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Here we present a case of de novo Stage Ⅳ breast cancer successfully treated with surgery and multiple endocrine therapies over a long period of time. A 75-year-old female presented with a breast tumor with skin invasion and multiple lung metastases. Diagnosed with infiltrating breast cancer of Luminal A-like subtype, endocrine therapy with anastrozole was initiated. Despite initial response to the treatment in both the primary site and lung metastases, the primary tumor regrew and surgery with lumpectomy was performed. After a 3-year-treatment of tamoxifen, axillary lymphadenopathy and bone metastases developed. The patient was treated with fulvestrant for 5 years, resulting in clinical complete response. The now 88-year-old patient has been free of disease without treatment for a year and a half. Generally, primary tumor resection of Stage Ⅳ breast cancer does not improve prognosis, but in this case it provided good local control and enabled long-term endocrine therapy, resulting in prolonged disease-free survival.

The patient was a 50-year-old male. At the age of 48 years, he had undergone total gastrectomy and right hemicolectomy simultaneously for gastric and ascending colon cancers. Since adjuvant chemotherapy has become common practice for patients with ascending colon cancer, capecitabine was administered for 6 months. One year and 6 months after the surgery, he was diagnosed with recurrence of the ascending colon cancer at the anastomotic site and underwent local colectomy. Considering he was pathologically diagnosed as pT4a, mFOLFOX6 therapy was prescribed as postoperative adjuvant chemotherapy. On the day the 11th course of treatment was initiated, the patient complained of weakness; however, his blood test results showed no abnormalities; therefore, he was followed-up as an outpatient. Three days later, he presented to the hospital with exacerbated symptoms and was diagnosed with rhabdomyolysis due to a marked increase in CK(2,031 U/L). Rhabdomyolysis was determined to be the adverse effect of oxaliplatin because out of all the drugs prescribed to the patient, this condition is listed as a side effect only in oxaliplatin's package insert. Fortunately, outpatient treatment was enough to alleviate rhabdomyolysis. Subsequently, adjuvant chemotherapy was completed without oxaliplatin. The patient has been followed-up without recurrence for 9 months after the surgery.

CREATE-X trial demonstrated the effectiveness of additional capecitabine therapy in prolonging disease-free survival among patients who are HER2 negative, especially those with triple-negative breast cancer who had residual invasive disease after standard neoadjuvant chemotherapy. We investigated our data regarding adjuvant capecitabine for residual disease. Ten patients were enrolled, and the average age of the patients was 54.2 years. All patients completed 8 courses of treatment; all adverse events were Grade 2 or lower. Five-year disease-free survival rate was 70.0% in an average observation period of 40.9 months. Three patients recurred within 2 years, and all patients had brain metastasis. In the CREATE-X trial, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group; our results were same as those of CREATE-X. Brain metastasis may be detected by the early phase of enhanced brain MRI.

Like most complex(or multifactorial)diseases, cancer results not from a single factor, but rather from the interaction of multiple genes and environmental factors. Thus patients can experience different signs and symptoms that reflect more than one consequence of suffering the disease. When evaluating the effects of new treatments in cancer clinical trials, the multidimensional assessment using multiple outcomes to measure improvements in the patients' signs and symptoms associated with treatments would be preferred. Most cancer clinical trials use more than one clinical outcome as multiple primary, or primary and(key)secondary endpoints, such as overall survival, endpoints based on tumor assessments(e.g., disease-free survival, event-free survival, objective response rate, time to progression, progression-free survival), and endpoints involving symptom assessment. Utilizing multiple endpoints may provide the opportunity for characterizing the intervention's multidimensional effects, but also creates challenges, specifically controlling the Type Ⅰ and/or Type Ⅱ errors in hypotheses testing and trial designs associated with multiple endpoints. In this article, we review issues in design, monitoring, analysis and reporting of clinical trials with multiple endpoints, with illustrating examples in oncology disease settings. We outline several methods for controlling the Type Ⅰ error associated multiple tests, which have been commonly used in clinical trials. We also briefly discuss issues in interim analyses and group sequential designs for clinical trials with multiple endpoints.

The present study reviewed 9 cases of pregnancy and delivery after breast cancer in our clinic, between 2007 and 2019, to evaluate treatment options for their safe and successful management. The mean age at primary surgery was 31.7 years(27- 37); the study included 1, 5, 2, and 1 cases of pTNM Stage 0, Ⅰ, ⅡA, and ⅡB, respectively. The pregnancies were allowed after at least 1 year since completion of treatment to wash out chemotherapy or endocrine therapy agents. There were a total of 17 natural pregnancies, including 15 natural deliveries and 2 spontaneous abortions. Four patients achieved 1 birth, 4 achieved 2 births, and 1 achieved 3 births. The mean age at the first delivery after surgery was 36 years(30-40), and the highest age at the last delivery was 45 years. The molecular subtypes of breast cancer involved included 5 Luminal types, 1 Luminal-HER2 type, 1 HER2-enrich type, and 2 triple-negative types. The mean interval between the primary surgery and the first delivery was 4.3 years(3-6). Six patients were disease-free, and 3 patients experienced recurrences. Among the 3 patients with recurrence, 1 patient suffered from a local recurrence 43 months after the surgery; it was successfully resected, and she delivered 2 children after the second surgery and is now disease-free. One patient delivered 2 children after surgery; 12 years after surgery, she suffered from bone metastasis, but fortunately, endocrine therapy plus zoledronic acid treatment induced complete remission. One patient achieved pregnancy 4 years after the surgery and routine examination demonstrated the liver and bone metastases. The patient safely delivered at 9th-month pregnancy; the metastases and recurrences were treated chemo-endocrine therapy, and the patient is currently doing well. In conclusion, although the present study includes only 9 patients with 15 births, it suggests that a safe and successful pregnancy and delivery can be achieved through a variety of patient-orientated post-surgical treatment options that consider fertility preservation.

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is a relatively new concept that refers to patients aged 15-39 years with unique pathophysiology and requiring specific clinical care. Many clinical studies have revealed that treatment with the pediatric protocol has better disease-free and overall survival than the adult protocol for AYA-ALL. AYA-ALL survival was significantly improved from 30% with the adult regimen to 60-70% with the pediatric regimen. Two types of strategies are available to adapt pediatric regimens to AYA-ALL, a pediatric-inspired and a fully pediatric regimen. Determining the recommended strategy from these two strategies is difficult at this time. New knowledge of AYA-ALL-specific genetic characteristics provides new strategies for targetable ALL, especially Ph-like ALL. New immunotherapy has been approved for refractory and recurrent ALL; however, treatment results of AYA-ALL were improved by introducing the first line of immunotherapy in BCP-ALL, which may have a poor prognosis such as residual MRD. Pediatric and adult hematologists must work together to improve the prognosis of AYA-ALL.

Tyrosine kinase inhibitor (TKI)-combined chemotherapy has become the standard option in pediatric Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ALL) treatment. Additionally, hematopoietic cell transplantation (HCT) in the first remission is no longer an absolute indication. However, pediatric Ph+ALL remains refractory leukemia, with a disease-free survival rate of approximately 60% for patients without HCT in the first remission due to treatment-related death or relapse after chemotherapy. Further outcome improvement will require an intensified targeted therapy with second- or third-generation TKIs or less toxic immunotherapies, as well as improved safety, with reduced conventional chemotherapy. Continuous attention to these issues in clinical trials will change pediatric Ph+ALL from intractable to manageable leukemia in the future.

Occult breast cancer is rare in practice. We studied the clinical outcomes of 5 occult breast cancers, including 2 with Luminal and 3 with non-Luminal subtypes, for which the primary site was not detected in the breast-by-breast MRI. The percentage of occult breast cancers that we encountered at our hospital was 0.11%. The mean age was 54 years. The Ki-67 labeling index value was 30% or higher for all the patients except one. Four patients were administered neoadjuvant chemotherapy and all but one patient received non-mastectomy and axillary dissection plus radiotherapy. We observed recurrent cases in one example each of the Luminal and HER2 subtypes, and both patients were less than 40 years old. The estimates of the probability of 5 year recurrence-free survival and 5 year overall survival were 40.0% and 66.7%, respectively. One recurrence case was a patient negative for ER and positive for HER2 wherein a breast cancer lesion appeared in the breast during post-treatment follow-up. Intrabreast relapse, which is itself rare in occult breast cancer, was observed 4 years postoperatively after standard treatment. Although there was no deviation according to subtype rate, the Ki-67 labeling index value was high and the prognosis was poor in our 5 cases.

From 1990 to 2019, 256 patients underwent surgery for metastatic lung tumors in our hospital, of which 23 (9.0%) had multiple surgeries. There were 15 cases of colorectal cancer, 2 cases of renal cancer, 2 cases of breast cancer, and 4 cases of others according to the primary lesion, and the number of operations was 2 times 18 cases, 3 times 4 cases, and 4 times 1 case. The average disease-free interval( DFI) was 27.2 months, and the average interval between the first and second operations was 25 months. The median observation period from the last surgery was 58.5 months, the 5-year survival rate was 67%, and the 10-year survival rate was 39%. If the surgical indication for metastatic lung tumor is satisfied and the prognostic factors such as long DFI or a small number of recurrences are met, re-surgery should be actively considered, and the significance of lung metastasectomy remains even now that drug therapy has advanced.

Klotho is one of the known anti-aging genes, and functions as an inhibitor of the insulin-like growth factor 1(IGF-1) pathway. However, the clinical significance of Klotho expression in cancer tissues have not been elucidated yet. In this study, we aimed to investigate the clinical significance of Klotho expression in breast cancer patients. We evaluated Klotho expression through immunohistochemical analysis and evaluating Ki-67 positive cell index in 142 patients who underwent surgery for breast cancer in our hospital. There was no significant correlation between age, menopausal state, historical type, hormone status, HER2 status, and distant metastases. High expression of Klotho was observed in the non-invasive compared to the invasive ductal carcinomas. The number of metastatic lymph nodes, clinical stage, and tumor size were correlated to Klotho expression level in the cancer tissues. The Klotho positive group exhibited low score for Ki-67 positive cell index than the Klotho negative group. No significant correlation in cumulative survival rates between Klotho positive and Klotho negative groups was observed. The Klotho negative group exhibited good prognosis than the Klotho positive group for the disease- free survival after the operation. These results suggest that the analysis Klotho expression in the breast cancer tissues using immunohistochemistry is a useful tool to assess the disease-free survival for breast cancer patients.

Objective: To evaluate the efficacy and safety of CAPOX plus bevacizumab as second-line chemotherapy for metastatic colorectal cancer., Methods: In this multicenter phase Ⅱ study, the planned number of patients was 48, but owing to poor case accumulation, registration was discontinued for 20 patients. The primary endpoint was the response rate(RR). Secondary endpoints were progression-free survival(PFS), overall survival(OS), disease control rate(DCR), and safety., Results: First-line treatment was combined with irinotecan in 14 cases and bevacizumab in 12 cases. The median number of second- line treatment courses was 7, and the median treatment period was 203 days. The reason for discontinuation of treatment was disease progression in 13 cases, adverse events in 4 cases, and other reasons in 3 cases. The best response was PR in 5 cases, SD in 8 cases, and NE in 4 cases. The RR was 25%, and the DCR was 65%. The median PFS was 7.2 months, and the median OS was 18.6 months. Grade≥3 adverse events were neutropenia in 3 cases and diarrhea and peripheral neuropathy in 2 cases each. There were no treatment-related deaths., Conclusion: CAPOX plus bevacizumab was a safe and effective second-line treatment option for metastatic colorectal cancer.

In an analysis of 653 cases of acute lymphoblastic leukemia associated with Down syndrome (DS-ALL) collected from clinical research groups worldwide, the 8-year disease-free survival for DS-ALL was 64%, which was worse than the 81% for non-DS-ALL during the same period. This could be because DS-ALL has less hyperdiploidy and ETV6-RUNX1 abnormalities, which have a favorable prognosis, more Ph-like ALL, which has a poor prognosis, as well as more adverse deaths due to infectious complications. It has been reported that optimizing the treatment intensity using minimal residual disease and by strengthening the measures against adverse effects improve the treatment outcome of DS-ALL. The incidence of DS-ALL is reported to be 20 times higher than that of non-DS-ALL. The mechanism is believed to be through proliferation of the lymphoid system caused by HMGN1 on chromosome 21 as well as activation of JAK-STAT and proliferation of ALL cells caused by overexpression of CRLF2, such as P2RY8-CRLF2 fusion. The CRLF2 abnormality is found in 30-60% of DS-ALL cases. In the future, treatment of CRLF2, targeting JAKs downstream of CRLF2, and administration of blinatumomab or CAR-T therapy will be incorporated into DS-ALL treatment.

Purpose: This study was aimed at evaluating the oncologic outcomes of our preoperative treatment strategies for cStage Ⅱ/Ⅲ lower rectal cancer. At our hospital, neoadjuvant chemotherapy is administered for patients with bulky mesenteric lymph nodes on pretreatment imaging, and neoadjuvant chemoradiotherapy is administered for patients whose circumferential radial or distal margin cannot be secured because of strong local extension., Methods: Thirty patients who underwent preoperative therapy followed by total mesorectal excision for cStage Ⅱ/Ⅲ lower rectal cancer were retrospectively analyzed from October 2010 to October 2015., Results: Twenty-five patients underwent neoadjuvant chemotherapy, and 5 patients underwent neoadjuvant chemotherapy. Tumor recurrence occurred in 10 patients at local(5 patients)and distant(5 patients)sites. The 5-year recurrence-free survival(5RFS)was 63.9%., Conclusion: We performed preoperative therapy in poor-risk locally advanced lower rectal cancer and obtained good results.

We investigated factors related to the recurrence and prognosis of patients with triple-negative breast cancer (TNBC)after neoadjuvant chemotherapy(NAC). Of the 545 patients who underwent surgery after NAC between January 2013 and December 2016, 131 patients had TNBC. An analysis of each TNBC case indicated that the presence or absence of clinical lymph node metastasis(cN)before treatment might be a predictive factor of prognosis. There were 57(43.5%)pathological complete response(pCR)(ypT0 or ypTis/N0)cases after NAC. Overall survival(OS)and disease free survival(DFS) were significantly better in pCR cases than in non-pCR cases. However, recurrence was observed in 8 of 57(14%)pCR cases and 29 of 74(39%)non-pCR cases. The factors defining DFS from the univariate analysis of the non-pCR group were cN, ypT, ypN, and vascular invasion. The multivariate analysis of these factors suggested that residual cN and vascular invasion might be independent factors predicting DFS. Residual vascular invasion was found to predict OS, and was considered to be a poor prognostic factor.

An 89-year-old woman with recurrent hormone receptor-positive and HER2-negative breast cancer was treated with fulvestrant-palbociclib combination therapy. However, 3 months after therapy initiation, she presented to our emergency room with dyspnea and fever and was admitted to our hospital because of respiratory failure. After radiological and microbiological evaluation, she was diagnosed with palbociclib-related pneumonitis. Accordingly, corticosteroids were administered, and the patient exhibited initial clinical and radiological improvement. However, pneumonitis recurred following corticosteroid tapering; her condition did not improve with high-dose intravenous corticosteroid administration, leading to death. Palbociclib- related pneumonitis is rare, but clinicians need to pay attention to this potentially lethal adverse event.

Recently, there has been an increasing drive to consider the cost effectiveness of healthcare. Since clinical trials usually examine disease-free survival without considering overall survival, it is difficult to determine which treatment is cost effective. At present, the overall survival time is estimated using a Markov model, and the quality-adjusted life year (QALY) is calculated by taking into account the quality and quantity of life lived. In Japan, the cost required to obtain 1 QALY is expected to be around 5 million yen, and drug prices are being influenced by policy. Indubitably, this type of health economics also has limitations and is not equal for everyone. Thus, collaboration is necessary to discuss better and more efficient medical care. It is hoped that this review of two diseases of hematopoietic malignancy will enhance our understanding of health economics.

Introduction: Surgery alone shows an insufficient result for distal cholangiocarcinoma, and postoperative adjuvant chemotherapy is commonly used. However, no definite opinion has yet been accepted., Subjects and Methods: A group of 46 patients who underwent surgery for distal bile duct cancer and who received adjuvant chemotherapy including gemcitabine (GEM)(Group A)and surgery alone group(Group S)were compared for disease-free survival(DFS)and overall survival (OS)., Results: Although the median DFS was 718 days in Group A and 367 days in Group S(p=0.306)and the median OS was 1,171 days in Group A and 859 days in Group S(p=0.07), no significant difference was observed; however, the prognosis improved., Conclusion: Postoperative adjuvant chemotherapy may improve prognosis.

A nomogram is a statistical tool that can provide the specific outcomes of individual patients. In this study, we used a nomogram developed by Beppu et al to evaluate the prognoses of 38 patients who underwent hepaticresec tion at our hospital. This nomogram predicts disease-free survival(DFS)after hepatic resection for colorectal liver metastasis based on 6 clinical and oncological factors. Using this nomogram, we divided the 38 patients into 3 groups: Group N, actual DFS was almost similar to the estimated median DFS(EMDFS)provided by the nomogram; Group A, DFS was longer than EMDFS; and Group B, DFS was shorter than EMDFS. Then, we compared and analyzed clinical and oncological factors between Groups A and B. Group B patients tended to have single metastasis and non-normal levels of CA19-9. Besides, Group B patients had DFS shorter than approximately 2 years. These results suggest that if CA19-9 levels are not normalized after hepaticresec tion for single metastasis, we should consider careful observation and adjuvant chemotherapy for potential micrometastasis.

We report a case of a 63-year-old man with a perirectal abscess due to rectal cancer referred to us from another clinic. We performed 3 courses of preoperative chemotherapy using mFOLFOX6 and then performed a Miles operation plus D3 dissection followed by reconstruction of an artificial anus using the ileum. The pathological diagnosis was tub2, pAI(prostate), pN0 (0/12), ND(v+), and fStage Ⅲa. Dehiscence of the perineum wound area occurred 4 months after surgery, for which drainage was required. Local recurrence was then discovered by cytology. We administered mild 40 Gy radiation and chemotherapy using Bmab combined with mFOLFOX6. CT scans showed a significant reduction in the tumor and the tumor marker levels returned to within normal ranges. We then converted to Pmab plus FOLFIRI, which has been administered bimonthly for 3 years to date. The overall chemoradiotherapy duration has been about 5 years. Follow-up imaging findings continue to show sustained remission.

Aim: This study aimed to retrospectively evaluate the efficacy and safety of ifosfamide plus paclitaxel(IT)in Japanese patients with recurrent or metastatic uterine carcinosarcoma., Methods: This study included 15 patients who received IT(ifosfamide [1.6 g/m / 2 on days 1-3]and paclitaxel[135mg/m2 on day 1]every 3 weeks)for recurrent or metastatic uterine carcinosarcoma., Results: The overall response rate was 38.4%, and the disease control rate was 92.3%. The median progression- free survival was 7.0 months, and the median overall survival was 9.0 months after initiation of IT therapy. The most common hematological adverse event was Grade 1-2 neutropenia. Peripheral neuropathy of Grade 1 or 2 was observed in 33.3% of cases. There was no treatment-related death., Conclusion: IT therapy showed good efficacy and tolerability in Japanese patients with recurrent or metastatic uterine carcinosarcoma.

Objectives: Pulmonary lobectomy is the standard surgical procedure for resectable non-small cell lung cancer (NSCLC), while sublobar resection is an important surgical alternative for high-risk patients with comorbidities. We evaluated the treatment outcome and prognostic factors of sublobar resection in high-risk patients with NSCLC., Methods: Eighty three high-risk patients who underwent compromised sublobar resection for clinical-N0 NSCLC with a solid appearance were retrospectively reviewed. A total of 47 wedge resections and 36 segmentectomies performed., Results: Poor pulmonary function and synchronous or metachronous multiple lung cancer were found in 56.7% and 20.5% of patients respectively, all requiring sublobar resection. There were 21 instances of tumor recurrence and 24 deaths during a mean follow-up of 1,500 days. There was no local recurrence in the segmentectomy group. The 3-year recurrence free survival (RFS) and overall survival (OS) were 72.6% and 73.8% respectively. A multivariate analysis indicated that resection type and lymphatic invasion were independent prognostic factors for RFS. In the wedge resection group, a ratio of surgical margin to clinical tumor size greater than 1 (MT ratio≥1) was an independent prognostic factor for RFS( 87.1%,p=0.001)., Conclusion: Segmentectomy leads to a favorable prognosis. MT ratio was independently associated with a longer RFS in the wedge resection group.

Because multiple myeloma is rare in young people, there are fewer reports on the same. Thus, its clinical aspects and prognosis remain unelucidated. We retrospectively evaluated 30 patients with multiple myeloma aged ≤ 45 years at diagnosis. We divided them into three groups based on their cytogenetic risks: standard risk (SR), high risk (HR), and unknown risk. The frequency of HR patients was 36.6%, the highest of the three groups, unlike the previous report. The median progression-free survival (PFS) was 35 months (SR vs. HR, 46 vs. 29 months), and the median overall survival (OS) was not reached (NR) (SR vs. HR, NR vs. 82 months). The OS was significantly worse, and the PFS also appeared inferior in HR patients. The International Staging System score was not associated with OS. Thus, young patients with myeloma appeared to have a higher frequency of HR features, suggesting that instead of age, the cytogenetic risk was a significant prognostic factor.

Background: As the aging of the Japanese population progresses, the administration of postoperative adjuvant chemotherapy( AC)to the elderly is also expected to increase., Objective: To examine the characteristics of AC in cases of colorectal cancer among elderly people aged over 75 years., Patients: Forty-eight cases of colorectal cancer patients who received AC., Methods: The clinicopathological factors, including 14 patient-related factors, 6 operation-related factors, and 2 AC-related factors, as well as the long-term outcomes, were compared between the elderly group of patients aged over 75 years(group O, 12 cases)and the non-elderly group(group Y, 36 cases)., Results: Significant differences were observed between groups in neutrophil count(p=0.044), operation time(p=0.044), AC regimen(p=0.006), and administration completion status (p=0.046). Compared to group Y, a higher proportion of oral drug alone(92% vs 39%)and completion rate of the initial setting dose(75% vs 39%)were observed in group O. There was no significant difference in the 2-year disease-free survival rate., Conclusion: Oral preparations of AC may be useful from the viewpoint of tolerability in the elderly.

Whether Langerhans cell histiocytosis (LCH) is an inflammatory disorder or a neoplasm is an ongoing debate. On the basis of the identification of the BRAF V600E mutation in 2010, LCH should be defined as an inflammatory myeloid neoplasia. Mutually exclusive BRAF V600E (50-60%) and MAP2K1 (12-25%) mutation renders the ERK activation. BRAF V600E mutations were detected in approximately 50-60% of patients with Erdheim-Chester disease (ECD), and these patients are being treated with vemurafenib, a selective BRAF V600 kinase inhibitor, approved by the US Food and Drug Administration. The Japan Langerhans cell histiocytosis study group-02 protocol study showed five-year overall survival rate of 92% and event-free survival of 46% in risk-organ involvement of positive multi-system LCH. We aimed to improve the quality of life by reducing relapses and development of late complications. It is essential to achieve a close cooperation between hematologists catering to pediatric and adult patients with LCH. Furthermore, novel targeted therapies of MAPK inhibitors are required along with intensified chemotherapy to achieve better outcomes in patients with LCH in Japan.

The is a case involving a 55-year-old man with advanced rectal cancer(type 3). MRI showed urinary tract and regional lymph node metastases without distant metastasis. The tumor was reduced(PR)after neoadjuvant chemotherapy(mFOL FOX6 plus Bmab, 4 courses). The patient underwent an abdominoperineal resection. Because infiltration of the tumor into the lower urinary tract was deep, it was also resected and repaired. The clip was placed to mark the repaired region. Pathological examination revealed that excision stump at the anterior wall of the urethra was cancer positive without lymph node metastasis. He was then administered chemotherapy(mFOLFOX6 4 courses)and irradiated 60 Gy in both sides of the inguinal lymph node to prevent metastasis to the pelvicdomain. One year and 6 months postoperatively, as the left inguinal lymph node swelled at 3.7 cm irregularly, he further received chemotherapy(FOLFIRI 8 courses). The size of the lymph node became normal with a good response to FOLFIRI. Six years postoperatively, he remains alive and well with no evidence of recurrence.

A 71-year-old man visited our hospital because ofepigastralgia and anorexia. Upper gastrointestinal endoscopy revealed type 1 gastric cancer. Contrast-enhanced abdominal CT revealed gastric wall thickening in the midgastric region and direct invasion ofthe transverse colon. CT findings also revealed a suspicion ofdissemination on the omentum and para-aortic lymph node swelling. We diagnosed gastric cancer with transverse colon invasion. Therefore, we performed distal gastrectomy with transverse colectomy and D2+No.16b1 lymph node dissection after obtaining patient consent. We observed direct tumor invasion into the transverse colon and seeding nodules on the omentum. Liver metastasis was not seen, and ascitic cytology was negative. He was discharged 16 days postoperatively, without any complications. Histopathological analysis revealed poorly differentiated adenocarcinoma and gastrocolic fistula. Postoperatively, S-1 was administered for 4 years as adjuvant chemotherapy. There has been no recurrence for 9 years after surgery.

We report the case of a 50-year-old female survivor of Hodgkin lymphoma (HL), who developed dropped head syndrome (DHS). The patient was diagnosed with HL at 20 years of age, and underwent chemo-radiotherapy, which led to complete remission. Undergoing supplemental therapy for post-radiation hypothyroidism, she had twin babies. She noticed white stains on her neck at the age of 30, and the decolored area gradually expanded. Sixteen years after the radiotherapy (RT), her posterior neck muscle strength began to decline. She had to make considerable efforts to keep her neck straight, and came to experience a severe pain in the neck and shoulders. The patient visited our department due to DHS at the age of 50. She had leukoderma, muscle weakness, and muscle atrophy in the neck and para-spinal region, which were consistent with the area of RT. The strength was preserved in the other parts of the muscle, including the proximal upper limbs. Sensory nerve disorder was not detected. The serum creatine kinase level was slightly elevated. Cervical spine or cervical cord disease that can cause DHS was not detected by MRI examination. The MRI and CT images revealed marked atrophy in the posterior neck and para-spinal muscles. The electromyogram revealed myopathic changes, and the cause of her DHS was diagnosed as radiation-induced myopathy. DHS is a well-known late-onset radiation injury, and Japanese cases have been reported in elderly persons with laryngeal or lung cancer. However, there have been no Japanese case reports of radiation-induced DHS due to RT against HL in younger persons. The patient had visited several clinics and hospitals before she came to our hospital, but RT-induced DHS had been overlooked. Greater recognition and consideration is required for DHS as one of the various issues arising after long passage of HL survivors.

Background: The standard approach for treating recurrence after complete resection of primary non-small cell lung cancer has been controversial. We present here a multidisciplinary strategy for postoperative recurrence in patients with primary lung cancer., Patients and Methods: Over the last 7 years, we examined the disease-free survival and overall survival of 70 patients who underwent multidisciplinary treatment for recurrence after surgical resection of primary lung cancer., Results: The median overall survival was 32.3 months after surgery and 17.4 months after recurrence developed, indicating significantly better prognoses in females and in patients with adenocarcinoma, stage I disease, driver mutation positivity, a longer postoperative disease-free period, and never smokers. Eight patients survived more than 5 years after recurrence;of these patients, all had adenocarcinomas, 7 had oligometastases and/or tumor dormancy, and 5 received multiple-drug regimens., Conclusion: Multidisciplinary treatment for recurrence after resection of primary lung cancer was effective for patients receiving various drug regimens. In patients with oligometastases, disease control was achieved by a combination of local treatments targeting each involved organ. In patients with tumor dormancy, follow-up or a drug holiday was important to maintain the patient's quality of life.

Palbociclib is the world's first cyclin dependent kinase (CDK) 4 and 6 inhibitor. It's believed that palbociclib stops the cell cycle progression by inhibiting the activity of the complex consisting of CDK 4/6 and cyclin D, and suppresses tumor growth. In preclinical study using nonclinical model, it was confirmed that most of the cell lines sensitive to palbociclib are estrogen receptor (ER) positive. In addition, it was suggested that the expression of retinoblastoma protein (Rb) is needed for palbociclib to show its antitumor effect. By the preclinical studies using ER positive human breast cancer cell lines in combination administration of palbociclib and anti-estrogen drugs, it was confirmed that the antitumor effect was enhanced as compared with single agent administration of each drug. Based on these findings, the clinical studies in which hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced or metastatic breast cancer were conducted in combination with endocrine therapy. The PALOMA-2 study showed that progression-free survival (PFS) was longer with palbociclib plus letrozole than with placebo plus letrozole in the initial treatment of postmenopausal women with ER+/HER2- advanced breast cancer. In the PALOMA-3 study, the combination of palbociclib and fulvestrant was associated with significant improvements in PFS compared with fulvestrant plus placebo in patients with metastatic breast cancer. The rate of dose reduction or interruption of dosing by adverse events is higher in palbociclib group compared with placebo group in both studies while the rate of discontinuation of treatment was comparable.

Graft-versus-host disease (GVHD) -free, relapse-free survival (GRFS) is an important, composite endpoint for clinical trials, which provides a patient-centered measure of transplant success. This review discusses the results of the Japanese Transplant Registry study. This large-scale study examined 23,302 patients with hematological malignancy and characterized GRFS according to a variety of graft sources. The GRFS rate at 1 year was 41% in all patients. GRFS was superior in patients undergoing bone marrow transplantation compared to peripheral blood stem cell transplantation, owing to lower risk of developing grades III-IV acute and chronic GVHD. The best GRFS rates were observed in patients that received HLA-matched related bone marrow transplants; however, this was not the case in HLA-mismatched donors. GRFS after single-cord blood transplantation was almost comparable with HLA-matched unrelated bone marrow transplantation, possibly due to the low risk of chronic GVHD. Other factors associated with increased GRFS rates included female patients; use of anti-thymocyte globulin prophylaxis for standard-risk disease; recent transplantations; gender combinations other than from a female donor to a male patient; absence of prior autologous transplantation; myeloablative conditioning; negative cytomegalovirus serostatus; and use of tacrolimus-based GVHD prophylaxis. These results provide valuable information for deciding the best choice of graft sources and type of GVHD prophylaxis to be used.

Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in the Western countries. Although a multi-step model has been proposed for the pathogenesis of CLL as well as other malignancies, the precise mechanism underlying the development of CLL remains complicated and unclear. In addition, several studies have investigated adverse prognostic factors, including gene abnormalities and the evolution of clones with the disease progression. FCR (fludarabine, cyclophosphamide, and rituximab) has been the standard first-line therapy for "fit" younger patients without TP53 abnormality/17p deletion. Patients with CLL with TP53 abnormality/17p deletion exhibit poor prognosis because of the resistance to chemoimmunotherapy such as FCR. However, several novel targeted therapies such as B-cell receptor inhibitors including Bruton's tyrosine kinase inhibitors, PI3 kinase inhibitors, and Bcl-2 antagonists have been developed and have proven effective for high-risk patients with CLL with TP53 dysfunction. Moreover, in patients with CLL with the IGHV somatic mutation, FCR therapy offers long-term disease-free survival. These promising findings suggest the possibility of a cure. Although the aim of CLL treatment has been disease control, it is gradually changing to the possibility of a cure. Furthermore, the evaluation of minimal residual disease is important for the cure of CLL.

A 34-year-old man, diagnosed with paraganglioma of the urinary bladder, was referred to our hospital. Computed tomography showed a bladder tumor measuring 64 mm along with right obturator lymphadenopathy. Abnormal uptake was observed on 123 I-MIBG scintigraphy. The tumor was, therefore, diagnosed as malignant paraganglioma. We performed cystectomy, pelvic lymph node dissection, and neobladder reconstruction. Pathological examination revealed a malignant paraganglioma of the urinary bladder with right obturator lymph node metastasis. Postoperatively, both the uptake on 123 I-MIBG scintigraphy and catecholamine levels in blood and urine normalized. However, 22 months later, positoron emission tomography-computed tomography showed the presence of 2 recurrent tumors in the pelvis. The patient underwent 9 courses of cyclophosphamide, vincristine, and dacarbazine chemotherapy and MIBG radiotherapy twice, following which the tumor size decreased by 35% and catecholamine levels normalized once again. At about 2 years of follow-up, the patient was found to be free of recurrence.

This study aimed to investigate the clinical outcomes of hematopoietic stem cell transplantation (HSCT) with total body irradiation-based myeloablative conditioning (TBI-MAC) in pediatric patients with acute lymphoblastic leukemia (ALL). We retrospectively examined patients with ALL who underwent HSCT with TBI-MAC from January 2000 to August 2016 at our institute. We enrolled 67 patients with a median follow-up period of 8 years. The 5-year event-free survival (EFS) and overall survival (OS) were 51.2% and 59.6%, respectively. At the first complete remission, HSCT exhibited significantly superior EFS and OS in our patients than that in patients with other diseases. We encountered 57.9% of patients with at least one late complication. Major late complications were short stature (26.3%) and hypogonadism (18.4%). While late complications were observed in several recipients of HSCT, late complication-related deaths occurred in three patients. The TBI-MAC regimen led to favorable clinical outcomes in pediatric patients with ALL who underwent HSCT. Thus, proper evaluation and management of late complications are mandatory.

Objective: To investigate residual disease status after primary cytoreductive surgery(PCS)in patients with advanced ovarian, Fallopian tube, or peritoneal carcinoma and long-term progression-free survival(PFS)., Methods: The study included patients with stage III C/IVepithelial ovarian, fallopian tube, or peritoneal carcinoma who had undergone surgery and carbo- platin/taxane chemotherapy, and had a PFSduration of ≥48 months., Results: The study group consisted of 11 patients with stage III C disease, which accounted for 23%(8/35)of stage III C patients aged ≤59 years and 11%(3/27)of stage III C patients aged ≥60 years. No stage IV patients had a long-term PFS(0/11). Of 8 patients aged ≤59 years, 2 had residual disease of 0.1-1 cm(optimal debulking), 5 had residual disease of >1 cm after PCS, and 1 who had received neoadjuvant chemotherapy(NAC)had optimal debulking during interval cytoreductive surgery. Of 3 patients aged ≥60 years, 2 had no macroscopic residual disease, and 1 had residual disease of >1 cm after PCS., Conclusion: In patients with stage III C ovarian, fallopian tube, or peritoneal carcinoma, a subgroup of those aged ≤59 years had long-term PFSdespite suboptimal PCS. In this age group, carboplatin/taxane chemotherapy may improve the prognosis, irrespective of residual disease status after PCS. In contrast, complete cytoreduction during PCSappears to be necessary in patients aged ≥60 years who achieve long-term PFS.

A new class of gene mutations, identified in the pathogenesis of adult acute myeloid leukemia (AML), includes DNMT3A, IDH1/2, TET2 and EZH2. However, these mutations are rare in pediatric AML cases, indicating that pathogeneses differ between adult and pediatric forms of AML. Meanwhile, the recent development of massively parallel sequencing technologies has provided a new opportunity to discover genetic changes across entire genomes or proteincoding sequences. In order to reveal a complete registry of gene mutations, we performed whole exome resequencing of paired tumor-normal specimens from 19 pediatric AML cases using Illumina HiSeq 2000. In total, 80 somatic mutations or 4.2 mutations per sample were identified. Many of the recurrent mutations identified in this study involved previously reported targets in AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1 and EZH2. On the other hand, several genes were newly identified in the current study, including BCORL1 and major cohesin components such as SMC3 and RAD21. Whole exome resequencing revealed a complex array of gene mutations in pediatric AML genomes. Our results indicate that a subset of pediatric AML represents a discrete entity that could be discriminated from its adult counterpart, in terms of the spectrum of gene mutations.

We retrospectively analyzed, and herein discuss, the outcomes of and prognostic factors for 35 untreated multiple myeloma patients less than 65 years of age who received induction therapies with bortezomib (Bor) and dexamethasone (BD) for the purpose of up-front autologous peripheral blood stem cell transplantation (SCT). The overall response rate was 77% (27 cases, including 4 [11%] complete response and 13 [37%] very good partial response cases). The rate of SCT accomplishment was 51% (18 cases). The 3 year-progression free survival (PFS) rate for the SCT group was significantly higher than that of the non-SCT group (41% vs 0%, P=0.0037). This result reflects the significantly more severe adverse effects of induction therapy for the non-SCT than the SCT group. Among reasons for SCT drop-out, 29% of cases suffered severe peripheral neuropathy with features such as irreversible numbness and pain. The analysis of PFS revealed a cytogenetic factor, favorable chromosomal type at diagnosis, to predict a better outcome (P values on univariate and multivariate analyses were 0.0004 and 0.0405, respectively). Our observations suggest establishment of induction therapy, aimed at reducing adverse effects and overcoming unfavorable cytogenetic abnormalities, to be necessary for improving the outcomes of patients with multiple myeloma.

Recent meta-analyses and systematic reviews focusing on the significance of high dose therapy with autologous hematopoietic stem cell transplantation for newly-diagnosed multiple myeloma patients have shown its benefit in terms of progression-free survival, but no over-all survival benefit versus conventional chemotherapy. New drug-containing regimens, with agents such as iMIDs and proteasome inhibitors, have not yet been established as high-dose therapy, because no phase III RCT has been conducted to date. Although several guidelines recommend maintenance therapy for non-CR patients after transplantation, caution is still warranted because the JSH guideline advocates further careful discussion of this clinical question.

The patient was a 77-year-old woman who underwent gastrectomy for gastric cancer. Since the patient had positive peritoneal washing cytology and positive peritoneal dissemination, she was started on oral S-1 therapy post-surgery for 4 weeks, followed by a 2-week rest period. During the first course of therapy, her white blood cell count decreased; therefore, the regimen was changed to a 1-week administration, followed by a 1-week rest period. No subsequent adverse events were noted. The patient has experienced no relapse in the four years she has been followed up after surgery in our outpatient clinic. We report our experience with an elderly patient for whom S-1 monotherapy was effective in the treatment of gastric cancer with peritoneal dissemination.

We investigated the incidence of inguinal lymph node metastasis in 66 penile cancer patients with no palpable or visibly enlarged inguinal lymph nodes (cN0). Median follow up interval was 35. 7 months. During follow up, 14 patients (21.2%) had inguinal lymph node metastasis and 6 patients died of cancer. Five-year disease-free survival was 77.3%. Univariate analysis demonstrated that local tumor staging (T), differentiation, lymphovascular invasion (LVI), and tumor infiltration pattern (INF, Yamamoto-Kohama grading system) were associated with the incidence of inguinal lymphnode metastasis. Multivariate analysis demonstrated that only LVI was associated with incidence of inguinal lymph node metastasis (p = 0.008, Hazard ratio 17.947). According to EAU risk classification, the incidence of inguinal lymph node metastasis in the low-risk group, intermediate risk group and high-risk group was 12.0, 17.6 and 55.6%, respectively. In conclusion, LVI is an independent prognostic factor for inguinal lymph node metastasis in cN0 penile cancer. Furthermore, EAU risk classification is valid judging from our cases and in incidence of inguinal lymph node metastasis. Either sentinel node biopsy or inguinal lymph node dissection is recommended in high and intermediate risk patient.

Retroperitoneal dedifferentiated liposarcoma is associated with a poor prognosis, and the efficacy of chemotherapy in such cases is controversial. We report a case of long -term survival in a patient with dedifferentiated liposarcoma treated with bevacizumab after repeated local recurrences. A 65-year-old man complained of abdominal pain. Abdominal computed tomography (CT) showed a well-enhanced retroperitoneal tumor. The tumor was resected together with the right kidney and adrenal gland. On the basis of histopathological findings, the tumor was diagnosed as a dedifferentiated liposarcoma adenocarcinoma. Eleven months later, local recurrence was diagnosed and the tumor was resected. Thereafter, repeated local recurrences were diagnosed, and repeated tumor resections were performed. Local recurrence and distant metastasis in the axilla and scapula soft tissue was detected 5.9 years after the initial operation. Bevacizumab therapy was initiated, and the tumor markedly reduced in size. Bevacizumab treatment has been continued for 6.7 years after the initial operation, with no tumor recurrence or metastasis.

Some trials have demonstrated the benefits of maintenance chemotherapy for advanced colorectal cancer. In chemotherapeutic strategies for advanced colorectal cancer, chemotherapy-related toxicity prevention and quality of life(QOL)maintenance are more important than the introduction of a strong regimen, especially when additional surgery is not possible. In Japan, the combination of a folinic acid/5-fluorouracil/oxaliplatin(FOLFOX)regimen and bevacizumab is a popular first-line chemotherapy regimen. However, despite its effectiveness, neuropathy or hand-foot syndrome after 5 or 6 cycles tends to lead to chemotherapy withdrawal. CAIRO3 trial reported the effectiveness of capecitabine and bevacizumab as a maintenance chemotherapy regimen. Additionally, the ML18147 trial demonstrated that bevacizumab beyond progression(BBP)prolonged overall survival(OS)and progression free survival(PFS)in patients with advanced colorectal cancer. Although those trials demonstrated the effectiveness of continuous or maintenance bevacizumab administration, no trials have compared the effectiveness of cytotoxic drugs with bevacizumab as maintenance therapies. Moreover, controversy exists regarding the selection of drugs as a maintenance therapy and the identification of patients who would benefit from maintenance therapy.

We retrospectively reviewed the records of the 30 patients with adenoid cystic carcinoma of the head and neck (ACCHN) who had undergone initial treatment in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1988 and 2007. The primary tumor site was the parotid gland in 10 patients and the submandibular gland in 4 patients, which account for about a half of the subjects. Thirty patients underwent surgical resection with curative intent as the primary treatment, of which 10 patients had post-operative radiotherapy. The 5-and 10-year disease-specific survival (DSS) was 73.9% and 62.4%, respectively, whereas the 5-and 10-year disease-free survival (DFS) was 64.3% and 59.7%, respectively. A univariate analysis revealed that DSS was significantly correlated with perineural invasion (p = 0.010) and lymphatic invasion (p = 0.036), while DFS was significantly correlated with higher T-stage (p = 0.044), a positive surgical margin (p = 0.012) and perineural invasion (p = 0.019). A multivariate analysis demonstrated that perineural invasion (p = 0.034, risk ratio = 9.530) was the independent prognostic factor for DSS, whereas for DFS it was a positive surgical margin (p = 0.038, risk ratio = 8.897). The histological grade classification, defined specifically for ACC, showed no correlation with the survival. Extended resection with wider margin and additional resection in cases with positive margin may improve treatment results, however, surgical resection alone can prevent neither the development of local recurrence mainly attributed to undetectable perineural invasion, nor that of delayed distant metastasis. Therefore, the roles of adjuvant radiotherapy and effective systemic therapies are also significant in ACCHN, although a reliable regimen for the latter has not yet been established. Development of a personalized strategy for the adjuvant therapy, which should be based on the accurate prediction of the long-term prognosis in combination with dependable molecular biomarkers, would be indispensable in the future to improve the clinical outcome of the patients with ACCHN.

The TNM classification of renal cell carcinoma was updated in 2009. In this new classification system, T3a consists of tumors with renal vein involvement and tumors with fat invasion. To assess risk factors for recurrence, we retrospectively reviewed 89 patients with pT3aN0M0 renal cell carcinoma who underwent radical or partial nephrectomy between 1992 and 2011. Analyzed risk factors for recurrence were age, gender, tumor size, grade, v factor, infiltrative growth (INF), adjuvant interferon, surgical technic (radical or partial), clinical T classification, renal vein thrombus, and pathological fat invasion. The median follow-up was 52.2 months. Five-year recurrence-free survival rate was 69.0%. Within the pT3a subcategory, the five-year recurrence-free survival was 76.7% in patients with fat invasion only, 42.9% in patients with renal vein thrombus only, and 28.6% in patients with the two concomitant features. On univariate analysis, tumor size, grade, INF, clinical T classification, and renal vein thrombus were significantly associated with recurrence. On multivariate analysis, INF (p = 0.023, HR 3.927) was an independent risk factor for recurrence. In pT3aN0M0 renal cell carcinoma, INF significantly affects recurrence, and patients with both fat invasion and renal vein thrombus have worst prognosis.

In another hospital, a 71-year-old man had been pointed out to have an abnormal shadow in the left lung field on chest radiograph at a medical checkup. Computed tomography( CT) scan revealed a mass both in the S1+2 and in the S10 of the left lung. The mass in the S1+2 was diagnosed as squamous cell carcinoma by bronchoscopy. CT scan revealed a swelling lymph node at the opposite side. He was diagnosed as having lung cancer (cT2N3M1:stage IV) and was given chemotherapy. The S1+2-mass showed a partial response and the S10-nodule was stable disease. He was then changed to gefitinib administration due to severe side effect of the chemotherapy. The side of S10-nodule once reduced, however, it grew up again after 16 months treatment with gefitinib. He was then referred to our hospital for surgery, and bisegmentectomy with mediastinal dissection was performed. He had no complications after the operation, and is well without recurrence for 8 years after the operation.

We reviewed 72 cases treated in our hospital for adenoid cystic carcinoma of the head and neck during the 37 years between 1972 and 2009. The disease-specific survival rate at 3, 5, 10, 15, and 20 years was 76%, 70%, 46%, 33%, and 33%, respectively so survival rate had decreased gradually to 15 years. There was no significant difference in the survival rate of primary site, but T3 & T4 disease indicated a worse prognosis, and patients with lymph node positive findings tended to have a worse prognosis. The loco-regional control rate was 65% at 5 years, but after that, it continued to decrease, and the loco-regional control rate at 15 years was 31%. In addition, the median of the period for loco-regional recurrence was 93 months, with the longest time being 168 months. The relatively long lapse was traced to recurrence. The rate of absence of distant metastasis was 54% at 5 years, but after that, it continued to decrease, with the rate at 20 years was being 22%. The median time of survival after patients tested positive for distant metastasis was 25 months, with longest recognized period being 216 months. The long-term prognosis of adenoid cystic carcinoma is generally poor, so a long-term follow-up is necessary.

A 79-year-old man was diagnosed with infrarenal abdominal aortic aneurysm extending to the right common iliac artery and rectal cancer. He underwent a Y graft replacement for abdominal aortic aneurysm and an anterior resection for rectal cancer after 1 month. No adjuvant therapy was performed. Eleven months after the operation to remove the rectal cancer, computed tomography examination revealed isolated para-aortic lymph node recurrence. The mass involved the right bundle branch of the synthetic graft and the right external and internal iliac artery. Therefore, we resected the area from the right bundle branch of the synthetic graft to the right external and internal iliac artery en bloc. Pathological examination of the resected specimen showed metastatic adenocarcinoma. No additional therapy was performed. As of 10 years after the second operation, the patient is alive and recurrence free. Isolated aortic lymph node recurrence may be cured by resection; hence, surgical resection should be considered if possible.