Naoyuki Ueno

Combination therapy of in vitro‐expanded natural killer T cells and α‐galactosylceramide‐pulsed antigen‐presenting cells in patients with recurrent head and neck carcinoma

The aim of this clinical trial was to investigate the feasibility of intra‐arterial infusion of in vitro‐expanded Vα24 natural killer T (NKT) cells combined with submucosal injection of α‐galactosylceramide (KRN7000; αGalCer)‐pulsed antigen‐presenting cells (APC). A phase I clinical study was carried out in patients with head and neck squamous cell carcinoma (HNSCC). Patients with locally recurrent HNSCC refractory to standard therapy were eligible. Eight patients received super‐selective transcatheter intra‐arterial infusion of activated Vα24 NKT cells into tumor‐feeding arteries and nasal submucosal injections of αGalCer‐pulsed APC twice with a 1‐week interval. Vα24 NKT cell‐specific immune responses, safety, and antitumor effects were evaluated. The number of Vα24 NKT cells and interferon‐γ‐producing cells in peripheral blood mononuclear cells increased in seven out of eight patients enrolled. Grade 3 toxicity with a pharyngocutaneous fistula related to local tumor reduction was observed in one patient and mild adverse events with grade 1–2 symptoms occurred in seven patients. Regarding the clinical responses, three cases exhibited a partial but significant response, four were classified as stable disease, and one patient continued to develop progressive disease. The use of the intra‐arterial infusion of activated Vα24 NKT cells and the submucosal injection of αGalCer‐pulsed APC has been shown to induce significant antitumor immunity and had beneficial clinical effects in the management of advanced HNSCC. The use of such therapeutic modalities may be helpful in the management of tumors and therefore needs to be explored in further detail. The clinical trial registration number was UMIN000000722. (Cancer Sci 2009; 100: 1092–1098)

Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy

Vα24 natural killer T (NKT) cells have potent anti-tumor activity. We performed a phase II clinical study in patients with head and neck squamous cell carcinoma (HNSCC) using ex vivo expanded Vα24 NKT cells and α-galactosylceramide (αGalCer; KRN7000)-pulsed antigen-presenting cells (APCs) to investigate the efficacy and induction of NKT cell-specific immune responses. The subjects were 10 patients with locally recurrent and operable HNSCC. One course of nasal submucosal administration of αGalCer-pulsed APCs and intra-arterial infusion of activated NKT cells via tumor-feeding arteries was given before salvage surgery. Anti-tumor effects, NKT cell-specific immune responses in extirpated cancer tissue and peripheral blood, safety, and pathological effects were evaluated. Five cases achieved objective tumor regression. The number of NKT cells increased in cancer tissues in 7 cases and was associated with tumor regression. The combination therapy induced NKT cell-specific immune responses in cancer tissues that were associated with beneficial clinical effects.

Intrafractional gastric motion and interfractional stomach deformity during radiation therapy

BACKGROUND AND PURPOSE To evaluate intrafractional gastric motion and interfractional variability of the stomach shape during radiation therapy (RT) for gastric lymphoma. MATERIALS AND METHODS For 11 patients with gastric lymphomas, we undertook fluoroscopic examinations at the time of the simulation, and once a week during RT to evaluate inter- and intrafractional gastric variations. We recorded anteroposterior and left to right X-ray images at inhale and exhale in each examination. We gave coordinates based on the bony landmarks in each patient, and identified the most superior, inferior, lateral, ventral, and dorsal points of the stomach on each film. The interfractional motion was assessed as the distance between a point at inhale and the corresponding point at exhale. We also analyzed interfractional variation based on each point measured. RESULTS The intrafractional gastric motion was 11.7+/-8.3, 11.0+/-7.1, 6.5+/-6.5, 3.4+/-2.3, 7.1+/-8.2, 6.6+/-5.8mm (mean+/-SD) for the superior, inferior, right, left, ventral and dorsal points, respectively, which was significantly different between each point. The interfractional variability of stomach filling was -2.9+/-14.4, -6.0+/-13.4, 9.3+/-22.0mm for the superior-inferior (SI), lateral (LAT), and ventro-dorsal (VD) directions, respectively, and the differences of variabilities were also statistically significant. Thus, the appropriate treatment margins calculated from both systematic and random errors are 30.3, 41.0, and 50.8mm for the SI, LAT, and ventro-dorsal directions, respectively. CONCLUSIONS Both intrafractional gastric motion and interfractional variability of the stomach shape were considerable during RT. We recommend regular verification of gastric movement and shape before and during RT to individualize treatment volume.

A case of gastric lymphoma with marked interfractional gastric movement during radiation therapy.

Radiation therapy (RT) with or without chemotherapy has been a widely accepted treatment for patients with localized gastric lymphoma. We encountered a patient with gastric diffuse large B-cell lymphoma, whose stomach volume, and the position and location of the clips that had been endoscopically placed to define the gastric lesions clearly differed considerably at three simulation times. The positions of the clips moved between 5 and 35 mm (mean 24 mm) laterally on simulation films. The mean movement of these clips along the cephalocaudal directions was 8 mm (range 0–15 mm). There have been no published articles which systemically evaluated interfractional gastric motion between each treatment session. Therefore this is an important observation in the management of patients with gastric lymphoma with RT.

Dose–volume factors predicting radiation pneumonitis in patients receiving salvage radiotherapy for postlobectomy locoregional recurrent non-small-cell lung cancer

BackgroundThe correlation between treatment-related factors and lung toxicity has not been sufficiently evaluated in salvage radiotherapy.MethodsTwenty-one patients with recurrent non-small- cell lung cancer (NSCLC) after lobectomy received salvage radiotherapy to a total dose of 46–60 Gy. The effects of radiotherapy parameters on the development of radiation pneumonitis (RP) were examined using dose–volume histograms.ResultsGrade 1 RP was observed in 4, grade 2 in 2, and grade 3 in 1 patient. Patients who developed RP had a significantly higher value in V dose (V13, V20) parameters and mean lung dose (MLD) than those who did not develop RP. Concerning G2 or higher RP, 3 patients who developed ≥G2 RP had a significantly higher value in V20, V13, and MLD than the remaining patients with P values of 0.01, 0.015, and 0.016, respectively. The mean V20, V13, and MLD in these 3 patients were 27%, 29.3%, and 14.8 Gy, respectively, whereas the mean V20, V13, and MLD in the remaining 18 patients were 15.8%, 18.3%, and 8.8 Gy, respectively. Three of 6 patients with a V20 ≥20% developed ≥G2 RP whereas this did not occur in the remaining patients (P = 0.015). Similarly, 3 of 6 patients with a V13 ≥23% developed ≥G2 RP whereas this did not occur in the remaining patients (P = 0.015).ConclusionsThese data suggest that a somewhat lower V dose value or MLD, as compared with the setting of definitive radiotherapy, could be a surrogate for RP in patients undergoing salvage radiotherapy for recurrent NSCLC.

Vessel-contouring-based Pelvic Radiotherapy in Patients with Uterine Cervical Cancer

OBJECTIVE The aim of this study was to assess clinically the adequacy of vessel-contouring-based pelvic radiotherapy with regard to nodal coverage for uterine cervical cancer. METHODS Fifty patients with Stages I-III cervical cancer, treated with vessel-contouring-based three-dimensional radiotherapy since August 2002, were entered into the study (median age: 54, 47 received concurrent daily cisplatin). All patients were treated with external beam radiotherapy using a four-field box technique with or without brachytherapy. Pelvic blood vessels were identified and contoured on computed tomography simulation images. A generous margin was set outside these vessels outlined on digitally reconstructed radiograph accounting for normal size lymph nodes, patients motion and set-up uncertainty. Multi-leaf collimator (MLC) was inserted and adjusted manually. Patterns of recurrence were clinically evaluated. RESULTS Distance between major vessels and MLC edges varied inter- and intra-individually. Median distance in the mid-iliosacral joint level was 25 mm (left) and 24 mm (right). The maximum and the minimum distances ranged from 25 to 45 mm (median, 32) and 9 to 27 mm (median, 15) for left side and 24 to 41 mm (median, 30) and 7 to 28 mm (median, 15) for right side, respectively. With a median follow-up of 43 months, 10 patients developed recurrence. However, no marginal recurrence was occurred just lateral to the contoured vessels. All three patients who developed regional recurrence had recurred at the internal iliac node or the obturator node medial to contoured vessels. CONCLUSIONS Contoured vessels can be used as surrogate markers for location of the pelvic lymph nodes.

Radiation Pneumonitis Following Twice-daily Radiotherapy with Concurrent Carboplatin and Paclitaxel in Patients with Stage III Non-small-cell Lung Cancer

OBJECTIVE To examine the effects of dose-volume factors on the development of radiation pneumonitis in patients with non-small-cell lung cancer who received twice-daily radiotherapy concurrently with carboplatin and paclitaxel chemotherapy. METHODS Radiotherapy consisted of twice-daily fractionation of 1.2 Gy, to a total dose of 60 Gy. Weekly carboplatin and paclitaxel were used as a concurrent chemotherapy. Effects of radiotherapy parameters on the development of radiation pneumonitis were retrospectively analyzed. RESULTS Fourteen of 37 patients developed Grade 2 or worse (> or = G2) radiation pneumonitis. Grade 2 or worse radiation pneumonitis occurred in all 5 patients with V5 >40%, all 4 patients with V10 >35%, all 4 patients with V13 >32%, 9 of 14 patients with V20 >24% and 8 of 11 patients with V30 >22%, whereas 9 of 32 patients with V5 <40%, 10 of 33 patients with V10 <35%, 10 of 33 patients with V13 <32%, 5 of 23 patients with V20 <24% and 6 of 26 patients with V30 <22%, with respective P values of 0.0045, 0.015, 0.015, 0.015 and 0.008. Eight of 11 patients with a mean lung dose of >14 Gy developed > or = G2 radiation pneumonitis in contrast to 6 of 26 patients with a mean lung dose of <14 Gy (P = 0.008). CONCLUSIONS Several cut-off values in the V(dose) and the mean lung dose differentiating probabilities of developing > or = G2 radiation pneumonitis were identified in this combination therapy.

Weekly cisplatin administration concurrent with radiation therapy for locoregionally advanced nasopharyngeal carcinoma

Radiation therapy (RT) with concurrent and adjuvant chemotherapy has been a widely accepted treatment for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We administered 40 mg/m2 cisplatin (CDDP) weekly, concurrently with RT, to six consecutive patients with locoregionally advanced NPC to evaluate its toxicity and efficacy. The median number of courses of CDDP administration was 4.5 and the median radiation dose was 69.7 Gy. Grade 3 leukopenia was observed in three patients. All but one patient experienced grade 3 or 4 skin reactions, pharyngitis, or dysphagia. All but one patient achieved a complete response, and the remaining patient received radical neck dissection for persistent cervical lymphadenopathies, which contained no cancer cells. All six patients were disease-free at last contact, with a median follow up of 23.5 months. This regimen is well tolerated in patients with locoregionally advanced NPC.