Thymidylate Synthase, Thymidine Phosphorylase and Orotate Phosphoribosyl Transferase Levels as Predictive Factors of Chemotherapy in Oral Squamous Cell Carcinoma

We conducted a clinicopathologic study on protein and mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) using biopsy tissue specimens before treatment. The mRNA levels have been measured in tumor cells microdissected from paraffin-embedded specimens (Danenberg Tumor Profile method: DTP method). We studied the mRNA and protein expression as effect predictive factors in chemotherapy. The subjects consisted of 20 cases of untreated oral squamous cell carcinoma who had undergone chemotherapy with TS-1 (16 males and 4 females, tongue in 8 cases, upper gingiva in 3 cases, lower gingiva in 3 cases, buccal mucosa in 5 cases and floor of the mouth in 1 case). TS gene expressions of the responders were lower than those for the nonresponders. Furthermore, regarding males who were less than 70 years of age, stage I and II, well differentiated type and tongue, TS mRNA expression of the responders were lower than that for the nonresponders. The mRNA expression of OPRT for the male responders was lower than that for the nonresponders. No remarkable difference was observed by immunohistochemistry. In this study, the measurement of the TS levels using the DTP method may potentially act as a predictive factor of antitumor effectiveness

Predicting the course of hematopoietic neoplasm through oral bacterial examination

Many medical institutions have recently conducted studies on the relationship between patients with hematopoietic neoplasms and oral cavity. Statistical analysis of the bacterial populations was performed in this study to identify how oral microflora and health conditions （e.g., dental caries and periodontal diseases） affect the prognosis of patients with hematopoietic neoplasms. Patients undergoing inpatient treatment from January to December 2020 at the Department of Hematology at Showa University, Japan, who required perioperative oral management were included in the study. The oral health of the patients was examined at the initial dental visit, and oral bacterial samples were collected from the tongue, buccal mucosa, and palate of 47 patients who consented to participate after receiving an explanation about the study. Statistical analyses performed after dividing the subjects into two groups following the treatment course showed that Stenotrophomonas maltophilia and Gemella sanguinis were significantly more common in the poor-course group. However, no significant difference in bacterial examination results was noted among the four groups （myeloid neoplasm chemotherapy, myeloid neoplasm hematopoietic stem cell transplantation （HSCT）, lymphoid neoplasm chemotherapy, and lymphoid neoplasm HSCT groups） classified based on disease and treatment method. The detection rate of bacteria potentially causing infectious diseases at the initial dental examination tended to be higher in this study in the poor-course group. The findings of the current study suggest that early detection of pathogenic bacteria after commencing hematology treatment could predict the poor-course that may lead to mortality or severe infections

口腔扁平上皮癌におけるp53蛋白,熱ショック蛋白(HSP)70, Ki-67の発現に関する免疫組織化学的検討

口腔扁平上皮癌患者70例の生体標本において,p53蛋白,熱ショック蛋白(HSP) 70の発現と,腫瘍細胞の増殖能をKi-67標識率を用いて免疫組織化学的に検索し,臨床病理学的因子,臨床経過との関連を検討した.P53癌抑制遺伝子異常は多くの臓器の癌細胞に高頻度に検出され,癌化およびその進展に他の遺伝子異常とともに寄与していると考えられている.またその産物である変異型p53蛋白は野生型p53蛋白に比べ構造が安定化し半減期が延長するため,過剰発現として免疫組織化学的に検出が可能である.この構造安定化の原因として変異型p53蛋白がHSP70と会合することが考えられている.p53蛋白の過剰発現は54.2%に認めたが,臨床病理学的因子,臨床経過との有意な相関は認めなかった.HSP70の発現は低分化なもの,核異型の高度なもの,核分裂像の多いものなど細胞増殖が活発な細胞で高頻度に認め,5年生存率はHSP70陽性群が陰性群に比べて有意に低下していた.細胞増殖能(Ki-67標識率)との関連性では低分化のもの,核異型が高度なもの,核分裂の多いものなどの細胞増殖が活発な細胞で,また臨床病期の進行した症例,頚部リンパ節転移を認めた症例でもKi-67標識率が有意に高値を示した.次にp53蛋白とHSP70の相関を検討すると,P53蛋白染色陽性の38例中31例がHSP70染色も陽性であり,変異p53蛋白とHSP70との相関が認められると考えた.p53蛋白,HSP70の同時発現と細胞増殖との関連では,p53蛋白,HSP70の同時陽性群では陰性群に比べKi-67標識率が有意に高値を示した.本研究の結果からp53蛋白,HSP70の免疫組織化学的発現とKi-67標識率を検索することは,口腔扁平上皮癌の生物的悪性度を知るうえで有用であり,さらに治療方針の決定や予後推定に際しての指標となり得ることが示唆された.We immunohistochemically analyzed the expression of the proteins p53, heat shock protein (HSP) 70 and Ki-67 labelling index (LI) in biopsy specimens from 70 patietns with oral squamous cell carcinoma (OSCC) and to analyze these findings in relation to the clinicopathologic parameters (CPP) and clinical course (CC) of these patients. Thirty eight (54.3%) of the 70 oral squamous cell carcinomas examined were positive for p53 protein. p53 protein expression was not correlated significantly with CPP and CC. Forty four (62.8%) of the 70 oral carcinomas were positive for HSP70. HSP70 positivity was significantly associated with a lower degree of histological differentiation (p<0.01), a high degree of nuclear polymorphism (p< 0.01), and a high frequency of mitosis (p<0.01). Kaplan-Meier's survival curves showed significantly shorter survival for HSP70-positive (41%) than the HSP70-negative patients (78%) according to the results of the Cox-Mantel test (p<0.01). Ki-67 LI was significantly associated with lower degrees of histological differentiation (p<0.01), markedly diffuse invasion of the tumor (p<0.01), high degrees of nuclear polymorphism (p<0.01), and high frequencies of mitosis (p<0.01). The index was also significantly high in patients in high clinical stages of cancer (p< 0.01) and patients with tumor metastasis to cervical lymph nodes (p<0.01). Coexpression of p53-HSP70 was found in 31 (81.6%) of the 38 p53 protein positive oral carcinomas. The mean value of Ki-67 LI was significantly higher in patients in whom both p53 protein and HSP70 were positive (39.1%) than in patients in whom both were negative (23.1%) (p<0.01). The results of this study suggest that an immunohistochemical examination for p53 protein and HSP70 and determination of the Ki-67 LI will be useful in assessing the biological malignancy level of OSCC, determining a therapeutic policy and predicting the prognosis of OSCC in a given case

口腔扁平上皮癌におけるp53蛋白,熱ショック蛋白(HSP)70, Ki-67の発現に関する免疫組織化学的検討

口腔扁平上皮癌患者70例の生体標本において,p53蛋白,熱ショック蛋白(HSP) 70の発現と,腫瘍細胞の増殖能をKi-67標識率を用いて免疫組織化学的に検索し,臨床病理学的因子,臨床経過との関連を検討した.P53癌抑制遺伝子異常は多くの臓器の癌細胞に高頻度に検出され,癌化およびその進展に他の遺伝子異常とともに寄与していると考えられている.またその産物である変異型p53蛋白は野生型p53蛋白に比べ構造が安定化し半減期が延長するため,過剰発現として免疫組織化学的に検出が可能である.この構造安定化の原因として変異型p53蛋白がHSP70と会合することが考えられている.p53蛋白の過剰発現は54.2%に認めたが,臨床病理学的因子,臨床経過との有意な相関は認めなかった.HSP70の発現は低分化なもの,核異型の高度なもの,核分裂像の多いものなど細胞増殖が活発な細胞で高頻度に認め,5年生存率はHSP70陽性群が陰性群に比べて有意に低下していた.細胞増殖能(Ki-67標識率)との関連性では低分化のもの,核異型が高度なもの,核分裂の多いものなどの細胞増殖が活発な細胞で,また臨床病期の進行した症例,頚部リンパ節転移を認めた症例でもKi-67標識率が有意に高値を示した.次にp53蛋白とHSP70の相関を検討すると,P53蛋白染色陽性の38例中31例がHSP70染色も陽性であり,変異p53蛋白とHSP70との相関が認められると考えた.p53蛋白,HSP70の同時発現と細胞増殖との関連では,p53蛋白,HSP70の同時陽性群では陰性群に比べKi-67標識率が有意に高値を示した.本研究の結果からp53蛋白,HSP70の免疫組織化学的発現とKi-67標識率を検索することは,口腔扁平上皮癌の生物的悪性度を知るうえで有用であり,さらに治療方針の決定や予後推定に際しての指標となり得ることが示唆された.We immunohistochemically analyzed the expression of the proteins p53, heat shock protein (HSP) 70 and Ki-67 labelling index (LI) in biopsy specimens from 70 patietns with oral squamous cell carcinoma (OSCC) and to analyze these findings in relation to the clinicopathologic parameters (CPP) and clinical course (CC) of these patients. Thirty eight (54.3%) of the 70 oral squamous cell carcinomas examined were positive for p53 protein. p53 protein expression was not correlated significantly with CPP and CC. Forty four (62.8%) of the 70 oral carcinomas were positive for HSP70. HSP70 positivity was significantly associated with a lower degree of histological differentiation (p<0.01), a high degree of nuclear polymorphism (p< 0.01), and a high frequency of mitosis (p<0.01). Kaplan-Meier\u27s survival curves showed significantly shorter survival for HSP70-positive (41%) than the HSP70-negative patients (78%) according to the results of the Cox-Mantel test (p<0.01). Ki-67 LI was significantly associated with lower degrees of histological differentiation (p<0.01), markedly diffuse invasion of the tumor (p<0.01), high degrees of nuclear polymorphism (p<0.01), and high frequencies of mitosis (p<0.01). The index was also significantly high in patients in high clinical stages of cancer (p< 0.01) and patients with tumor metastasis to cervical lymph nodes (p<0.01). Coexpression of p53-HSP70 was found in 31 (81.6%) of the 38 p53 protein positive oral carcinomas. The mean value of Ki-67 LI was significantly higher in patients in whom both p53 protein and HSP70 were positive (39.1%) than in patients in whom both were negative (23.1%) (p<0.01). The results of this study suggest that an immunohistochemical examination for p53 protein and HSP70 and determination of the Ki-67 LI will be useful in assessing the biological malignancy level of OSCC, determining a therapeutic policy and predicting the prognosis of OSCC in a given case

口腔疾患におけるEBウイルスの関与に関する検討

EBVはヒトに極めて広範に常在するヘルペスウイルスであり,バーキットリンパ腫,上咽頭癌の病因ウイルスと考えられる.口腔領域においては免疫不全者の舌白板症,唾液腺腫瘍への関連が指摘されている.今回,我々は当科で治療を行った口腔腫瘍および粘膜疾患105例について,疾患とEBV感染の関連を検討するため,PCR法,PCR-Southern blot hybridization法,PNA probeを使用したin situ hybridization (ISH)法でEBVゲノムの検出およびmRNAの局在の検討を行った.PCRでは口腔扁平上皮癌18/22例,線維腫11/21例,epulis 16/19例,白板症8/16例,多形性腺腫6/10例,乳頭腫6/9例,口腔扁平苔癬7/8例でEBVゲノムが検出され,EBV DNAの発現率は68.5%であった.ISHではEBVのEBERおよびBHLF mRNAの発現部位は主にリンパ球に観察された.EBERとBHLF陽性細胞の局在は調べた疾患によってまちまちであったが,口腔扁平苔癬にはEBERおよびBHLF陽性リンパ球のlabelling indexが他の疾患に比較して有意に高値を示した.以上の結果より口腔組織中にEBVが高率に存在し,EBV感染細胞の局在は主にリンパ球であり,口腔扁平苔癬の病因にEBV感染が関与している可能性が示唆された.To determine the role of the Epstein-Barr virus (EBV) in the pathogenesis of oral diseases, 105 formalin-fixed, paraffin-embeded specimens were examined. These specimens included 22 cases of oral squamous cell carcinoma, 21 cases of fibroma, 19 cases of epulis, 16 cases of oral leukoplakia, 10 cases of plemorphic adenoma, 9 cases of oral papilloma and 8 cases of oral lichen planus (OLP). The specimens were analyzed using for polymerase chain reaction (PCR), PCR-Southern blot hybridization, and in situ hybridization (ISH) with peptid nucleic acid probes for EBV-encoded small RNAs (EBER) and immediate early mRNAs of the BamH fragment of lower strand frame (BHLF). PCR products for EBV DNA were detected in 68.5% of the examined specimens. In the ISH analysis, EBER and BHLF hybridization signals were mainly localized in the infiltrating lymphocytes. Although the proportion of EBER or BHLF positive lymphocytes varied among the examined diseases, OLP specimens expressed a significantly high level of EBER or BHLF. These results suggest that EBV infection may be implicated in the pathogenesis of OLP

口腔疾患におけるEBウイルスの関与に関する検討

EBVはヒトに極めて広範に常在するヘルペスウイルスであり,バーキットリンパ腫,上咽頭癌の病因ウイルスと考えられる.口腔領域においては免疫不全者の舌白板症,唾液腺腫瘍への関連が指摘されている.今回,我々は当科で治療を行った口腔腫瘍および粘膜疾患105例について,疾患とEBV感染の関連を検討するため,PCR法,PCR-Southern blot hybridization法,PNA probeを使用したin situ hybridization (ISH)法でEBVゲノムの検出およびmRNAの局在の検討を行った.PCRでは口腔扁平上皮癌18/22例,線維腫11/21例,epulis 16/19例,白板症8/16例,多形性腺腫6/10例,乳頭腫6/9例,口腔扁平苔癬7/8例でEBVゲノムが検出され,EBV DNAの発現率は68.5%であった.ISHではEBVのEBERおよびBHLF mRNAの発現部位は主にリンパ球に観察された.EBERとBHLF陽性細胞の局在は調べた疾患によってまちまちであったが,口腔扁平苔癬にはEBERおよびBHLF陽性リンパ球のlabelling indexが他の疾患に比較して有意に高値を示した.以上の結果より口腔組織中にEBVが高率に存在し,EBV感染細胞の局在は主にリンパ球であり,口腔扁平苔癬の病因にEBV感染が関与している可能性が示唆された.To determine the role of the Epstein-Barr virus (EBV) in the pathogenesis of oral diseases, 105 formalin-fixed, paraffin-embeded specimens were examined. These specimens included 22 cases of oral squamous cell carcinoma, 21 cases of fibroma, 19 cases of epulis, 16 cases of oral leukoplakia, 10 cases of plemorphic adenoma, 9 cases of oral papilloma and 8 cases of oral lichen planus (OLP). The specimens were analyzed using for polymerase chain reaction (PCR), PCR-Southern blot hybridization, and in situ hybridization (ISH) with peptid nucleic acid probes for EBV-encoded small RNAs (EBER) and immediate early mRNAs of the BamH fragment of lower strand frame (BHLF). PCR products for EBV DNA were detected in 68.5% of the examined specimens. In the ISH analysis, EBER and BHLF hybridization signals were mainly localized in the infiltrating lymphocytes. Although the proportion of EBER or BHLF positive lymphocytes varied among the examined diseases, OLP specimens expressed a significantly high level of EBER or BHLF. These results suggest that EBV infection may be implicated in the pathogenesis of OLP

顎下腺転移を認めた肺小細胞癌の1例

小細胞癌は肺に好発する未分化癌で早期より多臓器へ転移する特徴がある.しかし唾液腺への転移はまれで,なかでも顎下腺への転移はきわめてまれである.今回われわれは肺小細胞癌が顎下腺に転移した症例を経験したので文献的考察を含めて報告する.患者は82歳男性で,顎下部の腫脹を主訴に2001年7月に来院した.左顎下部に鶉卵大,弾性硬の腫瘤を認め,またオトガイ下に拇指頭大のリンパ節を触知した.Gaシンチでは左顎下部に集積を認めたが,その他異常を認めなかった.頸部MRIではT1強調像にて左顎下腺下極に25×22mm大で類円形,内部不均一,境界不明瞭なlow intensity massを認め,オトガイ下リンパ節の腫脹も認められ,顎下腺悪性腫瘍が疑われたため,左顎下腺腫瘍切除生検術を施行した.腫瘍は類円形で顎下腺下極に癒着しており,割面は充実性で黄白色を呈していた.病理組織学的には顎下腺小細胞癌,オトガイ下リンパ節転移との報告であったため,全身精査を行った.胸部CTにて右肺門部付近に15mmの腫瘤を認めたため東京女子医科大学呼吸器内科を受診したところ原発性肺癌の可能性が示唆された.その他画像診断で腎臓,副腎,脳に転移が認められた.化学療法を予定していたが,脳転移による痙攣,意識レベルの低下が認められ傾眠傾向となったため施行せず,間質性肺炎のための呼吸不全で死亡した.剖検では右肺下葉気管支に原発巣と考えられる腫瘍を認めた.病理組織学的には肺小細胞癌の顎下腺転移と診断し,その他腎臓,肝臓,副腎,小腸に遠隔転移を認めた.小細胞癌は肺に好発する未分化癌で,腫瘍の進展速度が急速のため,診断時点でリンパ節転移や遠隔転移をきたしていることも多い.唾液腺への転移はまれで,なかでも顎下腺への転移はきわめてまれであるが,顎下腺腫瘍を認める場合には肺癌の転移も念頭に置く必要があると考える.Metastases to the salivary glands from distant neoplasms are unusual. Most reported cases of salivary gland neoplasms involve the parotid gland. Metastatic deposits in the submandibular gland are extremely rare. Herein, we present a case of lung carcinoma with submandibular gland metastasis. The clinical course is described and discussed with reference to the literature.Metastases to the salivary glands from distant neoplasms are unusual. Most reported cases of salivary gland neoplasms involve the parotid gland. Metastatic deposits in the submandibular gland are extremely rare. Herein, we present a case of lung carcinoma with submandibular gland metastasis. The clinical course is described and discussed with reference to the literature

顎下腺転移を認めた肺小細胞癌の1例

小細胞癌は肺に好発する未分化癌で早期より多臓器へ転移する特徴がある.しかし唾液腺への転移はまれで,なかでも顎下腺への転移はきわめてまれである.今回われわれは肺小細胞癌が顎下腺に転移した症例を経験したので文献的考察を含めて報告する.患者は82歳男性で,顎下部の腫脹を主訴に2001年7月に来院した.左顎下部に鶉卵大,弾性硬の腫瘤を認め,またオトガイ下に拇指頭大のリンパ節を触知した.Gaシンチでは左顎下部に集積を認めたが,その他異常を認めなかった.頸部MRIではT1強調像にて左顎下腺下極に25×22mm大で類円形,内部不均一,境界不明瞭なlow intensity massを認め,オトガイ下リンパ節の腫脹も認められ,顎下腺悪性腫瘍が疑われたため,左顎下腺腫瘍切除生検術を施行した.腫瘍は類円形で顎下腺下極に癒着しており,割面は充実性で黄白色を呈していた.病理組織学的には顎下腺小細胞癌,オトガイ下リンパ節転移との報告であったため,全身精査を行った.胸部CTにて右肺門部付近に15mmの腫瘤を認めたため東京女子医科大学呼吸器内科を受診したところ原発性肺癌の可能性が示唆された.その他画像診断で腎臓,副腎,脳に転移が認められた.化学療法を予定していたが,脳転移による痙攣,意識レベルの低下が認められ傾眠傾向となったため施行せず,間質性肺炎のための呼吸不全で死亡した.剖検では右肺下葉気管支に原発巣と考えられる腫瘍を認めた.病理組織学的には肺小細胞癌の顎下腺転移と診断し,その他腎臓,肝臓,副腎,小腸に遠隔転移を認めた.小細胞癌は肺に好発する未分化癌で,腫瘍の進展速度が急速のため,診断時点でリンパ節転移や遠隔転移をきたしていることも多い.唾液腺への転移はまれで,なかでも顎下腺への転移はきわめてまれであるが,顎下腺腫瘍を認める場合には肺癌の転移も念頭に置く必要があると考える.Metastases to the salivary glands from distant neoplasms are unusual. Most reported cases of salivary gland neoplasms involve the parotid gland. Metastatic deposits in the submandibular gland are extremely rare. Herein, we present a case of lung carcinoma with submandibular gland metastasis. The clinical course is described and discussed with reference to the literature.Metastases to the salivary glands from distant neoplasms are unusual. Most reported cases of salivary gland neoplasms involve the parotid gland. Metastatic deposits in the submandibular gland are extremely rare. Herein, we present a case of lung carcinoma with submandibular gland metastasis. The clinical course is described and discussed with reference to the literature