Clinical outcomes of medical treatments for progressive desmoid tumors following active surveillance: a systematic review.

Approximately 80% of desmoid tumors (DTs) show spontaneous regression or disease stabilization during first-line active surveillance. Medical treatment can be considered in cases of disease progression. This systematic review aimed to evaluate the effectiveness and toxicity of each medical treatment by reviewing only the studies that included progressive disease as the inclusion criterion. We searched the EMBASE, PubMed, and CENTRAL databases to identify published studies for progressive DTs. The disease control rates of the medical treatments, such as low-dose chemotherapy with methotrexate plus vinblastine or vinorelbine, imatinib, sorafenib, pazopanib, nilotinib, anlotinib, doxorubicin-based agents, liposomal doxorubicin, hydroxyurea, and oral vinorelbine for progressive DTs were 71-100%, 78-92%, 67-96%, 84%, 88%, 86%, 89-100%, 90-100%, 75%, and 64%, respectively. Low-dose chemotherapy, sorafenib, pazopanib, nilotinib, anlotinib, and liposomal doxorubicin had similar toxicities. Sorafenib and pazopanib were less toxic than imatinib. Doxorubicin-based chemotherapy was associated with the highest toxicity. Hydroxyurea and oral vinorelbine exhibited the lowest toxicity. Stepwise therapy escalation from an initial, less toxic treatment to more toxic agents is recommended for progressive DTs. Sorafenib and pazopanib had limited on-treatment side effects but had the possibility to induce long-term treatment-related side effects. In contrast, low-dose chemotherapy has some on-treatment side effects and is known to have very low long-term toxicity. Thus, for progressive DTs following active surveillance, low-dose chemotherapy is recommended in young patients as long-term side effects are minor, whereas therapies such as sorafenib and pazopanib is recommended for older patients as early side effects are minor.

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment.

BACKGROUND: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR. PATIENTS AND METHODS: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B). RESULTS: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. CONCLUSION: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer.

BACKGROUND: The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer. PATIENTS AND METHODS: We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS). RESULTS: Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027). CONCLUSIONS: Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of ≥95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments. CLINICAL TRIAL REGISTRATION: The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782.

[Post operative complications after hepatopancreatoduodenectomy (HPD)].

The postoperative complications, morbidity and mortality of hepatopancreatoduodenectomy (HPD) are reviewed based on reports by the Japanese Biliary Surgery Association, Japanese Pancreatectomy Association, and leading surgeons. Postoperative hepatic failure, the most important and lethal complication, is significantly correlated with patient age (older than 70 years), resected hapatic volume (hepatic bisegmentectomy or greater), combined resection of the portal vein, or temporal bypass of portal blood flow. In patients who undergo HPD with more than bisegmentectomy, the operative mortality rate is high rate, with reports of 39.7%, 23.0%, 12.5%, and 38.0%. To reduce the morbidity and mortality rates after HPD, it is important to avoid intraoperative hepatic ischemia and to maintain sufficient hepatic blood flow and high oxygen saturation of portal blood postoperatively using a respirator and inotropic agents.

[Combination chemotherapy with irinotecan hydrochloride plus carboplatin for patients with advanced or recurrent colorectal cancer--a pilot study].

A pilot study was performed to evaluate the feasibility and efficacy of irinotecan hydrochloride (CPT-11) plus carboplatin (CBDCA) for treatment of advanced or recurrent colorectal cancer. Fifteen patients with colorectal cancer (nonresectable, 1; noncurative resection, 5; recurrent disease, 9) were treated with CPT-11 (40-50 mg/m2) plus CBDCA (70-100 mg/m2) once a week for 2-3 weeks followed by a one-week rest. This treatment was repeated until disease progression or severe toxic effects were found. The total dose of CPT-11 ranged from 135 to 1,214 (median, 467) mg/m2 and that of CBDCA ranged from 267 to 2,022 (median, 933) mg/m2. Adverse effects included nausea (grade 2) in 2 (13.3%) diarrhea (grade 2) in 2 (13.3%), leukopenia (grade 3) in 2 (13.3%), thrombocytopenia (grade 1) in one (6.7%), and hair falling (grade 3) in one (6.7%). The response rate of 14 evaluable patients was 14.3% (CR, 1; PR,1; NC,7; PD,5). The median survival time of all patients was 405 days from the start of chemotherapy. The survival time of patients with CR, PR, and NC (n = 9) tended to be longer than that of those with PD (n = 5) (p = 0.06). The median time to disease progression was 105 days. These results suggest that this combination chemotherapy is feasible and effective in the treatment of advanced or recurrent colorectal cancer.

Anticoagulation during use of a left ventricular assist device.

Thirty-six mongrel dogs underwent 24hr left ventricular assist. The VAD was placed between the left atrium and the descending aorta, and the dogs were divided into four groups according to type of anticoagulation: no anticoagulation, argatroban, nafamostat mesylate, and nafamostat mesylate + prostacyclin analog. Results of this animal experiment revealed that a newly developed synthetic thrombin inhibitor argatroban can prevent activation of the intrinsic coagulation pathway. Argatroban is efficient under any blood coagulative condition, even lack of anti-thrombin III, because of its direct inhibitory effect on thrombin, making argatroban more useful than heparin as an anticoagulant for LVAD. Argatroban, as well as heparin, provides marked and significant prolongation of the prothrombin time from early assisted circulation, but produces a bleeding tendency. Nafamostat mesylate can maintain blood coagulation parameters within the acceptable range. Combined administration of nafamostat mesylate and a prostacyclin analog cause the least decrease in fibrinogen and alpha2-plasmin inhibitor among the four groups and causes no significant prolongation of prothrombin time.

A thromboxane A2 synthetase inhibitor as an anticoagulant for left ventricular assist devices.

A comparative study to establish more adequate anticoagulation therapy for left ventricular assist devices was done by administering various anticoagulants: heparin, argatroban (a pure thrombin inhibitor), a thromboxane A2 synthetase inhibitor, and protease inhibitor. Results of the investigation revealed that use of no anticoagulation activates the intrinsic pathway of blood coagulation and causes severe coagulopathy, heparin or argatroban causes bleeding tendency, and a thromboxane A2 synthetase inhibitor can maintain blood coagulation within the acceptable range, but not completely. Combined administration of a thromboxane A2 synthetase inhibitor and protease inhibitor was found to be the best anticoagulation therapy in this study.

Ideal anticoagulation for use with a left ventricular assist device.

To establish ideal anticoagulation therapy for use with a left ventricular assist device, a study was done administering various anticoagulants: heparin, argatroban, a prostacyclin analogue combined with a protease inhibitor, or a protease inhibitor alone. Cardiac asisting by LVAD without any anticoagulants results in marked activation of blood coagulation or fibrinolysis. Administration of argatroban, as well as heparin, produces a bleeding tendency. Administration of a protease inhibitor (nafamostat mesilate, FUT-175) as a sole anticoagulant induces activation of the blood coagulation system to some extent, but it is within acceptable limits. Combined administration of a prostacyclin analogue (PG) and FUT-175 is most effective in maintaining balanced blood coagulation and fibrinolysis.

Danger of urokinase as an anticoagulant with left ventricular assist devices.

The sole administration of urokinase causes no initial prolongation of activated partial thromboplastin time (A-PTT), but thereafter produces serious progressive prolongation of A-PTT; it also causes a progressive, severe decrease in fibrinogen levels and alpha 2-plasmin inhibitor activity by depletion. The antithrombogenicity of urokinase is not caused by prevention of blood coagulation system activation by antithrombin effect, but by secondary fibrinolysis by plasmin. Consequently, the administration of urokinase as a sole anticoagulant results in activation of coagulation and fibrinolysis, and, as a result, induces disseminated intravascular coagulation. Therefore, it is concluded that administration of urokinase is an inadequate anticoagulation therapy unless it is combined with other antithrombin agents.

[Thymic lymphoid hyperplasia of myasthenia gravis patients: correlation with clinical features and efficacy of thymectomy].

Thirty nine thymus tissues from myasthenia gravis patients without thymoma who underwent extended thymectomy were evaluated on thymic lymphoid hyperplasia with special emphasis on clinical features and the efficacy of thymectomy. Of 39 patients, 31 were women, but 3 of 7 patients without thymic lymphoid hyperplasia were men. The hyperplastic index of the thymus correlated largely with serum anti-Ach-R antibody titers before surgery. Age, myasthenic type and preoperative duration of the symptoms were almost unrelated to the hyperplastic change in the thymus. The effect of thymectomy was more remarkable in the patients with the hyperplastic thymus than that in them without it, who obtained still no remission after surgery, although the remission rate of them with it reached to 25%. Of 7 patients without the hyperplastic thymus, 4 had no detectable antibody to acetylcholine receptor, whereas in 32 patients with it only 2 were seronegative. This negative immunological factor might make adverse response to thymectomy. Although unfavorable response to thymectomy were observed in the patients without the hyperplastic thymus, most of them were significantly improved through a supplementary treatment with steroid after surgery. Thymectomy was a favorable treatment for myasthenia gravis patients with thymic lymphoid hyperplasia, whereas in them without it the result of thymectomy was unsatisfactory.

[Immediate breast reconstruction with the transverse rectus abdominis musculocutaneous flap (TRAM-flap)].

The surgical treatment of breast cancer shows a recent trend toward breast-saving procedures, in consideration of quality and body image. Surgeons who performed mastectomy, however, have not taken aggressive approaches to reconstructive surgery, leaving this to plastic surgeons. We adopted the transverse rectus abdominis musculocutaneous flap (TRAM-flap) for breast reconstruction in 1988 and performed immediate breast reconstructions in 37 cases. There were no major complications, and good cosmetic results were obtained. For general surgeons, this excellent technique can safely cope with tissue defects in radical mastectomy, as well as modified radical mastectomy. Immediate breast reconstruction with this technique will be an integral part of breast cancer surgery in company with breast-saving surgery.

A visual data analysis system for the medical image processing.

We developed a visual data analysis system that can easily manage a large volume of medical imaging data. This system can analyze sets of imaging data using general image processing methods, so that various kinds of medical imaging data such as ECG charts, X ray image films, and MRI images, can be processed. The system has a graphical user interface (GUI). A physician who is novice at the system can manipulate the imaging data intuitively by pull down menus, pop up menus and buttons within the window system. The system can run on a standard UNIX workstation which is faster and more powerful than most personal computers. The system needs an X window system/Motif and C compiler. These are standard system programs already available on most UNIX workstations. The source code of the system can be retrieved from our anonymous ftp site via Internet.

[B cell population and its autoimmune activity in the thymus of patients associated with myasthenia gravis].

Immunohistochemical studies using antibodies to B lymphocyte and to immunoglobulin G bearing cell were carried out for resected thymus-specimens of 10 patients associated with myasthenia gravis. In each case, abundant B cells (L26 positive cell) resided in the follicles and the medulla of thymus, especially, were congregated in the follicles developing germinal center and around Hassall's corpuscles. Amount of B cell population was various among each case regardless of type of myasthenia gravis or age. B cells were greatly increased in the thymus of patients with values of anti-acetylcholine receptor antibody titers over 100 nmol/l. Although numerous B cells were present in the thymus of these patients, IgG bearing cells were extremely rare. In the most cases, B cells lacked IgG expression. From the results, numerous B cells pre-activating autoimmune antibody production were accumulated in the thymus of patients associated with myasthenia gravis.

[Reoperation in patients with thymoma].

For past seven years, reoperations were carried out for six patients with thymoma and myasthenia gravis (MG). Of six patients, five patients were suspected recurrent thymoma and remaining one patient was diagnosed as the residual thymus after thymothymectomy or thymomectomy. Myasthenia gravis has been progressing in five patients after initial operation except for one patient. Two cases of pleural dissemination tumors, one case of local recurrent thymoma and one case of the residual thymus were confirmed by surgery, remaining two patients had no recurrent tumor. As surgical procedure, median sternotomy using for reoperation has a great surgical risk, because left brachiocephalic vein closely adhered to the sternum is apt to be injured. Clinical symptoms of MG were improved in all the patients after reoperation regardless of recurrent tumor.

A servomatic pneumatic driver system for left ventricular assist devices.

A new ventricular assist device (VAD) pneumatic driver with a servomatic left atrial pressure (LAP) control mechanism was developed for easy and safe control of left ventricular assist devices. The negative driving pressure (NP) can be automatically varied to control the assisted circulatory flow (AF), comparing the patient's LAP with prescheduled LAP (s-LAP). Animal experiments revealed this servomatic control system to be useful.