The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Validation of the distress and impact thermometer and the changes of mood during the first 6 months of treatment in gynecological cancer patients: a Kansai Clinical Oncology Group (KCOG)-G1103 prospective study.

PURPOSE: To verify distress and impact thermometer (DIT) for screening emotional distress in gynecological cancer patients by Hospital Anxiety and Depression Scale total (HADS-T) as gold standard and to assess emotional changes by DIT and HADS-T. METHODS: A prospective study was conducted in newly diagnosed gynecological cancer patients during the peri-treatment period after the cancer diagnosis followed by 6-month. We defined a HADS-T score of ≥11 as being indicative of emotional distress. RESULTS: 117 patients were enrolled between May 1, 2011 and March 31, 2012, and 95 were eligible. The median age was 54 years (range 31-77). (1) From the baseline to 3-month, distress (DIT-D) ≥4 with Impact (DIT-I) ≥2 exhibited sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of 0.776 [95 % confidential interval (CI) 0.688, 0.850], 0.889 (95 % CI 0.824, 0.954), 0.868 (95 % CI 0.792, 0.949), and 0.808 (95 % CI 0.731, 0.886), respectively. (2) At 6-month, DIT-D ≥2 with DIT-I ≥1 exhibited sensitivity, specificity, PPV and NPV of 0.893 (95 % CI 0.778, 1), 0.825 (95 % CI 0.707, 0.942), 0.781 (95 % CI 0.638, 0.928), and 0.917 (95 % CI 0.826, 1). (3) At 6-month, the HADS-T, DIT-D, and DIT-I scores in individual patients were significantly reduced by a mean of 4.57 (p < 0.0001), 2.34 (p < 0.0001), and 1.10 (p = 0.0031), respectively, compared with those scores of baseline (Student's paired t test), but still remained high. CONCLUSIONS: (1) On acute phase within 3-month setting, DIT; DIT-D ≥4 with DIT-I ≥2, is a reliable cut-off to screen emotional distress among gynecological cancer patients. (2) The patients' moods had improved, but not completely recovered at 6-month after the diagnosis.

Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases.

BACKGROUND: FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression. METHODS: Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments. RESULTS: FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome. CONCLUSIONS: Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species.

OBJECTIVE: In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS: Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS: High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS: ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma.

Long-term outcome of intravitreal ranibizumab treatment, compared with photodynamic therapy, in patients with polypoidal choroidal vasculopathy.

PURPOSE: To evaluate the functional outcomes of patients with polypoidal choroidal vasculopathy (PCV) who underwent intravitreal ranibizumab (IVR) treatment, compared with photodynamic therapy (PDT), after at least 2 years. METHODS: We retrospectively studied all the treatment-naïve patients with PCV who were scheduled to undergo IVR or PDT between August 2005 and June 2010. All the patients who had a 2-year or longer follow-up period were included in the study. The best-corrected visual acuity (BCVA) in the two groups was compared before treatment and at 3, 6, 12, 18 and 24 months after the initial treatment. The regression of the polyps was also assessed using indocyanine green angiography. RESULTS: A total of 77 patients were included in this study. Thirty-three eyes were treated with IVR, and 44 eyes were treated with PDT. Although no significant differences between the two groups were observed at baseline or at 3, 6, and 12 months after treatment, a significantly better BCVA was seen in the IVR group, compared with the PDT group, at 18 and 24 months after treatment (P=0.035 and P=0.021, respectively). No significant difference in the rate of polyp regression was observed between the two groups (P=0.092). CONCLUSION: IVR was well tolerated and maintained or improved the vision of patients with PCV, compared with PDT, as evaluated at 2-year follow-up examinations. PDT for the treatment of PCV might result in unfavorable outcomes, with no superiority to achieving the involution of polyps.

Clinical significance of serum growth-regulated oncogene alpha (GROalpha) in patients with gynecological cancer.

PURPOSE OF INVESTIGATION: To assess the clinical relevance of serum growth-regulated oncogene alpha (GROalpha) levels in gynecological cancer, we investigated its concentration in distinguishing patients with cervical cancer, endometrial cancer, ovarian cancer, benign ovarian tumor and control. METHODS: Preoperative serum GROalpha levels were measured in women with cervical cancer (n=46), endometrial cancer (n=39), ovarian cancer (n=124), benign ovarian tumors (n=52), and normal controls (n=38) using an enzyme-linked immunosorbent assay. RESULTS: Statistical analyses showed that the serum GROalpha concentration was significantly elevated in the cervical cancer, endometrial cancer and ovarian cancer patients compared with controls. Using GROalpha levels, the receiver operating characteristic (ROC) of cervical cancer (AUC approximately 0.775), endometrial cancer (AUC approximately 0.799), ovarian cancer (AUC approximately 0.749) and benign ovarian tumors (AUC approximately 0.568) vs. controls were identified. CONCLUSION: Our findings suggest that serum GROalpha measurement as a molecular marker might contribute to detection and diagnosis of gynecological cancer.

Perturbations of both nonregulatory and regulatory FOXP3+ T cells in patients with malignant melanoma.

BACKGROUND: 'FOXP3+ regulatory T cells' (Tregs) are reported to be increased in tumour-bearing hosts including patients with melanoma, leading to tumour immune suppression. However, this idea is challenged by recent evidence that the 'FOXP3+ Treg' fraction in fact contains activated 'nonregulatory' T cells. Also, FOXP3+ T cells are reported to have functionally and kinetically distinct subsets. OBJECTIVES: To investigate whether either or both of regulatory and 'nonregulatory' FOXP3+ T cells are perturbed in patients with melanoma. METHODS: FOXP3+ T cells were classified into three subsets, namely CD45RO+FOXP3(low) nonregulatory T cells, CD45RO+FOXP3(high) effector Tregs, and CD45RO-FOXP3(low) naïve Tregs, according to their expression levels of FOXP3 and CD45RO. The percentage and cytokine production of these FOXP3+ T-cell subsets were assessed by flow cytometry. RESULTS: Both regulatory and nonregulatory T cells were increased in patients with melanoma. Moreover, we found three unexpected perturbations in FOXP3+ T-cell subsets: (i) patients with melanoma showed higher frequencies of FOXP3(low) nonregulatory T cells, which decreased and normalized after tumour removal; (ii) FOXP3(low) naïve Tregs containing higher frequencies of interferon-γ+ cells increased with tumour progression; and (iii) CD45RO+FOXP3(high) effector Tregs were pronouncedly infiltrated around tumour tissues. CONCLUSIONS: These findings demonstrate that patients with melanoma have distinct and differential perturbation of both regulatory and nonregulatory FOXP3+ T cells. The degree of perturbation is associated with tumour burden and progression, suggesting that the perturbation reflects fundamental pathophysiological processes in patients with melanoma. The presented analysis provides a practical approach to investigate the immunological environment of cancer patients.

A case of atypical sporotrichosis with multifocal cutaneous ulcers.

We report an atypical case of sporotrichosis in an elderly woman working as a horticulturist, who presented with multiple ulcers and nodules on the face and the right upper back. Histological examination found numerous small yeast-like spores in the granulomatous reaction in the upper dermis. Culture and DNA analysis identified Sporothrix schenckii, group B. Misuse of topical steroids and self-inoculation may have caused the atypical features found in this patient.

Randomized comparison of intra-arterial chemotherapy versus intra-arterial chemotherapy and gelfoam embolization for treatment of advanced cervical carcinoma.

PURPOSE: We evaluated the effects of intra-arterial infusion therapy by comparing the results obtained with a combination of intra-arterial anticancer drugs with and without transcatheter arterial embolization (TAE) in patients with cervical cancer. METHODS: Between April 1999 and March 2003, intra-arterial therapy was administered to 45 patients (mean age 49 years) with cervical cancer. Of these, 18 had stage IIb , 4 had stage IIIa, 19 had stage IIIb, and 4 had stage IVb cancer; the histopathologic types were squamous cell carcinoma (n = 35), adenocarcinoma (n = 8), and adenosquamous carcinoma (n = 2). A total of 45 patients gave their informed consent and were randomized on a continuous basis into one of three groups according to the therapeutic protocols: group A consisted of 15 patients who received cisplatin, group B consisted of 17 patients who received cisplatin, mitomycin, doxorubicin hydrochloride, and 5-fluorouracil, and group C consisted of 13 patients who received cisplatin and TAE. Each protocol was administered twice with a 3 week interval between treatments. The efficacy of treatment was evaluated on the basis of the tumor reduction ratio (%) using MR imaging and the side effects were analyzed. RESULTS: In groups A, B, and C, the tumor reduction ratio was 54%, 84%, and 86%, respectively; it was significantly greater in groups B and C than in group A (p < 0.01). The difference between groups B and C was not statistically significant. Although all group C patients developed severe pain after TAE, the pain was controlled with analgesics. Thrombocytopenia occurred in 6 of 17 (35%) group B patients. CONCLUSION: Group B and C patients had better tumor reduction than those in group A. Fewer hematologic complications occurred in group C patients compared with group B.

Duodenal wall cysts may be derived from a ductal component of ectopic pancreatic tissue.

AIMS: To clarify the mechanism of origin of duodenal wall cysts in patients with chronic pancreatitis, developing into duodenal stenosis. METHODS AND RESULTS: Specimens from 12 pancreatoduodenectomized patients with chronic pancreatitis and 51 controls were studied histopathologically and immunohistochemically. Variously shaped cystic lesions, averaging about 15 mm in diameter, were found in the duodenum in six of the 12 patients with chronic pancreatitis, but were not observed in the controls. Each case had an average of two cysts, which were located mainly in the muscularis propria of the duodenum with or without submucosal or extraduodenal-peripancreatic extensions. The inner part of the cyst wall consisted of a moderate rim of granulation tissue, with both myofibroblasts and smooth muscle proliferation in the tissue surrounding the cyst and the submucosal layer of the duodenum, occasionally accompanied by an epithelial lining. A ductal structure in the muscularis propria of the duodenum, possibly a ductal component of ectopic pancreatic tissue, was found in five of the six cases. Some of these structures showed cystic changes. Three of the six patients had accompanying duodenal stenosis. CONCLUSIONS: Duodenal wall cysts occur mainly in the muscularis propria of the duodenum associated with both myofibroblasts and smooth muscle proliferation, and may result in duodenal stenosis. These cysts may be derived from a ductal component of ectopic pancreatic tissue.

Adenofibroma of the endometrium after tamoxifen therapy for breast cancer: MR findings.

We report a case of adenofibroma of the endometrium in a 69-year-old woman. This patient was receiving tamoxifen therapy after surgery for breast cancer. Magnetic resonance imaging showed an intracavitary mass containing multiple cystic components. We suggest adenofibroma as a possible diagnosis in cases of uterine masses with multiple cystic components and no clinical evidence of malignancy.

Pharmacokinetic and pharmacodynamic analysis of combined chemotherapy with carboplatin and paclitaxel for patients with ovarian cancer.

BACKGROUND: This study was conducted to assess the utility of pharmacokinetic and pharmacodynamic analyses of carboplatin (CBDCA) and paclitaxel (TAX) employed for chemotherapy in ovarian cancer patients. METHODS: The pharmacokinetics and pharmacodynamics of chemotherapy with CBDCA and TAX were analyzed in 13 patients with ovarian cancers. The pharmacodynamic model, based on myelosuppression, was assessed in terms of concentrations of free platinum (free-Pt) and TAX in blood samples. TAX (175 mg/m2) was administered intravenously (i.v.) over 3 h, and CBDCA (target area under the concentration curve [AUC], 5 mg/ml x min) over 1 h. Free-Pt and TAX concentrations in blood samples were measured at several time points after administration. RESULTS: The nadirs of both the leukocyte and neutrophil counts correlated significantly with the TAX AUC (AUCtax) and serum albumin level, and the percentage decrease in platelet count (pd-Plt) correlated significantly with AUCtax, free-Pt AUC (AUCpt), and the serum albumin level. A pharmacodynamic model corresponding to the nadirs of leukocytes and neutrophils and to pd-Plt was thus generated. CONCLUSION: This pharmacodynamic model may allow the ready prediction, from AUCtax, AUCpt, and the serum albumin value, of the degree of myelosuppression with combined CBDCA and TAX chemotherapy.

Differential diagnosis of small round cervical lymph nodes: comparison of power Doppler US with contrast-enhanced CT and pathologic results.

PURPOSE: The purpose of this study was to differentiate reactive small round lymph nodes (SRLNs) from metastases by power Doppler ultrasonography (PD-US) and contrast-enhanced CT (CE-CT). MATERIALS AND METHODS: Both PD-US and CE-CT were performed in 99 cervical lymph nodes (LNs) with a maximum diameter of 1.5 cm or smaller and maximum longitudinal/transverse ratio of 1.5 or smaller in 76 patients with head and neck cancer. At pathologic examinations, 45 were reactive and 54 were metastatic LNs. The vascular patterns on PD-US were classified as hilar, avascular, peripheral, and miscellaneous vascular patterns. The enhancement patterns on CE-CT were classified as homogeneous, heterogeneous, and ring enhancement. RESULTS: On PD-US, the hilar pattern was more frequently associated with benignancy (91%) and the peripheral, miscellaneous vascular pattern with malignancy (91%). The avascular pattern included both benign (58%) and malignant (42%) LNs. On PD-US, accuracy was 85%. On CE-CT, ring enhancement showed metastasis (100%), and these LNs showed avascular or peripheral patterns on PD-US. On CE-CT, accuracy was 77%. When information on CE-CT results was added to PD-US results, the accuracy rate increased significantly, to 94% (p=0.01). CONCLUSION: Vascular patterns evaluated with PD-US and enhancement patterns on CE-CT can characterize SRLNs. For an avascular pattern on PD-US, information on CE-CT results can significantly increase the accuracy of characterization.

Fast breath-hold T2-weighted MRI of the kidney by means of half-Fourier single-shot turbo spin echo: comparison with high resolution turbo spin echo sequence.

PURPOSE: The value of the fast half-Fourier single-shot turbo spin echo (HASTE) sequence in T2-weighted MRI of the kidney was evaluated as a substitute for the conventional turbo spin echo (TSE) sequence. METHOD: Forty-five patients with suspected abnormalities of the kidney underwent MRI with a 1.5 T system. Breath-hold HASTE and respiratory-triggered TSE sequences were performed. Qualitative and quantitative analyses were performed for comparison of these sequences. RESULTS: The signal-to-noise ratio (SNR) with HASTE was higher than that with TSE. The lesion-to-kidney contrast-to-noise ratio for solid masses with HASTE was almost equal to that with TSE. For cystic masses, the CNR with HASTE was significantly higher than that with TSE (p < 0.05). Respiratory and chemical shift artifacts were significantly smaller on HASTE than on TSE (p < 0.01). However, the blurring artifact was higher on HASTE than on TSE (p = 0.01). CONCLUSION: The HASTE sequence generates high contrast images and is free of motion and chemical shift artifacts, with much better time efficacy. The sequence provides comparable diagnostic information to TSE sequences.

Diagnostic accuracy of helical CT arterial portography and CT hepatic arteriography for hypervascular hepatocellular carcinoma in chronic liver damage. An ROC analysis.

PURPOSE: To evaluate the detectability of hypervascular hepatocellular carcinomas (HCCs) in chronic liver damage with helical CT arterial portography (CTAP) and CT hepatic arteriography (CTHA). MATERIAL AND METHODS: Thirty-nine HCC patients who underwent CTAP and CTHA were studied. Diagnostic abilities of CTAP alone, CTHA alone, or combined CTAP and CTHA were evaluated by receiver operating characteristic (ROC) analysis. Fifty-three images with 53 HCC nodules were evaluated. Tumor size ranged from 5 to 90 mm (mean 22.8 mm). Sensitivities and specificities for all techniques were calculated. RESULTS: ROC analysis showed the diagnostic ability significantly better with combined CTAP and CTHA (mean area under the ROC curve (Az)=0.95), or CTHA alone (Az=0.93) than CTAP alone (Az=0.87) (p<0.01). Combined CTAP and CTHA showed the best sensitivity (95.0%), followed by CTHA alone (88.1%) and CTAP alone (85.5%). The specificities of all three imaging techniques were relatively low (54.1% for combined CTAP and CTHA, 71.1% for CTHA alone, and 54.1% for CTAP alone) because of perfusion abnormalities of the liver parenchyma. CONCLUSION: The combination of CTAP and CTHA is superior to CTAP alone for detection of hypervascular HCCs. However, its specificity was relatively low in chronic liver damage.

Intraductal papillary tumors of the pancreas. Histopathologic correlation of MR cholangiopancreatography findings.

PURPOSE: To evaluate MR cholangiopancreatography (MRCP) findings of intraductal papillary tumors of the pancreas and correlate them with histopathology. MATERIAL AND METHODS: Seventeen patients with intraductal papillary tumor of the pancreas underwent MRCP before surgery. MRCP findings were correlated to histopathology with regard to the presence of septa and excrescent nodules in the cystic lesion, communication between the cystic lesion and the main pancreatic duct (MPD), degree of dilatation of MPD, and dilatation of the common bile duct (CBD). RESULTS: MRCP demonstrated septa in 17 cases (100%), excrescent nodules in 8 cases (47.1%), communication between the intraductal papillary tumor and the MPD in 14 cases (82.3%), dilatation of MPD over 50% in 6 cases (35.3%), and dilatation of CBD in 3 cases (17.6%). These findings showed excellent correlation with histopathology. The septum on MRCP corresponded with a layer of connective tissue with pancreatic duct epithelium. Excrescent nodules in the carcinomas consisted not only of malignant cells, but also of dysplasia and adenoma. Excrescent nodules in adenomas were consistent not only with minimal papillary growth of adenoma, but also with proliferation of fibrosis, and hematoma and organized fibrin with minimal fibrosis. Pancreatic tissue was affected by chronic pancreatitis in all cases. Cases with dilatation of CBD on MRCP were due to microscopic invasion by the carcinoma. CONCLUSION: MRCP appearances of intraductal papillary tumors are well correlated with the findings at histopathology.

Improved tissue characterization of focal liver lesions with ferumoxide-enhanced T1 and T2-weighted MR imaging.

The purpose of our study was to evaluate the potential value of ferumoxide-enhanced T1-weighted magnetic resonance (MR) imaging for tissue characterization of focal liver lesions when combined with T2-weighted sequences. Images were acquired within 30 minutes after the end of ferumoxide administration, when ferrite particles were not totally cleared from the intravascular compartment. Thirty-eight patients with 47 focal liver lesions underwent T1-weighted gradient-echo (TR/TE 150/4.1 msec) and T2-weighted fast spin-echo (3180-8638/90 msec) MR imaging at 1.5 T before and after intravenous administration of ferumoxides (10 micromol/kg body weight). A qualitative and quantitative analysis was performed. During the early phase after infusion of ferumoxide, blood vessels showed hypersignal intensity on T1-weighted fast low-angle shot (FLASH) images, while liver signal decreased. Hemangiomas showed both homogeneous and inhomogeneous enhancement patterns, and liver metastasis most typically showed ring enhancement. Hypervascular tumors (hepatocellular carcinomas and focal nodular hyperplasias) showed a slight degree of homogeneous enhancement. Quantitatively, the degree of enhancement and lesion-to-liver contrast on ferumoxide-enhanced images were significantly different among these tumors. Our results demonstrate that distinct enhancement patterns obtained on ferumoxide-enhanced T1-weighted MR imaging improve tissue characterization of focal liver lesions when combined with T2-weighted images.