A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.

BACKGROUND: An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting. PATIENTS AND METHODS: This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0). RESULTS: Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed. CONCLUSIONS: Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.

Temporal Profiles of Symptom Scores After Palliative Radiotherapy for Bleeding Gastric Cancer With Adjustment for the Palliative Prognostic Index: An Exploratory Analysis of a Multicentre Prospective Observational Study (JROSG 17-3).

AIMS: Although palliative radiotherapy for gastric cancer may improve some symptoms, it may also have a negative impact due to its toxicity. We investigated whether symptoms improved after radiotherapy with adjustment for the Palliative Prognostic Index (PPI) considering that patients with limited survival tend to experience deterioration of symptoms. MATERIALS AND METHODS: This study was an exploratory analysis of the Japanese Radiation Oncology Study Group study (JROSG 17-3). We assessed six symptom scores (nausea, anorexia, fatigue, shortness of breath, pain at the irradiated area and distress) at registration and 2, 4 and 8 weeks thereafter. We tested whether symptoms linearly improved after adjusting for the baseline PPI. Shared parameter models were used to adjust for potential bias in missing data. RESULTS: The present study analysed all 55 patients enrolled in JROSG 17-3. With time from registration as the only explanatory variable in the model, a significant linear decrease was observed in shortness of breath, pain and distress (slopes, -0.26, -0.22 and -0.19, respectively). Given that the interaction terms (i.e. PPI × time) were not significantly associated with symptom scores in any of the six symptoms, only PPI was included as the main effect in the final multivariable models. After adjusting for the PPI, shortness of breath, pain and distress significantly improved (slope, -0.25, -0.19 and -0.17; P < 0.001, 0.002 and 0.047, respectively). An improvement in fatigue and distress was observed only in patients treated with a biologically effective dose ≤14.4 Gy. CONCLUSION: Shortness of breath, pain and distress improved after radiotherapy. Moreover, a higher PPI was significantly associated with higher symptom scores at all time points, including baseline. In contrast, PPI did not seem to influence the improvement of these symptoms. Regardless of the expected survival, patients receiving radiotherapy for gastric cancer can expect an improvement in shortness of breath, pain and distress over 8 weeks. Multiple-fraction radiotherapy might hamper the improvement in fatigue and distress by its toxicity or treatment burden.

Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02).

Background: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN. Patients and methods: Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients. Results: Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia. Conclusions: The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population. Registered clinical trial number: UMIN000010507.

Multiple hepatic vein reconstruction using an all-in-one sleeve patch graft technique in living donor liver transplantation: a case report.

Maintaining hepatic inflow and appropriate venous drainage is important for maximizing the capacity of the retrieved graft in liver transplantation. Here, we report a successful case of multiple hepatic vein (HV) reconstruction using an all-in-one sleeve patch graft of the autologous great saphenous vein to ensure adequate blood flow through the HV. A patient with hepatocellular carcinoma caused by hepatitis C virus-induced cirrhosis underwent living donor liver transplantation using a right lobe graft. A preoperative dynamic computed tomography scan and intraoperative findings revealed that the graft had three middle HV tributaries, a superficial vein, segment VIII HV (V8), and segment V HV (V5). The openings of the superficial vein and V8 were located very close to that of the right hepatic vein (RHV) in the cutting surface. Each HV had significant diameter and drainage territory requiring reconstruction. An autologous great saphenous vein was used to create a sleeve patch to incorporate the close-packed HV openings. The autologous sleeve patch graft was sutured to the openings of the RHV and the superficial vein and the hole created on the sleeve patch graft was anastomosed to the openings of V8 directly on the back table to create an all-in-one sleeve patch. For the V5 reconstruction, the recipient's intrahepatic portal vein graft was used to create an interpositional conduit from the recipient's V5 to the inferior vena cava. The postoperative course was uneventful and postoperative studies revealed good graft function with excellent blood flow in the HV.

Complex vascular reconstruction using donor's vessel grafts in orthotopic liver transplantation.

The vascular abnormalities of recipients are associated with reconstructive difficulties with an increased risk of postoperative complications. We performed an orthotopic liver transplantation that required a complex vascular reconstruction using donor vascular grafts. A patient with hepatitis B virus cirrhosis received a liver from a brain-dead donor. Dynamic computed tomography revealed complete obstruction of the portal vein due to thrombosis as well as narrowing of the hepatic arteries. We employed orthotopic liver transplantation using the piggy-back technique with complex reconstruction of the portal vein and the hepatic arteries. For portal vein reconstruction, we used the donor's iliac vein as an interpositional conduit from the recipient's gastric coronary vein to graft the portal vein. The hepatic arteries of the graft were reconstructed at the back-table before anastomosis to the side of superior mesenteric artery using an interpositional conduit of the donor's external iliac artery. All postoperative studies revealed good graft function with an excellent blood flow through all vascular anastomoses during the first year postoperatively.

SU-E-J-183: Dose Distribution Generated from 131 I Radionuclide Using SPECT-CT.

PURPOSE: 131 I radionuclide therapy is widely performed in a thyroid cancer treatment, but there has been almost no evaluation of the dose distribution. The aim of this work is to develop the calculation system using the data of SPECT-CT and to examine the effects of their image resolutions on the dose distribution. METHODS: We designed and constructed an acrylic phantom for measurement. A radioactive iodine capsule and glass dosimeters can be set in the layer structure of the phantom. We put iodine capsules (37MBq, 111MBq, 185MBq) in the middle of the phantom and acquired SPECT-CT (Infinia Hawkeye4 (GE)) images. Both the CT value data (image resolution: 1.1 mm) and the intensity map data of SPECT (image resolution: 4.4 mm) were independently used for the estimation of the cumulative dose distribution generated from the radioactive iodine in the phantom. We adopted Monte Carlo program PHITS2.0 as the simulation of the dose calculation. The absolute dose was measured by glass dosimeters. RESULTS: The measurement result by glass dosimeters was very similar to the Monte Carlo simulation result, in which the difference was about 0.3 %. We obtained the dose distributions reconstructed by the radioactive iodine distribution using CT value data and SPECT data, respectively. The iodine distribution from CT could be finer than that of SPECT data because of its higher image resolution. As a result, the difference was found to be factor two in the middle of the iodine distribution. On the other hand, both of the dose distribution was almost same above 2.2 cm distance from the center. CONCLUSIONS: We can reconstruct the 131I dose distribution using SPECT-CT data. For more accurate calculation of the dose distribution, it would be crucial to increase the resolution of SPECT data.

Long-term outcome of hepatic artery reconstruction during living-donor liver transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) after living-donor liver transplantation (LDLT) is a potentially life-threatening complication. Although the introduction of microsurgical techniques has significantly decreased the incidence of HAT after LDLT, it remains a challenge for microsurgeons. We previously reported the use of the microsurgical hepatic arterial reconstruction technique during LDLT using the head-mounted surgical binocular system. METHODS: In this study, we describe the long-term outcome of microsurgical hepatic artery reconstruction using the head-mounted surgical binocular system and our hepatic arterial reconstruction techniques on LDLT patients, including intimal dissection cases and clinical courses. Between August 2001 and February 2010, 146 patients underwent LDLT at our institution. Using a surgical loupe, the Varioscope AF3, which is a head-mounted surgical binocular system with automatic focusing and continuous zoom magnification from 3.6× to 7.2×, 150 arteries of 146 liver grafts were reconstructed. When the tunica intima was separated from the tunica media, suturing was performed from the inside of the vessels to the outside using an 8-0 monofilament Prolene with double needles, which facilitates secure sutures with good intima adaptation. RESULTS: The 1- and 3-year survival rates of the 146 patients were 80.3% and 74.9%, respectively, with a mean follow-up of 40.2 months. The mean diameter of the graft hepatic artery was 2.79 mm. HAT was not encountered in this series of patients. CONCLUSION: The use of the Varioscope and the application of our suturing techniques have provided entirely satisfactory long-term results of hepatic artery reconstruction during LDLT, even in intimal dissection cases.

Effect of ACE gene polymorphism on age at renal death in polycystic kidney disease in Japan.

Polycystic kidney disease (PKD) is one of the most common genetic disorders and a major cause of renal death or end-stage renal disease (ESRD) requiring regular hemodialysis. The responsible genes recently have been cloned; however, genetic factors influencing the rate of progression to ESRD in patients with PKD have yet to be defined. Several studies have shown increased activity of the renin-angiotensin system (RAS) in patients with PKD. In addition, genetic polymorphisms of the RAS have been associated with the development of cardiovascular diseases. Therefore, these polymorphisms are good candidates for disease-modifying genetic factors or markers in PKD. In two previous reports of white subjects with a cumulative survival analysis, it was suggested that patients with P:KD1 homozygous for the deletion allele of the angiotensin-converting enzyme (ACE) gene are at increased risk for early renal death. To confirm this hypothesis in Japanese subjects, 103 individuals with PKD were genotyped for several components of the RAS, ie, ACE insertion/deletion (I/D) polymorphism, angiotensinogen (AGT) M235T, and angiotensin II type 1 receptor (AT1) A1166C. Seventy-six of the 103 patients (73.8%) reached ESRD at an average age of 52.1 +/- 11.3 years. The frequencies of each genotype of the genes were similar to those expected from Hardy-Weinberg equilibrium. There was a tendency to an excess of patients homozygous for the D allele in patients with ESRD (DD in patients with ESRD, 11.8%; DD in patients without ESRD, 3.7%; chi-square, 1.505; P: = 0.22). Cumulative renal survival was significantly less in those with the DD genotype compared with ID/II genotypes. Estimated mean renal survival was 46.4 years (95% confidence interval, 39.5 to 53.3) in subjects with the DD genotype and 57.2 years (95% confidence interval, 54.2 to 60.2) in ID/II genotypes (chi-square, 7.76; P: = 0.0053). There was no association between age at onset of ESRD and either M235T or A1166C polymorphism. These findings suggest that Japanese patients with PKD homozygous for the D allele of the ACE gene are at increased risk for developing ESRD at an early age.

Reversible peritoneal calcification in a patient treated by CAPD.

The patient, a female, aged 65 years, developed diffuse peritoneal calcification nine years after commencing CAPD therapy. No abdominal symptoms or evidence of peritonitis were discovered during this period. Before peritoneal calcification was detected, a dialysate with a high glucose concentration (3.86%) had been used once daily for 16 months. In the case of this patient, it was not possible to discover any of the previous indicated etiologies of peritoneal calcification such as significantly elevated values for the product Ca x P, overt secondary hyperparathyroidism, or relapsing peritonitis. It was realized that the use of a high-glucose dialysate in a patient on long-term CAPD treatment had been one causative factor. After peritoneal calcification had been confirmed, the calcium concentration of the dialysate changed from 3.5 mEq/l to 2.5 mEq/l and the patient was put on a regime of 2.0 g alumigel (aluminum-containing phosphate binders) a day. Eight months later, a CT scan was taken. The peritoneal calcification has clearly been mitigated. At present, CAPD therapy is being continued in the absence of any abdominal symptoms.

Bactericidal effect of electrolyzed neutral water on bacteria isolated from infected root canals.

OBJECTIVE: The purposes of this study were to examine the time-related changes in pH, oxidation-reduction potential, and concentration of chlorine of electrolyzed neutral water and to evaluate the bactericidal effect of electrolyzed neutral water against bacteria from infected root canals. STUDY DESIGN: Various properties of electrolyzed neutral water--pH value, oxidation-reduction potential, and concentration of chlorine--were measured at different times after storage of the water in the open state, the closed state, or the closed-and-dark state. The bactericidal effect of the various electrolyzed neutral water samples was then tested against 17 strains of bacteria, including 15 strains isolated from infected canals, as well as against 1 strain of fungus. Each bacterial or fungal suspension was mixed with electrolyzed neutral water, and the 2 substances were reacted together for 1 minute. After incubation for 1 to 7 days, the bactericidal effect of the electrolyzed neutral water was determined. RESULTS: The pH value and oxidation-reduction potential of electrolyzed neutral water remained almost unchanged when the water was stored in a dark, closed container. However, the concentration of chlorine decreased from 18.4 ppm to 10.6 ppm. Electrolyzed neutral water showed a bactericidal or growth-inhibitory effect against the bacteria. CONCLUSIONS: The results indicate that electrolyzed neutral water maintains a constant pH and oxidation-reduction potential when kept in a closed container without light and that it exhibits a bacteriostatic/bactericidal action against isolates obtained from infected root canals.

[Detection of human papillomavirus types 16, 18 and 33 in exfoliated cervical cells by polymerase chain reaction].

Human papillomavirus (HPV) types 16, 18 and 33 were identified by means of the polymerase chain reaction using exfoliated cells from the uterine cervix in 361 patients. Of 261 patients without cervical lesions, 10(3.8%) patients had HPV DNA whereas 7(70.0%) of 10 patients with invasive cervical carcinomas had HPV DNA. The younger patients' group (29 year-old or less) without cervical lesions had a 6.5% HPV positive rate which was distinctly higher than the older patients' groups. No menopausal patient without cervical lesions had HPV DNA. In the cervical dysplasia group, the HPV DNA positive rate tended to be higher in the older patients. Type 16 was detected more often than types 18 or 33. However, the detectable incidence of type 16 in the follow up group was lower than in the cervical carcinoma groups. The younger patients without cervical lesions had a higher incidence of type 16 than the older patients. The younger patients with cervical neoplastic lesions had a lower incidence of type 16 than the older patients. These results suggest that type 16 has a higher frequency of cervical HPV infections than types 18 and 33. In addition, human papillomavirus is not the only causative factor in cervical carcinomas.

[Oral condition of infantile acute lymphatic leukemia with microbisme substitute].

The oral condition of a 7 year old boy at the 12th and 13th remission induction therapy sessions since contracting acute lymphatic leukemia was investigated clinically and microbiologically. The findings obtained were as follows: 1) The appearance of gingivitis coincided with the decrease of white blood cells 7 to 9 days after administration of the anti-leukopenic drugs. 2) Gingivitis appeared on the same site of the oral cavity at both remission induction therapies sessions. 3) The bleeding from the gingival lesions corresponded to the decrease of blood platelet at both remission induction therapies sessions. Conversely, gingivitis disappeared with the improvement of peripheral blood conditions. 4) The total number of oral bacteria decreased after administration of the antibiotics, although the ratio of Candida in the oral microbial flora increased markedly. 5) Typical symptoms of oral candidiasis were not observed after the appearance of the microbisme substitute.

Malignant fibrous histiocytoma of the heart.

A case of cardiac sarcoma was reported. The tumor, which arose from the posterior wall of the left atrium, was demonstrated by echocardiography, contrast-enhanced computed tomography and direct observation during surgery. The tumor was successfully excised under emergency operation and was diagnosed as malignant fibrous histiocytoma after histologic examination. The patient had been free of symptoms for several months, but died of rapidly progressive congestive heart failure 6 months after surgery.

Histochemical and cytochemical study of butyrylcholinesterase activity in rat hepatocellular carcinomas induced by 3'-methyl-4-dimethylaminoazobenzene.

The activity of butyrylcholinesterase (BCHE), a liver fetal isozyme (Zone L-V) of a nonspecific esterase, was studied histochemically and cytochemically in rat hepatocellular carcinomas induced by 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). In normal adult rats, BCHE activity was very prominent in cells of the intestinal mucosa but was not detectable in the liver. On the other hand, in fetal rat liver, a few cells scattered throughout the organ were BCHE positive. 3'-Me-DAB induced poorly differentiated hepatocellular carcinomas showing an intense BCHE activity, especially in areas consisting of small tumoral cells proliferating in a sheet-like pattern. Surrounding noncancerous liver tissue was completely devoid of reaction products. Less-differentiated trabecular hepatocellular carcinomas also showed a positive reaction. On the other hand, well-differentiated hepatocellular carcinoma and hepatocellular carcinoma with an adenomatous pattern were barely stained, while areas of cholangiofibrosis were usually negative. Thus, in confirmation of a previous report, BCHE appears to be a positive marker of poorly differentiated hepatocellular carcinomas induced by 3'-Me-DAB. By electron microscopy, reaction products were demonstrated in the cisternae of the endoplasmic reticulum, in the nuclear envelopes, and sometimes on the cell surface of undifferentiated tumoral cells. The significance of the appearance of BCHE activity in hepatocellular carcinomas induced by 3'-Me-DAB is discussed.

An ultrastructural study of subacute necrotizing lymphadenitis.

Fifteen cases of a unique lymphadenitis called subacute necrotizing lymphadenitis were studied electron-microscopically. The large lymphoreticular cells proliferating at cortical or paracortical areas of the lymph nodes mainly consisted of immunoblasts and histiocytoid cells, which were characterized by numerous intracytoplasmic myelinlike inclusions. Such histiocytoid cells seemed to be derived from the immunoblasts. Tubuloreticular structures, which had been often noticed within endothelial cells or lymphocytes of the patients with systemic lupus erythematosus (SLE) or SLE-related diseases, were also observed with high frequency in most cases examined. They were present within the cytoplasm of immunoblasts, endothelial cells, and histiocytoid cells. Immunoblasts in mitosis occasionally contained these structures. We offer the hypothesis that subacute necrotizing lymphadenitis with still unknown etiology may reflect a self-limited SLE-like autoimmune condition induced by virus-infected transformed lymphocytes.

Induction of gamma-glutamyltranspeptidase-positive altered hepatocytic lesions by combination of transplacental-initiation and postanal-selection.

The purpose of this study was to induce in postnatal life the selective growth of altered hepatocytic populations which had been induced in utero by various chemicals. Pregnant rats of a Wistar strain were given a single dose of various chemical carcinogens on the 18th gestational day. From two months postpartum, both the mothers and offspring were given a diet containing 2-acetylamino-fluorene (2-AAF) at a concentration of 0.02% for two weeks. Then, at the end of the first week after the 2-AAF feeding, a two-third partial hepatectomy was performed. All the animals were killed one week after the partial hepatectomy and were examined for the incidence of gamma-glutamyltranspeptidase (GGT)-positive altered hepatocytic foci in the liver. The transplacental administration of not only a hepatic carcinogen, diethylnitrosamine (DEN) but also 7,12-dimethylbenzanthracene (DMBA), which does not usually produce hepatocellular carcinomas in adult rats, induced GGT-positive altered hepatocytes in the liver of the offspring. These hepatocytes grew into grossly visible hyperplastic nodules within a week after the two-third partial hepatectomy. The possible applicability of the transplacental initiation-postnatal selection model for the short-term assay of transplacental carcinogenicity is discussed.

Spontaneous occurrence of gamma-glutamyl transpeptidase-positive hepatocytic foci in 105-week-old Wistar and 72-week-old Fischer 34 male rats.

Spontaneous hepatic changes in old male rats of Wistar and F344 inbred strains were studied histochemically. gamma-Glutamyl transpeptidase-positive hepatocytic foci and cholangiolar proliferation associated with fibrosis and inflammatory infiltration were common findings in the old rats of both strains. Histochemical properties of the hepatocytes of the foci were similar to those of hyperplastic foci seen in early stages of liver carcinogenesis due to various chemical carcinogens. The incidence of the foci was 2.52/cm2 of the histochemically stained sections in 105-week-old male Wistar and F344 rats, and the presence of other spontaneous neoplastic and nonneoplastic changes was revealed.