[Application of Bevacizumab beyond Progressive Disease in Patients with Lung Cancer Recurrence after Surgery].

BACKGROUND: The benefits of continuing bevacizumab (BEV) beyond progressive disease (PD) in patients with non-small cell lung cancer (NSCLC) remain unclear. We present our experience of continuing chemotherapy with BEV in patients with recurrent NSCLC after surgery. PATIENTS: From January 2010 to December 2016, chemotherapy with BEV was continued beyond PD in 20 patients. These patients included 10 men and 10 women, and their mean age at surgery was 71±10 years. Recurrence was observed at 630±460 days after surgery. RESULTS: The average number of protocols with BEV was 3±1 (1-6). The presented side effects were acceptable. Eight patients died of cancer. The 5-year survival rates after surgery, recurrence, and initiation of BEV were 78.8%, 50.1%, and 34.3%, respectively, and the median survival times were 2,465, 2,017, and 1,120 days, respectively. CONCLUSION: The majority of patients with operable NSCLC had a good performance status. We could detect recurrence early on, before the symptoms appeared, by regular examination. Therefore, these patients had an advantage in that more chemotherapeutic regimens could be administered to them and their prognosis could be improved by the continuation of BEV beyond over PD.

Minute pulmonary meningothelial-like nodule that was difficult to differentiate from lung adenocarcinoma due to specific computed tomography findings changes: A case report.

Minute pulmonary meningothelial-like nodules (MPMNs) are benign lesions characterized by the appearance of ground-glass nodules (GGN) on computed tomography (CT). In the present case, an MPMN gradually developed into a substantial component during chest CT follow-up, and the GGN gradually transformed into a part-solid nodule. The imaging course described in this case is quite unique. Such CT images are characteristic of malignant tumours, especially, highly differentiated adenocarcinomas, which are difficult to differentiate preoperatively. Therefore, it is important to report this case.

[Pulmonary epithelioid hemangioendothelioma].

A 62-year-old asymptomatic woman was referred to the National Cancer Center Hospital in Japan because of an abnormal shadow on an annual checkup chest X-ray. Chest computed tomography(CT)showed a well-demarcated nodular lesion of 3 cm in diameter in the right lower lobe. Since the nodule was located at the right pulmonary hilum, she underwent a right lower lobectomy. Histologically, the tumor was composed of solid nests or anastomosing strands of cells that were embedded in a hyalinized, focally myxoid stroma. Some of the tumor cells showed a striking feature of the presence of intracytoplasmic lumina that were visualized as clear spaces or vacuoles. These lumina were negative for alcian blue and periodic Schiff, and contained erythrocytes. Immunohistochemically, the tumor cells were stained for CD31 and FLI1. The tumor was diagnosed as a pulmonary epithelioid hemangioendothelioma.Pulmonary epithelioid hemangioendothelioma is a relatively rare entity.

Efficacy of Continuous Saline Irrigation Therapy for Descending Necrotizing Mediastinitis.

Objectives Descending necrotizing mediastinitis (DNM) is a poor prognosis disease. This study aims to examine the patient background and treatment of DNM and to identify more effective treatments for DNM. Methods The patient background and treatment of 11 patients who underwent surgery for DNM between November 2010 and June 2021 were studied. The patients were divided into six patients who underwent continuous saline irrigation (group I) and five patients who did not (group N). The differences in the drainage duration and length of hospital stay between the two groups were retrospectively investigated. Results Eleven patients were treated for DNM: six male and five female, with a median age of 61 years (35-79). Comorbidities included diabetes mellitus in three cases; one patient was administered steroids. The pathways of occurrence were anterior tracheal gap/vascular visceral gap/posterior visceral gap in group I (2/1/2) and group N (0/2/4). Progression was I/IIA/IIB according to Endo's classification in group I (1/1/4) and group N (3/1/1). The mean duration of irrigation was 9.0 ± 3.7 days, and the drainage duration in group I was 17.5 ± 8.2 days, which was significantly shorter than 31 ± 13.6 days in group N ( p < 0.048). The hospital stays in group I was 29.3 ± 8.4 days, which was significantly shorter than that in group N (68 ± 27.1 days; p < 0.015). Conclusions Irrigation therapy significantly shortened the drainage duration and hospital stay. Irrigation is a useful treatment for DNM.

Hypercalcemia in metastatic parathyroid carcinoma followed by hypocalcemia after resection: A case report.

A 72-year-old man was diagnosed with hypercalcaemia 13 years ago. He was diagnosed with hyperparathyroidism associated with a parathyroid tumour and surgery was performed. Postoperatively, his serum calcium levels, which had once normalized, rose again. Medical treatment for hypercalcaemia failed to control the condition. A chest computed tomography showed multiple pulmonary nodules which were diagnosed as pulmonary metastases of parathyroid carcinoma. The tumour was considered to be the cause of the hypercalcaemia and volume reduction surgery was performed. Immediately after surgery, the patient presented with hypocalcaemia and required calcium correction with Calcium Gluconate Hydrate. Since then, the serum calcium level has stabilized and the patient has progressed without medical treatment. Parathyroid carcinoma is rare. This is a valuable case in which the serum calcium level was controlled by surgery. The patient also developed post-operative hypocalcaemia, which should be reported.

Resection of a capillary haemangioma using robotic-assisted thoracic surgery: A case report.

Capillary haemangioma is a rare condition that is difficult to diagnose preoperatively because of its rarity and nonspecific imaging findings. In this report, we describe a case of capillary haemangioma diagnosed by robot-assisted thoracic surgery (RATS). A 72-year-old man was incidentally found to have an anterior mediastinal tumour on chest computed tomography. The preoperative imaging findings were indicative of thymoma, and surgical treatment by RATS was selected. The intraoperative findings suggested that the tumour was a haemangioma originating from the pericardiophrenic vein. The pathological findings revealed a well-defined tumour with capillaries in a vascular-like structure and some thrombus formation. The pathological diagnosis was capillary haemangioma. The patient was discharged unaided at 7 days postoperatively and no recurrence was observed at 16 months postoperatively.

Pulmonary vein thrombosis following a right upper lobectomy preceding acute arterial occlusion: a case report.

Our medical team observed a right upper lobe nodule in a 78-year-old man who was treated with warfarin for chronic atrial fibrillation. The nodule was diagnosed as adenocarcinoma via intraoperative frozen sectioning. We performed video-assisted right upper lobectomy and mediastinal lymph node dissection. Warfarin was discontinued in the perioperative period. However, unfractionated heparin was administered. Nonetheless, the patient developed acute arterial occlusion of the lower extremities on post-operative day 7. Contrast-enhanced computed tomography showed thrombosis in the right upper lobe pulmonary vein stump, which was considered to be the cause of the acute arterial occlusion. The patient underwent emergency thrombectomy following which his symptoms immediately improved. Herein, we report a rare case of pulmonary vein thrombosis occurring after a right upper lobectomy. Our findings may facilitate effective clinical decision-making.

Granulation after stenting for tuberculous bronchial stenosis treated with tranilast: A case report.

A 63-year-old woman was diagnosed with tuberculous bronchial stenosis of the left main bronchus following recurrent pneumonia. She underwent airway dilatation and stenting for long and severe stenosis. Initially, a Dumon Y-stent was implanted, but repeated granulation occurred at the distal end of the stent. The granulation reappeared repeatedly despite cauterization and stent replacement. An attempt at stent removal led to worsening of scar stenosis; therefore, it was reinstalled. Finally, two self-expandable metallic stents were implanted sequentially, and she remained asymptomatic for 14 months. After this, she presented with fever and a computed tomography showed obstructive pneumonia due to associated granulation at the distal end of the stent. She was then started on tranilast to treat the granulation with the stent in situ. Granulation almost completely disappeared after 4 months and no recurrence was noted at 12 months since the start of tranilast.

Combination treatment by the cervical approach with mediastinal drainage and continuous saline irrigation for descending necrotizing mediastinitis type IIb: a three-case series.

Descending necrotizing mediastinitis (DNM) is a severe, life-threatening disease and requires prompt treatment. The primary treatment for DNM is cervical and mediastinal drainage in addition to antibiotic treatment. However, the most appropriate drainage approach and the effectiveness of additional treatment remain unclear. In this study, we performed cervical and mediastinal drainage for three patients with type IIB DNM using the cervical approach alone. Continuous saline irrigation was administered as additional treatment. There is little evidence for the use of saline irrigation for DNM. We propose that this combination treatment may be more effective and has the potential to improve patient prognosis. In our report, the average drainage duration was 13 days, and the average hospital stay was 30 days. Furthermore, both drainage duration and hospital stay were shorter than those in previously reported cases. Our case series provides valuable insight into the use of combination treatment to treat DNM.

Unique clinicopathological characteristics of pulmonary squamous cell carcinoma with part-solid nodule.

Chest high-resolution computed tomography (HRCT) finding of part-solid nodule (PSN) is related to pulmonary adenocarcinoma (AC) with lepidic growth. We recently experienced a pulmonary squamous cell carcinoma (SCC) showing PSN pattern on HRCT. We present a 70-year-old man who had a small nodule with PSN pattern in the right lung field on HRCT. After clinical diagnosis of AC, lobectomy was performed. The tumour was pathologically diagnosed as SCC with lepidic growth. Histopathologically, the central area of the tumour showed keratinizing SCC, whereas the peripheral area revealed lepidic SCC cell growth between non-neoplastic type II pneumocytes and alveolar basement membrane. On the basis of the present case and five from the literature, SCC with lepidic growth had the following clinical characteristics: peripheral location, early stage detection, clinical misdiagnosis as AC, less progression, and favourable prognosis. This case may be a special type of SCC with less progression and favourable prognosis.

A rare case of thymoma with CA 19-9 production.

A 72-year-old man was diagnosed as having myasthenia gravis (MG). He underwent computed tomography which revealed an anterior mediastinal tumour. Laboratory examination revealed elevated levels (106.3 U/ml) of carbohydrate antigen (CA) 19-9 in serum. However, no malignant disease was detected on fluorodeoxyglucose-positron emission tomography. A diagnosis of thymoma associated with MG was considered and an extended thymectomy was performed. Histopathologically, thymoma was categorized as stage I based on the Masaoka classification, and as type AB according to the World Health Organization classification. Immunohistochemistry was positive for CA 19-9. The serum levels returned to the normal range post-operatively (16.7 U/ml). Herein, we report an extremely rare case of thymoma with raised levels of CA 19-9.

Quantitative Evaluation of Hormesis in Breast Cancer Using Histoculture Drug Response Assay.

PURPOSE: Hormesis is a phenomenon of growth stimulation at low doses and inhibition at higher doses. In cancer treatment, little is known about how hormesis affects cancer cell proliferation. We evaluated the hormetic dose-response relationship of paclitaxel using surgically resected breast cancer specimens on the basis of histoculture drug response assay (HDRA). METHODS: We used surgically resected fresh tumor specimens from 22 patients with breast cancer: 17 invasive ductal, 3 mucinous, and 2 other "special-type" cancers. All patients were female, ranging in age between 40 and 86 (median 60) years. Small pieces of viable cancer tissue were placed on collagen gel and cultured for 7 days with paclitaxel. Inhibition rates of paclitaxel at several concentrations were measured and fitted to a sigmoid dose-response curve. RESULTS: Hormesis was observed in 9 of the 22 cases; ED50 of cytotoxic effect was significantly higher (P = .0036) in hormesis (H) group (44.6 ± 4.2 µg/mL) than in nonhormesis (N) group (26.7 ± 3.5 µg/mL). CONCLUSION: We evaluated hormesis in breast cancer tissue using HDRA for the first time although previously confirmed in cultured cells. Hormesis seems to occur in patients undergoing treatment with anticancer agents, especially in a metastatic setting. Meanwhile, tumor growth may be stimulated in patients who are resistant to paclitaxel.

Imbalanced Expression of IGF2 and PCSK4 Is Associated With Overproduction of Big IGF2 in SFT With NICTH: A Pilot Study.

Context: Nonislet cell tumor hypoglycemia (NICTH) is a rare but serious paraneoplastic syndrome associated with large tumors. The high molecular weight IGF2, known as "big" IGF2, is produced by culprit tumors and leads to severe hypoglycemia. The detailed mechanism of its production in NICTH, however, remains unclear. Objective: To clarify the mechanism of production of big IGF2 in light of the processing of pro-IGF2 in patients with solitary fibrous tumor (SFT) and NICTH. Design: We enrolled 14 patients with SFT and divided them based on the presence or absence of hypoglycemia. In light of the processing of pro-IGF2 in SFT with hypoglycemia, we, retrospectively, compared the production levels of big IGF2 and the expression levels of IGF2 and proprotein convertase subtilisin/kexin type 4 (PCSK4), a proteolytic enzyme of pro-IGF2. Results: In all patients with NICTH, big IGF2 was detected in serum by western immunoblotting analysis. Moreover, we showed that two patients without hypoglycemia also had a small amount of big IGF2 in their serum. By immunohistochemical analysis, the protein expression level of IGF2 was significantly higher in the NICTH group than in the non-NICTH group (P = 0.043). The IGF2/PCSK4 protein expression-level ratio in the NICTH group was significantly higher than that in the non-NICTH group (P = 0.021). Conclusion: In patients with SFT and hypoglycemia, an imbalance of IGF2 and PCSK4 expression could lead to increased serum levels of big IGF2.

[Cut-off level of docetaxel, paclitaxel and gemcitabine in histoculture drug response assay for non-small cell lung cancer].

Cut-off levels of docetaxel (DOC), paclitaxel (PAC), and gemcitabine (GEM) in histoculture drug response assay are determined by data acquisition of non-small cell lung cancer. Inhibition rates were 47.5 +/- 22.2% in DOC (n=181), 66.6 +/- 25.1% in PAC (n=57), and 25.4 +/- 18.4% in GEM (n=63), respectively. Cut-off levels were determined as 50% in DOC, 60% in PAC, and 30% in GEM. The positive rates such as 47.5% in DOC, 68.4% in PAC, and 33.3% in GEM were obtained.

Fast Fourier transform analysis of pulmonary nodules on computed tomography images from patients with lung cancer.

PURPOSE: The outlines of primary lung cancers are more complicated than those of metastatic lung tumors on computed tomography (CT) images. This feature is useful for clarifying the diagnosis of pulmonary nodules before surgery. We applied fast Fourier transform (FFT) analysis for quantification of complexity of tumor outline. METHODS: Sequential cases of 72 primary lung cancers (Group PL) and 54 metastatic lung tumors (Group MT) were included. The outline of each tumor on chest CT images was described using polar coordinates, and converted to rectangular coordinates, yielding wave data of the tumor outline. The FFT was then used to analyze the wave data. The complexity index (Cxi) was defined as the sum of the amplitude of all harmonics over a fundamental frequency. RESULTS: The Cxi was higher (P <0.0001) for group PL (10.3 ± 6.7 mm) than for group MT (3.2 ± 2.4 mm), and it was correlated with tumor diameter in both groups. The cut-off equation "Cxi = 0.127 DT + 2.23" provided the highest diagnostic accuracy for distinguishing Group PL from Group MT such as a sensitivity of 95.8%, a specificity of 81.5%, and an accuracy of 89.7%. CONCLUSION: FFT analysis appears useful for quantification of complexity of the tumor outline.

Closure of esophagotracheal fistula after esophagectomy for esophageal cancer.

Fistula between the trachea and esophagogastric anastomosis after esophagectomy is rare. We successfully treated a 75-year-old woman with such a lesion by single-stage repair. The patient had undergone radical esophagectomy 20 years ago, and repeatedly developed aspiration pneumonia for recent 5 years. Radiological and endoscopic examinations demonstrated the fistula between the trachea at the level of sternal notch and esophagogastric anastomosis. The fistula was separated and the defects on both sides were closed. A sternocleidomastoid muscle flap was inserted between the two structures. The postoperative course was uneventful.

A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents.

In the present article, we quantitatively evaluated the dose-response relationship of hormetic reactions of anticancer agents in vitro. Serial dilutions of gemcitabine, cisplatin, 5-fluorouracil, vinorelbine, and paclitaxel were administered to the A549 non-small-cell lung cancer cell line. The bi-phasic sigmoidal curve with hormetic and cytotoxic effects is given by the formula y=(a-b/(1+exp(c(*)log(x)-d)))/(1+exp(e(*)log(x)-f)), that was used to perform a non-linear least square regression. The dose-responses of the five anticancer agents were fitted to this equation. Gemcitabine and 5-fluorouracil, which had the lowest ED50 for their hormetic reaction, had the most pronounced promotive effects out of the five anticancer agents tested. The hormetic reaction progressed exponentially with culturing time. Our theoretical model will be useful in predicting how hormetic reactions affect patients with malignant tumors.

Class III Beta-tubulin Expression in Non-small Cell Lung Cancer: A Predictive Factor for Paclitaxel Response.

AIM: In order to clarify whether class III beta-tubulin (TUBB3) is a predictive marker for paclitaxel (PTX) chemotherapy, chemosensitivity was examined using an in vitro drug sensitivity assay. PATIENTS AND METHODS: Twelve specimens from non-small cell lung cancer (NSCLC) patients were obtained for dose-response curve analysis and measurement of the half-maximal effective dose (ED50) of PTX using the histoculture drug response assay (HDRA). Forty-one specimens were evaluated using the HDRA and the inhibition ratio (IR) at a concentration of 25 µg/ml PTX (IR25) was measured. TUBB3 expression was evaluated by H-score in immunohistochemical staining. RESULTS: The ED50 of PTX was 24.5 ± 8.06 µg/ml. The median H-score was significantly higher (p=0.0076) in the high effective dose (HE)-group (ED50 >25 µg/ml) than in the low effective (LE)-group (ED50 ≤ 25 µg/ml). The mean IR25 was 53.8 ± 26.6%. The median H-score for the high-inhibition ratio (HI)-group (IR25 >50%) was significantly higher (p=0.0337) than the low-inhibition ratio (LI)-group (IR25 ≤ 50%). CONCLUSION: High TUBB3 expression in NSCLC appeared to correlate with lower PTX sensitivity.

[Histoculture drug response assay for solitary fibrous tumor--a case report].

A 49-year-old male was referred to our hospital because of an abnormal shadow in his left lower lung field on chest X-ray. Magnetic resonance imaging scans revealed a large mass on the left diaphragm. The tumor was surgically extirpated. The tumor, encapsulated and growing from the center of the left diaphragm, measured 18 x 8 x 4 cm and weighed 440 g. Microscopic examination revealed a solitary fibrous tumor with mitotic activity of 7/ 50 hpf. Immunohistochemically, the tumor was negative for cytokeratin, s-100 protein, desmin, and alpha-smooth muscle actin, while positive for vimentin and CD34. On a histoculture drug response assay using the resected tissue, the tumor was sensitive to 5-FU, adriamycin, mitomycin C and docetaxel, and resistant to cisplatin, irinotecan, and gemcitabine.

Intrapleural administration of gelatin-embedded, sustained-release basic fibroblast growth factor for the regeneration of emphysematous lungs in rats.

BACKGROUND: Intra-airway and intra-arterial administration of gelatin-embedded, sustained-release basic fibroblast growth factor has stimulated regeneration of emphysematous lungs in animal experiments, but these routes of administration may also cause harm. This study investigated the effectiveness of intrapleural administration of gelatin-embedded, sustained-release basic fibroblast growth factor. This animal experiment preceded our clinical trial of intrapleural administration of sustained-release basic fibroblast growth factor in patients with chronic obstructive pulmonary disease accompanied by pneumothorax. METHODS: Pulmonary emphysema was induced in Sprague-Dawley rats using porcine elastase. Gelatin-embedded, sustained-release basic fibroblast growth factor was administered via the left pleural cavity. The rats were divided into a group that received gelatin-embedded, sustained-release basic fibroblast growth factor (FGF(+) group, n = 6), and a group that did not (FGF(-)group, n = 6). Animals were sacrificed after 14 days, and the results were evaluated by histologic examination. RESULTS: In the FGF(+) group, the mean linear intercept value of the alveolar septa was significantly shorter on the treated side than on the untreated side (65.1 ± 7.0 vs 114.4 ± 7.5 µm; P = .0005). There was no significant difference in the mean linear intercept value between the treated and untreated sides in the FGF(-) group. CONCLUSIONS: Intrapleural administration of sustained-release basic fibroblast growth factor induced lung regeneration in rats with elastase-induced pulmonary emphysema.