with a deseased margin, followed thoracic irradiation 60 to 75 Gy. In three patients in Group A the N2 disease was pathologically downstaged to N1 or N0 disease. Overall survival at five years in Group A and in Group B was 48% and 39%, and median survival time was 49 months and 38 months. Although complete resection rate was lower in Group A (28.6%) than in Group B (78.2%), there was no significant difference between five year survival and median survival time in Group A and Group B. These data may be thought to suggest that induction chemotherapy in Group A was effective on occult micrometastatic disease.

Organ-specific colonization of metastatic tumor cells is regulated through complex interactions of specific adhesion molecules on the tumor cell surface with organ specific microvascular endothelium. The present paper shows the real time tumor cell trafficking under the actual blood flow, which became able to be determined using a new technology, positron emission tomography. This technology would be useful to evaluate the interaction of characteristic tumor cells with various organs in vivo. High and low metastatic rat mammary adenocarcinoma cell variants, MTLn3 and MTC, respectively, were labeled with [2-18F]2-fluoro-2-deoxy-D-glucose in vitro. The labeled cells preferentially accumulated in the lungs, in which the disposition was more intense for MTLn3 than for MTC cells especially for the first 2-10 min after injection, apparently reflecting the organ specific interaction of metastatic tumor cells which may lead to metastasis. Such a short time change of cell disposition is easily determined in a living animal by this new technique. Furthermore, sialidase treatment of MTLn3 cells suppressed the accumulation of these cells in lungs, suggesting that some sialyl glycoconjugates on the MTLn3 cell surface play an important role in cell adhesion to lung endothelium. Positron emission tomography scanning thus enables the noninvasive study of the interaction of characteristic tumor cells with specific endothelium in a living animal.